Alternative titles; symbols
SNOMEDCT: 58756001; ICD10CM: G10; ICD9CM: 333.4; ORPHA: 248111, 399; DO: 12858;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4p16.3 | Huntington disease | 143100 | Autosomal dominant | 3 | HTT | 613004 |
A number sign (#) is used with this entry because Huntington disease (HD) is caused by a heterozygous expanded trinucleotide repeat (CAG)n, encoding glutamine, in the gene encoding huntingtin (HTT; 613004) on chromosome 4p16.
In normal individuals, the range of repeat numbers is 9 to 36. In those with HD, the repeat number is above 37 (Duyao et al., 1993).
Huntington disease (HD) is an autosomal dominant progressive neurodegenerative disorder with a distinct phenotype characterized by chorea, dystonia, incoordination, cognitive decline, and behavioral difficulties. There is progressive, selective neural cell loss and atrophy in the caudate and putamen. Walker (2007) provided a detailed review of Huntington disease, including clinical features, population genetics, molecular biology, and animal models.
The classic signs of Huntington disease are progressive chorea, rigidity, and dementia. A characteristic atrophy of the caudate nucleus is seen radiographically. Typically, there is a prodromal phase of mild psychotic and behavioral symptoms which precedes frank chorea by up to 10 years. Chandler et al. (1960) observed that the age of onset was between 30 and 40 years. In a study of 196 kindreds, Reed and Neel (1959) found only 8 in which both parents of a single patient with Huntington chorea were 60 years of age or older and normal. The clinical features developed progressively with severe increase in choreic movements and dementia. The disease terminated in death on average 17 years after manifestation of the first symptoms.
Folstein et al. (1984, 1985) contrasted HD in 2 very large Maryland pedigrees: an African American family residing in a bayshore tobacco farming community and a white Lutheran family living in a farming community in the western Maryland foothills and descended from an immigrant from Germany. They differed, respectively, in age at onset (33 years vs 50 years), presence of manic-depressive symptoms (2 vs 75), number of cases of juvenile onset (6 vs 0), mode of onset (abnormal gait vs psychiatric symptoms), and frequency of rigidity or akinesia (5/21 vs 1/15). In the African American family, the mean age at onset was 25 years when the father was affected and 41 years when the mother was affected; the corresponding figures in the white family were 49 and 52 years. Allelic mutations were postulated. In another survey in Maryland, Folstein et al. (1987) found that the prevalence of HD among African Americans was equal to that in whites.
Adams et al. (1988) found that life-table estimates of age of onset of motor symptoms have produced a median age 5 years older than the observed mean when correction for truncated intervals of observation (censoring) was made. The bias of censoring refers to the variable intervals of observation and loss to observation at different ages. For example, gene carriers lost to follow-up, those deceased before onset of disease, and those who had not yet manifested the disease at the time of data collection were excluded from the observed distribution of age at onset.
Kerbeshian et al. (1991) described a patient with childhood-onset Tourette syndrome (137580) who later developed Huntington disease.
Shiwach (1994) performed a retrospective study of 110 patients with Huntington disease in 30 families. He found the minimal lifetime prevalence of depression to be 39%. The frequency of symptomatic schizophrenia was 9%, and significant personality change was found in 72% of the sample. The age at onset was highly variable: some showed signs in the first decade and some not until over 60 years of age.
The results of a study by Shiwach and Norbury (1994) clashed with the conventional wisdom that psychiatric symptoms are a frequent presentation of Huntington disease before the development of neurologic symptoms. They performed a control study of 93 neurologically healthy individuals at risk for Huntington disease. The 20 asymptomatic heterozygotes showed no increased incidence of psychiatric disease of any sort when compared to the 33 normal homozygotes in the same group. However, the whole group of heterozygous and homozygous normal at-risk individuals showed a significantly greater number of psychiatric episodes than did their 43 spouses, suggesting stress from the uncertainty associated with belonging to a family segregating this disorder. Shiwach and Norbury (1994) concluded that neither depression nor psychiatric disorders are likely to be significant preneurologic indicators of heterozygous expression of the disease gene.
Giordani et al. (1995) performed extensive neuropsychologic evaluations on 8 genotype-positive individuals comparing them to 8 genotype-negative individuals from families with Huntington disease. They found no significant differences between these 2 groups, casting further doubt on earlier reports that suggested cognitive impairments are premonitory signs of the classical neurologic syndrome of Huntington disease.
Rosenberg et al. (1995) performed a double-blind study on 33 persons at risk for HD who had applied for genetic testing. Significantly inferior cognitive functioning was disclosed in gene carriers by a battery of neuropsychologic tests covering attentional, visuospatial, learning, memory, and planning functions. Primarily, attentional, learning, and planning functions were affected.
Bamford et al. (1995) performed a prospective analysis of neuropsychologic performance and CT scans of 60 individuals with Huntington disease. They found that psychomotor skills showed the most significant consistent decline among cognitive functions assessed.
Lovestone et al. (1996) described an unusual HD family in which all 4 affected members presented first with a severe psychiatric syndrome which in 3 cases was schizophreniform in nature. Two other living members with no apparent signs of motor disorder had received psychiatric treatment, 1 for schizophrenia.
Mochizuki et al. (1999) described a case of late-onset Huntington disease with the first symptom of dysphagia. The 61-year-old man was admitted with dysphagia and dysarthria, which had developed gradually over 2 years. The patient had no psychologic signs, dementia, paresis, involuntary movements, ataxia, or sensory disturbance in the limbs. Dysphagia and dysarthria appeared to be caused by a 'cough-like movement' just before or during speaking or swallowing. Because the 'cough-like movement' progressed for 3 years and was eventually suppressed with disappearance of dysphagia after administration of haloperidol, this symptom was thought to be due to HD.
Paulsen et al. (2006) studied the brain structure of 24 preclinical HD patients as measured by brain MRI and compared them to 24 healthy control subjects matched by age and gender. Preclinical HD individuals had substantial morphologic differences throughout the cerebrum compared to controls. The volume of cerebral cortex was significantly increased in preclinical HD, whereas basal ganglion and cerebral white matter volumes were substantially decreased. Although decreased volumes of the striatum and cerebral white matter could represent early degenerative changes, the finding of an enlarged cortex suggested that developmental pathology occurs in HD.
Marshall et al. (2007) compared psychiatric manifestations among 29 HD mutation carriers with no clinical symptoms, 20 HD mutation carriers with mild motor symptoms, 34 manifesting HD patients, and 171 nonmutation controls. The mild motor symptoms group and the manifesting HD group showed significantly higher scores for obsessive-compulsive behavior, interpersonal sensitivity, anxiety, paranoia, and psychoticism compared to the nonmutation control group. The mutation carriers without symptoms had higher scores for anxiety, paranoid ideation, and psychoticism compared to the nonmutation control group. The results indicated that individuals in the preclinical stage of HD exhibit specific psychiatric symptoms and that additional symptoms may manifest later in the disease course. Walker (2007) noted that suicidal ideation is a frequent finding in Huntington disease and that physicians should be aware of increased suicide risk both in asymptomatic at-risk patients and symptomatic patients.
Clinical Variability
Behan and Bone (1977) reported hereditary chorea without dementia. The oldest affected person in their family was aged 61 years.
Juvenile Onset
Juvenile-onset Huntington disease, typically defined as onset before age 20 years, is estimated to comprise less than 10% of all HD cases. It is usually transmitted from an affected father, is associated with very large CAG repeat sizes (60 or more) in the HTT gene, and typically shows rigidity and seizures (Nance and Myers, 2001; Ribai et al., 2007).
The juvenile form of Huntington disease was first described by Hoffmann (1888) using data from a 3-generation family. He identified 2 daughters with onset at 4 and 10 years who showed rigidity, hypokinesia, and seizures.
Barbeau (1970) pointed out that patients with the juvenile form of Huntington chorea seem more often to have inherited their disorder from the father than from the mother. Ridley et al. (1988) showed that Huntington disease shows anticipation, but only on paternal inheritance, with the consequence that patients with juvenile Huntington disease inherit the disease from their fathers.
Navarrete et al. (1994) described a family in which a brother and sister had very early onset of Huntington disease. Clinical manifestations were apparent in both sibs at the age of 8 years; the brother died at age 10. The father of these sibs was affected from the age of 29 years.
Milunsky et al. (2003) described 1 of the youngest children ever reported with juvenile HD. The girl, 5 years old at the time of report, had been adopted because of the inability of her biologic parents to care for her. Her biologic father was subsequently found to have HD. The girl demonstrated near-normal development until about 18 months of age. Brain MRI had been normal at 2 years of age; at 3.5 years of age, there was marked cerebellar atrophy involving the vermis and cerebellar hemispheres, diminutive middle cerebellar peduncles, and an enlarged fourth ventricle. By age 3 years and 10 months, the patient required gastric tube feeding. Choreiform movements, predominantly on the right side, developed at approximately 4 years of age. Milunsky et al. (2003) developed a modified PCR method using XL (extra long)-PCR that allowed them to diagnose 265 triplet repeats on one HTT allele and 14 on the other.
Nahhas et al. (2005) reported a girl with a maternal family history of HD who had onset of symptoms at age 3 and died at age 7 due to complications of HD. The patient's mother had symptoms of HD at age 18. Molecular analysis revealed that the mother had 70 CAG repeats whereas the daughter had approximately 130 CAG repeats. Nahhas et al. (2005) stated that this was the largest reported molecularly confirmed CAG expansion from a maternal transmission, demonstrating that very large expansions can also occur through the maternal lineage.
Yoon et al. (2006) reported 3 patients with onset of HD before age 10 years. All had speech delay in early childhood as the first symptom, which predated motor symptoms by at least 2 years. All children later developed severe dysarthria. Initial gross motor symptoms included ataxic gait and falls; initial behavioral problems included aggression, irritability, and hyperactivity. CAG repeats were 120, 100, and 93, respectively, and all children inherited the disorder from their fathers.
Ribai et al. (2007) performed a retrospective analysis of 29 French patients with juvenile-onset HD. The mean delay before diagnosis was 9 years. The most common signs at onset were severe cognitive and psychiatric disturbances (65.5% of patients), including severe alcohol or drug addiction and psychotic disorder. In these patients, motor signs occurred a mean of 6 years after cognitive or psychiatric signs. Three other patients presented with myoclonic head tremor, 3 with chorea, and 1 with progressive cerebellar signs. Thirteen (46%) had fewer than 60 CAG repeats (range, 45 to 58). Six patients inherited the disease from their fathers, and 7 from their mothers, with similar anticipation. However, all cases with onset before age 10 years were paternally inherited.
Sakazume et al. (2009) reported a girl with onset of HD beginning at age 2 years with motor regression, speech difficulties due to oromotor dysfunction, and frequent temper tantrums. Onset of severe prolonged generalized seizures began at age 4 years. Brain MRI showed severe cerebellar atrophy in the vermis and cortex, in addition to atrophy in the caudate, putamen, and globus pallidus. Her mother, grandparent, and great-grandparent were affected. Molecular analysis showed that the child had 160 CAG repeats, whereas her mother had 60 repeats. A review of 7 reported patients with early-onset HD showed that 4 had inherited the expanded allele from the mother, and that the mothers were relatively young at the time of pregnancy, ranging from 20 to 27 years. These findings suggested that the incidence of maternal transmission in early-onset HD may be higher than that in adult-onset HD. Three of the 7 previously reported patients with early-onset HD had cerebellar atrophy.
Enna et al. (1976) found 50% reduction in binding at serotonin and muscarinic cholinergic receptors in the caudate nucleus but not the cerebral cortex of patients with Huntington chorea. Goetz et al. (1975) could not confirm a report that fibroblasts grew poorly. Contrariwise, they found that Huntington disease cells grew to a higher maximal density than did control fibroblasts.
Reiner et al. (1988) used immunohistochemical methods to study neurons producing substance P and enkephalin, projecting to the globus pallidus and to the substantia nigra, in brains from 17 patients with Huntington disease in various stages of the disorder. The authors found that in the early and middle stages of HD, the enkephalin-producing neurons with projections to the external portion of the globus pallidus were more affected than substance P-containing neurons projecting to the internal pallidal segment. This result was confirmed by Sapp et al. (1995). Reiner et al. (1988) also found that substance P-producing neurons projecting to the substantia nigra pars reticulata were more affected than those projecting to the pars compacta. In the advanced stages of the disease, neurons projecting to all striatal areas were depleted. Richfield and Herkenham (1994) found greater loss of cannabinoid receptors on striatal nerve terminals in the lateral globus pallidus compared to the medial pallidum in Huntington disease of all neuropathologic grades, supporting the preferential loss of striatal neurons that project to the lateral globus pallidus.
Aronin et al. (1995) detected mutant huntingtin protein in cortical synaptosomes isolated from brains of Huntington disease heterozygotes and demonstrated that the mutant species is synthesized and transported with the normal protein to nerve endings. In half of the juvenile cases, huntingtin resolved as a complex of bands after electrophoresis and immunostaining, which confirmed previous DNA evidence for somatic mosaicism. Mutant huntingtin was present in both normal and affected regions.
Using genetic and pharmacologic approaches in yeast, mammalian cells, and Drosophila, Mason et al. (2013) found that glutathione peroxidase (GPX; see 138320) activity robustly ameliorates Huntington disease-relevant metrics and is more protective than other antioxidant approaches tested in their study. Mason et al. (2013) found that GPX activity, unlike many antioxidant treatments, does not inhibit autophagy, which is an important mechanism for clearing mutant HTT.
Huntington disease is an autosomal dominant disorder. When the number of CAG repeats reaches 41 or more, the disease is fully penetrant. Incomplete penetrance can occur with 36 to 40 repeats. The number of repeats accounts for approximately 60% of the variation in age at onset, with the remainder determined by modifying genes and environment (Walker, 2007).
Intrafamilial variability of Huntington disease was illustrated by the report by Campbell et al. (1961) of the juvenile rigid form in 2 brothers in a kindred in which 3 preceding generations had disease of the more classic type. Brackenridge (1972) showed a relationship between age at onset of symptoms in parent and child. Wallace and Hall (1972) suggested that in Queensland, Australia, 2 possibly allelic forms of HD may exist, one with early onset and the other with late onset.
Myers et al. (1982) confirmed the preponderance of inheritance from the father when HD had an early onset. 'Anticipation' was thought to reflect the finding that persons with early onset in prior generations were selectively nonreproductive because of manifestation of the disorder. In 238 patients, Myers et al. (1983) correlated age at onset with whether inheritance was from the father or the mother. More than twice as many of the late-onset cases (age 50 or later) inherited the HD gene from an affected mother than from an affected father. Affected offspring of late-onset females also had late-onset disease while those of late-onset males had significantly earlier ages of onset. The authors interpreted these findings as suggesting a heritable extrachromosomal factor, perhaps mitochondrial. They cited Harding (1981) as suggesting that autosomal dominant late-onset spinocerebellar ataxia is marked by earlier age at onset and death in offspring of affected males. After it was found that both Huntington disease and some forms of spinocerebellar ataxia are caused by expanded repeats, the mechanism of anticipation in the paternal line was interpreted as an increase in the extent of the repeats during paternal meiosis.
Boehnke et al. (1983) tested models to account for the stronger parent-offspring age-of-onset correlation when the mother is the affected parent and the excess of paternal transmission in cases with onset at less than 21 years. They proposed 2 models in which a maternal factor acts to delay onset: cytoplasmic, possibly mitochondrial, or autosomal/X-linked.
Went et al. (1984) confirmed the earlier report that early-onset HD is almost always inherited from the father, but could not confirm the notion that late-onset disease is more often inherited from the mother. Farrer and Conneally (1985) postulated that age at onset is governed generally by a set of independently inherited aging genes, but expression of the HD genes may be significantly delayed in persons with a particular maternally transmitted factor. Myers et al. (1985) presented data that suggested a protective effect conferred on the offspring of affected women, who show an older mean age at onset than offspring of affected men, regardless of the onset age in the parent. Pointing out that some repetitive elements in many chromosomes of the mouse are methylated differently in males and females, Erickson (1985) suggested differences such as chromosomal imprinting may be responsible for the greater severity and earlier onset of Huntington disease in offspring of affected males and greater severity of myotonic dystrophy (DM1; 160900) in offspring of affected females.
Among 195 reported cases of juvenile Huntington disease, van Dijk et al. (1986) found a preponderance of 'rigid cases,' whose affected parent was the father in a significantly high number of cases. Rigid paternal cases have a significantly lower age at onset as well as a shorter duration of disease than choreic paternal cases.
Ridley et al. (1988) found that while the mean age at onset in offspring of affected mothers did not differ greatly from that in their mothers, the distribution of age at onset in the offspring of affected fathers fell into 2 groups; the larger group showed an age at onset only slightly younger than that in their affected fathers, and a smaller group had, on average, an age at onset 24 years younger than that of their affected fathers. Analysis of the grandparental origin of the Huntington allele suggested that while propensity to anticipation could be inherited for a number of generations through the male line, it originated at the time of differentiation of the germline of a male who acquired the Huntington allele from his mother. Ridley et al. (1988) suggested that major anticipation indicates an epigenetic change in methylation of the nucleic acid of the genome, which is imposed in the course of 'genomic imprinting,' that is, in the mechanism by which the parental origin of alleles is indicated (Reik et al., 1987; Sapienza et al., 1987). Differences in gene expression according to the parent from whom the gene was derived, in HD, in myotonic dystrophy (DM1; 160900) and perhaps in other conditions, might be due to a difference in methylation of the genes in the 2 sexes (see review by Marx, 1988).
In South Wales over a 10-year period, Quarrell et al. (1986) found 192 patients with HD in whom there was a positive family history and an additional 37 patients who had clinical features consistent with HD but who had no affected relatives despite detailed inquiries. After review, 22 of the 37 were still thought to have HD on clinical grounds; the diagnosis was considered less likely in 15. Postmortem supported the diagnosis in 6 of 7 cases so studied; a patient labeled HD on the death certificate had Kufs disease (204300) at postmortem.
Adams et al. (1988) also found that the offspring of affected males had significantly younger onset than did offspring of affected females, and a trend suggested an excess of paternal descent among juvenile-onset cases. Reik (1988) also suggested genomic imprinting as an alternative mechanism to maternally inherited extrachromosomal factors to account for the parental origin effect. By imprinting, the gene itself becomes modified in a different way depending on whether it passes through the maternal or the paternal germline. The modification may involve methylation of DNA and could result in earlier or higher level of expression of the gene when it is transmitted by the father. Ridley et al. (1988) reviewed extensively the ascertainment bias producing or working against the observation of anticipation. Reik (1989) reviewed the topic of genomic imprinting in relation to genetic disorders of man, and as possible examples pointed to the earlier onset of spinocerebellar ataxia (164400) with paternal transmission, the increased severity of neurofibromatosis I (NF1; 162200) with maternal transmission, the earlier onset of neurofibromatosis II (NF2; 101000) with maternal transmission, and the preferential loss of maternal alleles in sporadic osteosarcoma.
Wolff et al. (1989) reported an isolated case of HD in an extensively studied family. Nonpaternity appeared to be excluded, and DNA markers closely linked to the HD gene indicated several clearly unaffected sibs who shared one or the other or both of the patient's haplotypes. The posterior probability of a new mutation to HD in the patient was calculated to exceed 99%, even if an a priori probability of nonpaternity of 10% and a mutation rate of HD of 1 in 10 million gametes were assumed.
In 2 families with Huntington disease linked to the short arm of chromosome 4, Sax et al. (1989) demonstrated remarkable intrafamilial variability. In 1 family, affected persons of 3 generations showed a 50-year variation in age at onset. The member with the latest onset (at age 67) died at age 91 with autopsy-confirmed HD. The next generation had hypotonic chorea beginning in the fourth decade with death in the fifth. In the third generation, a rigid patient, inheriting the illness from an affected father, had onset at age 16, while her sibs had chorea beginning in the third decade. In the second family, several members had cerebellar signs as well as chorea and dementia; MRI and CT showed olivopontocerebellar and striatal atrophy. Whether these phenotypes were the result of different allelic genes at the HD locus or of unlinked autosomal modifying loci was unknown.
A large Tasmanian family with Huntington disease was first described by Brothers (1949). Pridmore (1990) traced 9 generations, starting with the father of the woman who brought the disease to Tasmania. From that woman, 6 lines had living affected descendants and a total of 765 living descendants at risk. The numbers of affected males and females were equal. The mean age at onset was 48.6 years and the mean age of death, 61.8 years. Affected members were at least as fertile as members of the general population. Pridmore (1990) concluded that late-onset disease (defined as death after 63 years of age) was associated with significantly greater fertility (in men more so than women) compared with that of affected sibs of the same sex. Unaffected sibs produced fewer offspring than in the general population.
Ridley et al. (1991) showed that the age at onset varies between families and between paternal and maternal transmission and that rigidity is associated specifically with very early onset, major anticipation, paternal transmission, and young parental age at onset. Major anticipation was defined as an age at onset of the proband more than 15 years less than that in the affected parent. They proposed that age at onset depends on the state of methylation of the HD locus, which varies as a familial trait, and as a consequence of 'genomic imprinting' determined by parental transmission. They further suggested that young familial age at onset and paternal imprinting occasionally interact to produce a major change in gene expression, that is, the early-onset/rigid variant.
Farrer et al. (1993) tested the hypothesis that the normal HD allele or a closely linked gene on the nonmutant chromosome influences age at onset of HD. Analysis of the transmission patterns of genetically linked markers at the D4S10 locus in the normal parent against age at onset in the affected offspring in 21 sibships and 14 kindreds showed a significant tendency for sibs who have similar onset ages to share the same D4S10 allele from the normal parent. Affected sibs who inherited different D4S10 alleles from the normal parent tended to have more variable ages at onset, thus providing support for the hypothesis.
Goldberg et al. (1993) reported findings in 3 families in which a new mutation for HD had arisen. In all 3 families, a parental intermediate allele (with expansion to 30-38 CAG repeats, greater than that seen in the population but below the range seen in patients with HD) had expanded in more than 1 offspring. In one of the families, 2 sibs with the expanded CAG repeat were clinically affected with HD, thus presenting a pseudorecessive pattern of inheritance.
The U.S.-Venezuela Collaborative Research Project and Wexler (2004) genotyped 3,989 members of the 83 Venezuelan HD kindreds for their HD alleles, representing a subset of the population at greatest genetic risk. There were 938 heterozygotes, 80 people with variably penetrant alleles, and 18 homozygotes. Analysis of the 83 Venezuelan HD kindreds demonstrated that residual variability in age at onset had both genetic and environmental components. A residual age at onset phenotype was created from a regression analysis of the log of age at onset on repeat length. Familial correlations (correlation +/- SE) were estimated for sib (0.40 +/- 0.09), parent-offspring (0.10 +/- 0.11), avuncular (0.07 +/- 0.11), and cousin (0.15 +/- 0.10) pairs, suggesting a familial origin for the residual variance in onset. By using a variance-components approach with all available familial relationships, the additive genetic heritability of this residual age at onset trait was 38%. A model, including shared sib environmental effects, estimated the components of additive genetic (0.37), shared environment (0.22), and nonshared environment (0.41) variances, confirming that approximately 40% of the variance remaining in age at onset was attributable to genes other than the HD gene and 60% was environmental.
Homozygosity
Wexler et al. (1985, 1987) identified persons homozygous for the Huntington gene by study of branches of the large Venezuelan kindred in which there are instances of both parents being affected. Homozygosity was indicated by homozygosity for the G8 probe. Remarkably, comparison with the usual heterozygotes revealed no difference of phenotype. Wexler et al. (1987) suggested that this is the first human disease in which complete dominance has been demonstrated. Myers et al. (1989) performed molecular genetic studies in 4 offspring of 3 different affected x affected matings for possible homozygosity. One of the 4 was found to have a 95% likelihood of being an HD homozygote. The individual's age at onset and symptoms were similar to those in affected HD heterozygous relatives. Thus, the findings from the New England Huntington Disease Research Center corroborated the finding of Wexler et al. (1987). Connarty et al. (1996) identified 2 patients in Wessex in the U.K. in whom expansion of the HD triplet repeat was found on both chromosomes. Both were males who presented in middle age with typical clinical features. Unfortunately, no other family members were available for analysis.
Twin Studies
Bird and Omenn (1975) reported a family in which a pair of male monozygotic twins were concordant for Huntington disease. At age 30 years, the twins had a similar degree of cognitive defect but differed slightly in the severity of chorea. The daughter of 1 of the twins had childhood-onset HD, and the mother of the twins had the adult-onset rigid form of HD. Sudarsky et al. (1983) reported a pair of monozygotic twins with Huntington disease. Although they were raised in separate households from birth, age at onset, disease course, and behavioral abnormalities were strikingly similar. The findings supported the hypothesis that the main features of the disorder are genetically determined.
Georgiou et al. (1999) reported a pair of monozygotic twins with HD confirmed by genetic analysis. Twin A was more impaired at a motor level, with a hyperkinetic hypotonic variant of the disease, whereas twin B showed greater attentional impairment and demonstrated a more hypokinetic hypertonic, or rigid, variant. Twin B, who was the more impaired, showed more progressive deterioration. Georgiou et al. (1999) concluded that epigenetic environmental factors must play a role in disease modification.
Norremolle et al. (2004) reported a pair of 34-year-old male monozygotic twins belonging to a family segregating Huntington disease. The mother died of the disorder at the age of 41 years. The twins were reported to have been monochorionic and diamniotic. Twin A had no symptoms and only minor abnormalities in the form of slight impersistence of lateral gaze and mild upper limb ataxia. In contrast, twin B had a slow and slurred speech, headthrust, slow saccades, orolingual apraxia, impaired coordination, positive milk maid sign, and discrete choreic movements of the limbs and head. Mini-Mental Status Examination (MMSE) was 29 of 30 in twin A and 26 of 30 in twin B. Twin A worked as a full-time smith, whereas twin B was unemployed after he was dismissed 2 years previously from a job he had held for 15 years. The wife of twin B stated that he had become more introverted and unenterprising. Two different cell lines, carrying the normal allele together with either an expanded allele with 47 CAGs or an intermediate allele with 37 CAGs, were detected in blood and buccal mucosa from both twins. This appeared to have been the first case described of HD gene CAG repeat length mosaicism in blood cells. Haplotype analysis established that the 37 CAG allele most likely arose by contraction of the maternal 47 CAG allele. The contraction must have taken place postzygotically, possibly at a very early stage of development, and probably before separation of the twins. Twin B had presented symptoms of HD for 4 years; his skin fibroblasts and hair roots carried only the cell line with the 47 CAG repeat allele. Twin A, who was without symptoms at the time of report, displayed mosaicism in skin fibroblasts and hair roots. Norremolle et al. (2004) concluded that if the proportion of the 2 cell lines in the brain of each twin resembled that of the hair roots (another tissue originating from the ectoderm), the mosaicism in the unaffected twin would mean that only a part of his brain cells carried the expanded allele, which could explain why he, in contrast to his brother, had no symptoms at the time of report.
Friedman et al. (2005) reported a pair of female monozygotic twins who were discordant for HD. The affected twin had onset of declining gait and cognition at age 65 years, and genetic analysis showed a 39-CAG repeat in the HTT gene, which is considered a borderline expansion in which the disease may be less than 100% penetrant. Although MRI showed no caudate atrophy, she had generalized chorea, ataxia, and mild cognitive impairment. Her twin sister shared the 39-CAG repeat but was unaffected 7 years after disease onset in the affected twin. Detailed history suggested possible environmental influences: both twins grew up near a factory that was later made a federal toxic cleanup site, but the asymptomatic twin moved away at age 23 years, whereas the affected twin remained in the same house. The affected twin also smoked until her sixties, while the unaffected twin quit smoking at age 35 years. Finally, the affected twin had several comorbid conditions, including type II diabetes mellitus, chronic bronchitis, rheumatoid arthritis, hypertension, and chronic anemia, for which she took several medications. The unaffected twin had only hypertension. Friedman et al. (2005) suggested that the borderline CAG expansion of 39 repeats as well as different environmental factors contributed to the disparity in disease manifestation in these twins.
Panas et al. (2008) reported a pair of 55-year-old monozygotic twin sisters with HD due to a 45-CAG repeat who showed phenotypic discordance for the disease. At age 43, twin 1 showed anxiety, irritability, and mildly aggressive behavior. At age 46, she had prominent hyperkinesias, behavioral disturbances, and mild cognitive deterioration. By age 54, she had an independence scale of 30%. Twin 2 had onset at age 51 of depressive symptoms and mild hyperkinesias. By age 54, she had an independence scale of 50%. The age of onset differed by 8 years with regard to behavioral changes, or by 6 years with regard to choreic movements. The first twin showed prominent choreic hyperkinesias and aggressivity, while the second had severe depression with marked withdrawal and mild choreic hyperkinesias. Panas et al. (2008) postulated that the phenotypic differences may be due to epimutations in critical DNA regions.
Huntington disease was first mapped to the tip of the short arm of chromosome 4 in 1983; the HD gene was not isolated until 1993. The Huntington's Disease Collaborative Research Group, comprising 58 researchers in 6 research groups, used haplotype analysis of linkage disequilibrium to spotlight a small segment of 4p16.3 as the likely location of the defect (MacDonald et al., 1992).
The Huntington disease gene was assigned to chromosome 4 by demonstration of close linkage to an arbitrary DNA segment that had been mapped to chromosome 4 by somatic cell hybridization. The DNA segment was detected by a sequence called 'G8' and renamed 'D4S10' at the seventh Human Gene Mapping Workshop in Los Angeles in August 1983 (Gusella et al., 1984; Wexler et al., 1984).
Gusella et al. (1984) found close linkage of G8 to Huntington disease in a large Venezuelan kindred and a smaller American kindred. In the initial study, the total lod score was 8.53 at theta = 0.00. No obligatory recombinants were found. Linkage was with different haplotypes in the 2 kindreds studied. The upper limit of 99% confidence was set at 10 cM. D4S10 and HD were found to be remote from GC and MNS (known to be on 4q), as indicated by negative lod scores. Gusella et al. (1984) identified further restriction enzyme polymorphism of the G8 probe found to be linked to HD; with this, the frequency of identifiable heterozygosity could be raised to about 90%. Folstein et al. (1985) found close linkage of HD and the G8 probe in both of 2 large Maryland kindreds (Folstein et al., 1984).
Harper et al. (1985) stated that the polymorphism with 4 enzymes (HindIII, EcoRI, NciI, and BstI) applied to the G8 locus shows that over 80% of subjects are heterozygous. They further stated that the latest estimate of the interval between the G8 and the HD loci was 5 cM.
The G8 locus (D4S10) and presumably the Huntington disease locus are deleted in the Wolf-Hirschhorn (4p-) syndrome (WHS; 194190) (Gusella et al., 1985). This information helped map the HD locus to 4p. Most 4p- syndrome patients do not survive long enough to develop manifestations of HD. Tranebjaerg et al. (1984) concluded that the 'critical segment' in Wolf syndrome is 4p16.3. McKeown et al. (1987) found that the G8 locus was not deleted in a case of 4p- syndrome.
In 16 British kindreds, Youngman et al. (1986) found 2 recombinants yielding a maximum lod score of 17.6 at theta = 0.02 for marker D4S10, providing evidence against multilocus heterogeneity in Huntington disease.
By in situ hybridization (Wang et al., 1985; Magenis et al., 1985; Zabel et al., 1985; Wang et al., 1986), the HD-linked marker, G8, was mapped to 4p16.1. From studies by in situ hybridization to partially deleted chromosomes with known breakpoints, Magenis et al. (1986) concluded that the G8 probe is located in the distal half of band 4p16.1. Wang et al. (1986), also by in situ hybridization in patients with deletions of 4p, mapped G8 to 4p16.1-p16.3. Of their 2 patients, 1 had the typical phenotype of the Wolf-Hirschhorn syndrome (WHS) with a minute deletion of the segment p16.1-p16.3. Wang et al. (1986) concluded that the 4pter region could be excluded as a site.
Landegent et al. (1986) used a nonfluorescent method of in situ hybridization to assign the D4S10 locus to 4p16.3 rather than 4p16.1. The in situ hybridization method involved haptenization of nucleic acids in the probe by chemical attachment of 2-acetylaminofluorene (AAF) groups, marking of the hybridized probe by an indirect immunoperoxidase/diaminobenzidine reaction, and reflection-contrast microscopic visualization of the precipitated dye.
Froster-Iskenius et al. (1986) described a kindred in which an apparently balanced reciprocal translocation between 4q and 5p was segregating together with Huntington disease in 2 generations. In situ hybridization studies revealed that the linked DNA marker (G8) was located in the region 4p16 of both the normal and translocated chromosome 4. Thus, the association may be a chance occurrence.
Collins et al. (1987) applied the strategy of chromosome jumping to identify new probes from the terminal portion of 4p. Jumping clones were identified that traveled in each direction from G8. In 2 of 3 persons recombinant for G8 and HD who were also informative for the newly identified probes, the jumping clone traveled with HD. Thus, a jump of approximately 200 kb had crossed 2 out of 3 recombination points between G8 and HD. The information defined unequivocally the location of HD distal to G8, and suggested that the physical distance between them may not be as large as previously suspected.
Gilliam et al. (1987) presented evidence that the HD gene lies in 4p16.3 between D4S10 proximally and the telomere distally. Multipoint linkage analysis of the 4 loci--HD, D4S10, RAF2 (see 164760), and D4S62--indicated that D4S62 is close to D4S10 and centromeric to it. One particularly informative individual from the large Venezuelan kindred showed recombination between 2 RFLPs within the D4S10 segment. The 2 are located about 33 kb apart. The information at hand indicated the direction of cloning necessary for reaching the HD gene.
Gilliam et al. (1987) described an anonymous DNA segment, D4S43, which is exceedingly tightly linked to HD. Like the disease gene, it is located in the most distal portion of 4p, flanked by D4S10 and the telomere. In 3 extended HD kindreds, no recombination with HD was found, placing it less than 1.5 cM from the genetic defect. Expansion of the region to include 108 kb of cloned DNA led to the identification of 8 RFLPs and at least 2 independent coding segments. These genes might be candidates for the site of the HD defect; however, D4S43 RFLPs did not display linkage disequilibrium with the disease gene as one would expect if such were the case. Wasmuth et al. (1988) characterized a new RFLP marker, D4S95, a highly polymorphic locus which displayed no recombination with HD in the families tested. Robbins et al. (1989) used genetic linkage analysis to demonstrate that the gene causing Huntington disease is telomeric to D4S95 and D4S90, both markers known to be tightly linked to the HD locus.
The fact that no evidence of linkage disequilibrium has been found in HD with the G8 marker (Conneally et al., 1989) may suggest that the mutation is ancient and has occurred on very few occasions.
Doggett et al. (1989) prepared a physical map that extended from the most distal of the loci linked to HD (but proximal to HD) to the telomere of chromosome 4. The mapping identified at least 2 CpG islands and placed the most likely location of the HD defect remarkably close (within 325 kb) to the telomere. Conneally et al. (1989) pooled linkage data on G8 versus HD from 63 HD families (57 Caucasian, 4 Black American, and 2 Japanese). The combined maximum lod score was 87.69 at theta = 0.04 (99% confidence interval, 0.018-0.071). The maximum frequency of recombination was 0.03 in males and 0.05 in females. The data suggested that there is only 1 HD locus, though a second rare locus could not be ruled out. Kanazawa et al. (1990) presented linkage data in 9 Japanese families supporting the view that the Japanese Huntington disease gene is identical with the 'Western gene,' in spite of the lower prevalence rate in Japan. The linkage relationships appear to be the same as those that have been observed in European families.
Pyrimidine oligodeoxyribonucleotides bind in the major groove of DNA parallel to the purine Watson-Crick strand through formation of specific Hoogsteen hydrogen bonds to the purine Watson-Crick base. Specificity is derived from thymine (T) recognition of adenine/thymine (AT) basepairs (TAT triplets); and N3-protonated cytosine (C+) recognition of guanine/cytosine (GC) basepairs (C + GC triplets). By combining oligonucleotide-directed recognition with enzymatic cleavage, near quantitative cleavage at a single target site can be achieved. Strobel et al. (1991) used this approach to 'liberate' the tip of 4p that contains the entire candidate region for the HD gene. A 16-base pyrimidine oligodeoxyribonucleotide was used with success.
Buetow et al. (1991) provided a genetic map of chromosome 4 with extensive information on the mapping of 4p16.3. They presented evidence for linkage heterogeneity in this region and suggested that it might explain the fact that in some families (Doggett et al., 1989; Robbins et al., 1989), HD has been localized to the most distal 325 kb of 4p16.3, telomeric to D4S90, the most distal marker in the map presented by Buetow et al. (1991), whereas in other families (MacDonald et al., 1989; Snell et al., 1989) HD has been localized proximal to D4S90. A microinversion in 4p16.3 in HD patients could provide an explanation. In 10 South African families of black, white, and mixed ancestry, Greenberg et al. (1991) found tight linkage to D4S10 (G8); maximum lod score = 8.14 at theta = 0.00. Because of the diverse ethnic backgrounds, the data provided evidence that there is only a single HD locus.
The existence of many genes in the telomeric region of 4p is indicated by the work of Saccone et al. (1992). By chromosomal in situ hybridization, they determined the localization of the G+C-richest fraction of human DNA. Bernardi (1989) pointed out that the human genome is a mosaic of isochores, i.e., large DNA regions (more than 300 kb, on the average) that are compositionally homogeneous (above a size of 3 kb) and belong to a small number of families characterized by different G+C levels. The G+C-richest fraction of DNA has the highest gene concentration, the highest concentration of CpG islands, the highest transcriptional and recombinational activity, and a distinct chromatin structure. The in situ hybridization results showed a concentration of this isochore family, called H3, in telomeric bands and in chromomycin A3-positive/4-prime,6-diamidino-2-phenylindole-negative bands. Mouchiroud et al. (1991) found that the gene density in the GC-richest 3% of the genome is about 16 times higher than in the GC-poorest 62%. Figure 2 of Saccone et al. (1992) showed dramatically the concentration of G+C-rich DNA in the telomeric band of 4p as well as regions on other chromosomes that have been found to be rich in genes by mapping studies, e.g., distal 1p and much of chromosomes 19 and 22.
Sabl and Laird (1992) proposed an epigenetic mechanism to explain inconsistencies in mapping of the candidate HD gene. Dominant position-effect variegation (PEV) is a variable but clonally stable inactivation of a euchromatic gene that has been placed adjacent to heterochromatic sequences. In an example in Drosophila melanogaster, a fully dominant mutant phenotype, such as HD, results from stable epigenetic inactivation of an allele adjacent to the structural alteration (cis-inactivation) combined with a complementary inactivation of the homologous normal allele (trans-inactivation). Sabl and Laird (1992) proposed that the trans-inactivation of the normal allele may occasionally persist through meiosis. This so-called epigene conversion occurring at the HD locus in a few percent of meioses could account for anomalies in the region's genetic map.
Bates et al. (1992) characterized a YAC contig spanning the region most likely to contain the HD mutation. Zuo et al. (1992) prepared a set of YAC clones spanning 2.2 Mb at the tip of the short arm of chromosome 4 presumably containing the HD gene. Skraastad et al. (1992) detected highly significant linkage disequilibrium with D4S95 in 45 Dutch families, consistent with studies in other populations. The area of linkage disequilibrium extended from D4S10 proximally to D4S95, covering 1,100 kb. The results confirmed the suggestion that the HD gene maps near D4S95.
Using a direct cDNA selection strategy, Goldberg et al. (1993) identified at least 7 transcription units within the 2.2-Mb DNA interval thought to contain the HD gene. Screening with one of the cDNA clones identified an Alu insertion in genomic DNA from 2 persons with HD, which showed complete cosegregation with the disease in these families but was not found in 1,000 control chromosomes. A gene that encodes a 12-kb transcript, which maps in close proximity to the Alu insertion site, was considered a strong candidate for the HD gene.
In an analysis of 78 HD chromosomes with multiallelic markers, MacDonald et al. (1992) found 26 different haplotypes, suggesting a variety of independent HD mutations. The most frequent haplotype, accounting for about one-third of disease chromosomes, suggested that the disease gene is between D4S182 and D4S180. However, alternative mechanisms for creating haplotype diversity do not require a multiple mutational origin.
The Huntington's Disease Collaborative Research Group (1993) identified an expanded (CAG)n repeat on 1 allele of the HTT gene (613004.0001) in affected members from all of 75 HD families examined. The families came from a variety of ethnic backgrounds and demonstrated a variety of 4p16.3 haplotypes. The findings indicated that the HD mutation involves an unstable DNA segment similar to those previously observed in several disorders, including the fragile X syndrome (300624), Kennedy syndrome (313200), and myotonic dystrophy. The fact that the phenotype of HD is completely dominant suggested that the disorder results from a gain-of-function mutation in which either the mRNA product or the protein product of the disease allele has some new property or is expressed inappropriately (Myers et al., 1989).
Duyao et al. (1993), Snell et al. (1993), and Andrew et al. (1993) analyzed the number of CAG repeats in a total of about 1,200 HD genes and in over 2,000 normal controls. Read (1993) summarized and collated the results. In all 3 studies, the normal range of repeat numbers was 9-11 at the low and 34-37 at the high end, with a mean ranging from 18.29 to 19.71. Duyao et al. (1993) found a range of 37-86 in HD patients with a mean of 46.42.
Ambrose et al. (1994) found that both normal and HD alleles are represented in the mRNA population in HD heterozygotes, indicating that the defect does not eliminate transcription. In a female carrying a balanced translocation with a breakpoint between exons 40 and 41, the HD gene was disrupted but the phenotype was normal, arguing against simple inactivation of the gene as the mechanism by which the expanded trinucleotide repeat causes HD. The observation suggested that the dominant HD mutation either confers a new property on the mRNA or, more likely, alters an interaction at the protein level.
Rubinsztein et al. (1996) studied a large cohort of individuals who carried between 30 and 40 CAG repeats in the IT15 (HTT) gene. They used a PCR method that allowed the examination of CAG repeats only, thereby excluding the CCG repeats, which represent a polymorphism, as a confounding factor. No individual with 35 or fewer CAG repeats had clinical manifestations of HD. Most individuals with 36 to 39 CAG repeats were clinically affected, but 10 persons (aged 67-95 years) had no apparent symptoms of HD. The authors concluded that the HD mutation is not fully penetrant in individuals with a borderline number of CAG repeats.
Gusella et al. (1996) gave a comprehensive review of the molecular genetic aspects of Huntington disease.
Genetic Anticipation
Brinkman et al. (1997) defined the relationship between CAG repeat size and age at onset of HD in a cohort of 1,049 persons, including 321 at-risk and 728 affected individuals with a CAG size of 29 to 121 repeats. Kaplan-Meier analysis provided curves for determining the likelihood of onset at a given age, for each CAG repeat length in the 39 to 50 range. These curves were significantly different, with relatively narrow 95% confidence intervals, indicating the correlation between CAG repeat size and age at onset. Brinkman et al. (1997) stated that, although complete penetrance of HD was observed for CAG sizes equal to or greater than 42, 'only a proportion of those with a CAG repeat length of 36-41 showed signs or symptoms of HD within a normal life span.' Their data provided information concerning the likelihood of being affected, by a specific age, with a particular CAG size, and may be useful in predictive-testing programs and for the design of clinical trials for persons at increased risk for HD.
Snell et al. (1993) found a negative correlation between the number of repeats on the normal paternal allele and the age at onset in individuals with maternally transmitted disease. They interpreted this as suggesting that normal gene function varies because of the size of the repeat in the normal range and a sex-specific modifying effect. However, Read (1993) commented that this was not seen by the other groups and 'is hard to square with the reported normal age at onset in homozygotes.'
In an examination of 8 probands with sporadic HD whose parental DNA was available, Goldberg et al. (1993) found that 1 of the parental HD alleles was significantly greater than that seen in the general population, but smaller than that seen in patients. The CAG repeats were in the range of 30 to 38, and were designated 'intermediate alleles.' These alleles were found to be unstable and prone to expansion upon transmission. The expansions occurred on the paternal allele in the 7 cases in which sex of the parent could be determined and were associated with advanced paternal age.
In a study of the HD mutation and the characteristics of its transmission in 36 HD families, Trottier et al. (1994) found that instability of the CAG repeats was more frequent and stronger upon transmission from a male than from a female, with a clear tendency toward increased size. They found a significant inverse correlation (p = 0.0001) between the age at onset and the CAG repeat length. The observed scatter would, however, not allow an accurate individual prediction of age at onset. An HD mutation of paternal origin was found in 3 juvenile-onset cases analyzed. In at least 2 of these cases, a large expansion of the HD allele upon paternal transmission may explain the major anticipation observed.
Illarioshkin et al. (1994) found significant positive correlation between the rate of progression of clinical symptoms and CAG repeat length in a group of 28 Russian patients with Huntington disease. Ranen et al. (1995) found that the change in repeat length with paternal transmission was significantly correlated with the change in age at onset between the father and offspring. They confirmed an inverse relationship between repeat length and age at onset, the higher frequency of juvenile-onset cases arising from paternal transmission, anticipation as a phenomenon of paternal transmission, and greater expansion of the trinucleotide repeat with paternal transmission.
Coles et al. (1997) identified 7 alleles in the conserved 303-bp region upstream of the +1 translation start site in the HD gene in a sample of 208 English Huntington patients and 56 unrelated control East Anglians, 30 black Africans, and 34 Japanese. There was no correlation between these alleles and age at onset in the Huntington disease patients.
Using a logarithmic model to regress the age of HD onset on the number of CAG triplets, Rosenblatt et al. (2001) found that CAG number alone accounts for 65 to 71% of the variance in age at onset. The 'siblingship' to which an individual belonged accounted for 11 to 19% of additional variance. They suggested that a linkage study of modifiers would be feasible given the cooperation of major centers and might be rendered more efficient by concentrating on sib pairs that are highly discordant for age at onset.
Djousse et al. (2003) presented evidence that the size of the normal HD allele influences the relationship between the size of the expanded repeat and age at onset of HD. Data collected from 2 independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence age at onset. The effect of the normal allele was seen among persons with large HD repeat sizes (47 to 83 repeats). The findings suggested that an increase in the size of the normal repeat may mitigate disease expression among HD-affected persons with large expanded CAG repeats.
Among 921 patients with HD, Aziz et al. (2009) observed a significant interaction between CAG repeats in the normal HTT allele and CAG repeats in the disease allele with age at onset. At the low range of mutant CAG repeat size (36 to 44 repeats), higher normal CAG repeat sizes were related to an earlier age at onset, while in the high range of the mutant repeat size (44 to 64 repeats), higher values of the normal repeat size were related to a later age at onset. Thus, the known association between mutant CAG repeat size and age at onset progressively weakens for higher normal CAG size, suggesting a protective effect of the normal allele. Statistical modeling indicated that this interaction term could account for 53.4% of the variance in the age at onset. Among 512 patients, there was also a significant and similar interaction between normal and mutant CAG repeat sizes on severity or progression of motor, cognitive, and functional skills, but not on behavioral symptoms. Among 16 premanifest HTT mutation carriers, there was a similar interaction effect on basal ganglia size. Aziz et al. (2009) concluded that increased CAG size in the normal allele diminishes the association between mutant CAG repeat size and disease severity in HD, suggesting an interaction between the 2 proteins.
In 51 families, Semaka et al. (2010) found that 54 (30%) of 181 transmissions of intermediate alleles, defined as 27 to 35 CAG repeats, were unstable. The unstable transmissions included both 37 expansions and 17 contractions. Of the expanded alleles, 68% expanded into the HD range (greater than 36 CAG). Thus, 14% (25 of 181) of the intermediate allele transmissions examined were consistent with a new mutation for HD. However, Semaka et al. (2010) cautioned that additional studies were needed before their findings are used for genetic counseling.
In a statistical analysis of 4,448 HD patients, including 878 individuals with both a known age at onset and age at death, Keum et al. (2016) found an inverse association between the length of the CAG repeat expansion and age at death, although there were additional factors that influenced the time of death, including a correlation between age at onset and age at death. There was no contribution of the normal CAG allele to age at death. Duration of disease was not associated with length of the expanded CAG repeat. Keum et al. (2016) provided 2 explanations for these seemingly counterintuitive findings: that CAG-driven damage occurs to permit CAG-independent damage contributing to death, including external factors, or that CAG-dependent damage shows different time courses in different cell types that are independent of the motor or characteristic neurodegenerative features of the disease.
Modifier Genes
MacDonald et al. (1999) analyzed the age at onset in 258 individuals with Huntington disease. Variability in the age at onset attributable to the CAG repeat length alone in this sample was found to be R(2) = 0.743. The presence of a TAA repeat polymorphism in the GluR6 gene (GRIK2; 138244) explained an additional 0.6% of the variability in age of onset.
Kehoe et al. (1999) showed that the APOE (107741) epsilon-2/epsilon-3 genotype is associated with significantly earlier age at onset of Huntington disease in males than in females. This sex difference was not apparent for any other APOE genotypes. Andresen et al. (2007) could not replicate the findings of Kehoe et al. (1999).
Li et al. (2003) stated that although the variation in age at onset of HD is partly explained by the size of the expanded CAG repeat, it is strongly heritable, which suggests that other genes modify the age at onset. They performed a 10-cM genomewide scan in 629 sib pairs affected with HD, using ages at onset adjusted for the expanded and normal CAG repeat sizes. Because all those studied were affected with HD, estimates of allele sharing identical by descent at and around the HD locus were adjusted by a positionally weighted method to correct for the increased allele sharing at 4p. Suggestive evidence for linkage was found at 4p16 (lod = 1.93), 6p23-p21 (lod = 2.29), and 6q24-q26 (lod = 2.28).
Djousse et al. (2004) used data from 535 patients with HD and the cohort involved in the genome scan of Li et al. (2003) to assess whether age at onset was influenced by any of 3 markers in the 4p16 region: MSX1 (142983), a deletion within the HD coding sequence, and D4S127 (BJ56). Suggestive evidence for an association was seen between MSX1 alleles and age at onset, after adjustment for normal CAG repeat, expanded repeat, and their product term. Individuals with MSX1 genotype 3/3 tended to have younger age at onset. No association was found between the other 2 markers and age at onset. These findings supported previous studies suggesting that there may be a significant genetic modifier for age at onset in Huntington disease in the 4p16 region. Djousse et al. (2004) concluded that the modifier may be present on both the HD chromosome and the chromosome bearing the 3 allele of the MSX1 marker.
Many genetic polymorphisms had been shown to be associated with age of onset of HD in several different populations. As reviewed by Andresen et al. (2007), these included 12 polymorphisms in 9 genes. Andresen et al. (2007) undertook to replicate these genetic association tests in 443 affected people from a large set of kindreds from Venezuela. GRIN2A (138253) and TCERG1 (605409) were thought to show true association with residual age of onset for Huntington disease. The purported genetic association of the other genes could not be replicated. The most surprising negative result was that for the GRIK2 (TAA)n polymorphism, which had previously shown association with age of onset in 4 independent populations with Huntington disease. Andresen et al. (2007) suggested that the lack of association in the Venezuelan kindreds may have been due to the exceedingly low frequency of the key (TAA)16 allele in that population.
In a study of 250 HD patients and 15 presymptomatic female mutation carriers, Arning et al. (2007) observed significant associations between age at onset in women and 2 intronic SNPs (rs2650427 and rs8057394) in the GRIN2A gene and a synonymous 2664C-T SNP in exon 12 of the GRIN2B gene (138252). The significant findings were predominantly due to premenopausal women, suggesting a role for hormones. Arning et al. (2007) concluded that together GRIN2A and GRIN2B genotype variations explain 7.2% additional variance in age at onset for HD in women.
Among 889 patients with Huntington disease, Metzger et al. (2008) found a significant association between age at onset and a thr441-to-met (T441M) substitution in the HAP1 gene (rs4523977). In HD patients with less than 60 CAG repeats, those who were homozygous for the met/met allele developed symptoms about 8 years later than HD patients with the thr/met or thr/thr genotypes (p = 0.015). In vitro studies showed that met441 bound mutated HTT more tightly than thr441, stabilized HTT aggregates, reduced the number of soluble HTT degraded products, and protected neurons against HTT-mediated toxicity. Metzger et al. (2008) concluded that the T441M SNP can modify the age at onset in adult patients with HD. They estimated that the T441M SNP may represent 2.5% of the variance in age at onset that cannot be accounted for by expanded CAG repeats in the HTT gene.
In a study of 4,068 patients with HD, Lee et al. (2012) found that CAG repeat length in the HTT gene in the expanded allele determined age of onset of motor symptoms in a dominant fashion, and that the unexpanded, wildtype allele CAG length did not have an effect. Furthermore, in 10 patients with 2 expanded CAG alleles, onset of motor symptoms was consistent with what would be expected for the longer repeat allele. Aziz et al. (2012) noted that in assessing the results of Lee et al. (2012), one should consider that behavioral disturbances often precede motor onset and that age of motor onset may not correlate to rate of disease progression.
Wright et al. (2019) assessed the effect of a sequence variant downstream of the CAG repeat in the HTT gene, a change from (CAG)n-CAA-CAG to (CAG)n-CAG-CAG, in 16 patients with HD from 6 families. The variant resulted in complete loss of interrupting (LOI) adenine nucleotides in this region. The LOI was associated with increased somatic CAG tract instability and increased repeat size as assessed in patient blood and sperm. Patients who were carriers of the LOI variant had an average of disease onset 25 years earlier than predicted by models. This effect was particularly seen in patients who were carriers of reduced penetrance alleles of 36 to 39 CAG repeat lengths in the HTT gene.
Based on an analysis of GWAS data evaluating genetic modifiers of age of onset of HD, the Genetic Modifiers of Huntington's Disease (GeM-HD) Consortium (2019) found that timing of appearance of HD symptoms was dependent on the length of the CAG repeat rather than on the length of the polyglutamine tract in HTT. Specifically, the CAA-CAG sequence at the distal end of the CAG tract in most HTT alleles, although it encodes for 2 glutamines, does not contribute to earlier onset of disease. The Consortium further concluded that HD disease presentation is also associated with the degree to which genetic modifiers influence the CAG expansion rate and threshold by which the CAG length causes toxicity in specific cells that are important for HD disease pathogenesis.
Schultz et al. (2021) evaluated cognitive performance in asymptomatic individuals with expanded CAG repeats (36-43 repeats or greater) in the HTT gene who were 30 years of age or younger. Higher CAG repeat numbers were associated with improved performance in tasks that assess attentional-executive functions, which are mediated by frontostriatal circuits.
Using a survival model corrected for age at onset, Langbehn (2022) analyzed survival time after disease onset in 8,422 patients with HD (826 of whom had an age of death reported). The expansion length of the CAG trinucleotide sequence in the HTT gene was significantly associated with time from the onset of motor symptoms until death. The CAG repeat length had a stronger influence on the age of death in women compared to men. Lee et al. (2022) commented that the methodology used by Langbehn (2022) may not have been able to account for other factors that contribute to time until death (non-CAG repeat length factors).
Andrew et al. (1994) found that 30 (2.9%) of 1,022 persons with HD did not have an expanded CAG repeat in the disease range. They showed that most of these individuals with normal-sized alleles, namely 18, represented misdiagnosis, sample mix-up, or clerical error. The remaining 12 patients represented possible phenocopies for HD. In at least 4 cases, family studies of these phenocopies excluded 4p16.3 as the region responsible for the phenotype. Mutations in the HD gene other than CAG expansion have not been excluded for the remaining 8 cases; however, in as many as 7 of these patients, retrospective review of their clinical features identified characteristics not typical for HD. Andrew et al. (1994) concluded that on rare occasions mutations in other, as-yet-undefined genes can present with a clinical phenotype very similar to that of HD.
Several Huntington disease-like phenotypes have been described, including HDL1 (603210), caused by repeats in the PRNP gene (176640.0001); HDL2 (606438), caused by repeats in the JPH3 gene (605268.0001); HDL4 (see 607136), caused by repeats in the TBP gene (600075.0001); and HDL3 (604802), which maps to chromosome 4p15.3.
The mutant huntingtin protein in HD results from an expanded CAG repeat leading to an expanded polyglutamine strand at the N terminus and a putative toxic gain of function. Neuropathologic studies show neuronal inclusions containing aggregates of polyglutamines (polyQ) (Walker, 2007).
Paulson et al. (2000) reviewed the mechanisms of neural cell death in the so-called polyQ expansion diseases. Reddy et al. (1999) provided a comprehensive review of the pathogenesis of HD, including cellular and animal models.
Aggregation of Mutant Huntingtin
In addition to Huntington disease, there are at least 8 other diseases of the central nervous system, each of which is known to be associated with a different protein containing an expanded polyglutamine sequence. Except for their polyglutamine sequences, the 7 proteins, whose complete sequences are known, are unrelated; the expanded polyglutamine must therefore be the primary cause of the disorders. This is supported by the fact that transgenes expressing little more than an expanded polyglutamine produce neurologic disease in mice (Ikeda et al., 1996; Mangiarini et al., 1996). Thus, it appears clear that expanded polyglutamine is ultimately lethal to neurons and exerts its effect by a gain of function (Green, 1993). Affected regions of the brain show aggregates or inclusions containing the protein with expanded polyglutamine.
DiFiglia et al. (1997) demonstrated that an amino-terminal fragment of mutant huntingtin localizes to neuronal intranuclear inclusions (NIIs) and dystrophic neurites (DNs) in the HD cortex and striatum, and that polyglutamine length influences the extent of huntingtin accumulation in these structures. Ubiquitin (UBB; 191339), which is thought to be involved in labeling proteins for disposal by intracellular proteolysis, was also found in NIIs and DNs, suggesting to DiFiglia et al. (1997) that abnormal huntingtin is targeted for proteolysis but is resistant to removal. The aggregation of mutant huntingtin may be part of the pathogenic mechanism in HD.
Sisodia (1998) reviewed the significance of nuclear inclusions in glutamine repeat disorders.
Lunkes and Mandel (1998) developed a stable cellular model of HD, using a neuroblastoma cell line in which the expression of full-length or truncated forms of wildtype and mutant huntingtin could be induced. While the wildtype forms had the expected cytoplasmic localization, the expression of mutant proteins led to the formation of cytoplasmic and nuclear inclusions in a time- and polyglutamine length-dependent manner. The inclusions were ubiquitinated, appeared more rapidly in cells expressing truncated forms of the mutant huntingtin, and were correlated with enhanced apoptosis. In lines expressing mutant full-length huntingtin, major characteristics present in HD patients could be modeled. Selective processing of the mutant, but not the wildtype, full-length huntingtin was observed at late time points, with appearance of a breakdown product corresponding to a predicted caspase-3 cleavage product. A more truncated N-terminal fragment of huntingtin was also produced, which appeared to be involved in building up cytoplasmic inclusions at early time points, and later on also nuclear inclusions. The findings fit with the observation that inclusions in the brain of HD patients are detected only when using antibodies directed against epitopes very close to the polyglutamine stretch.
Scherzinger et al. (1999) reported that the formation of amyloid-like huntingtin aggregates in vitro not only depends on polyglutamine-repeat length but also critically depends on protein concentration and time. Furthermore, the in vitro aggregation of huntingtin could be seeded by preformed fibrils. Together, these results were interpreted as indicating that amyloid fibrillogenesis in HD, as in Alzheimer disease (104300), is a nucleation-dependent polymerization. Using a cell culture model, Narain et al. (1999) investigated the proposal that HD shows true dominance. Protein aggregate formation was used as an indicator of pathology. Using constructs comprising part of exon 1 of huntingtin with varying CAG repeat length, the authors found that the rate of protein aggregation was dependent on the number of repeats, and that the presence of wildtype huntingtin neither enhanced nor interfered with protein aggregation.
Heiser et al. (2000) investigated whether the accumulation of insoluble protein aggregates in intra- and perinuclear inclusions, a hallmark of HD and related glutamine-repeat disorders, plays a direct role in disease pathogenesis. By use of a filter retardation assay, they showed that a monoclonal antibody that specifically recognizes the polyQ stretch in huntingtin, and the chemical compounds Congo Red, thioflavine S, chrysamine G, and direct fast yellow, inhibited HD exon 1 protein aggregation in a dose-dependent manner. On the other hand, potential inhibitors of amyloid-beta formation such as thioflavine T, gossypol, melatonin, and rifampicin had little or no inhibitory effect on huntingtin aggregation in vitro. Results obtained by the filtration assay were confirmed by electron microscopy, SDS/PAGE, and mass spectrometry. Furthermore, cell culture studies showed that the Congo red dye at micromolar concentrations reduced the extent of HD exon 1 aggregation in transiently transfected COS cells. Heiser et al. (2000) thought that these findings contributed to a better understanding of the mechanism of huntingtin fibrillogenesis and provided a possible basis for the development of new huntingtin aggregation inhibitors that may be effective in treating HD.
Dyer and McMurray (2001) evaluated huntingtin protein from human brain, transgenic animals, and cells and observed that mutant huntingtin is more resistant to proteolysis than normal huntingtin. The N-terminal cleavage fragments that Dyer and McMurray (2001) observed arose from the processing of normal huntingtin and were sequestered by full-length huntingtin. Dyer and McMurray (2001) proposed a model in which inhibition of proteolysis of mutant huntingtin leads to aggregation and toxicity through the sequestration of important targets, including normal huntingtin.
Proteolytic processing of mutant HTT is a key event in the pathogenesis of HD. Mutant HTT fragments containing a polyglutamine expansion form intracellular inclusions and are more cytotoxic than full-length mutant HTT. Lunkes et al. (2002) showed that 2 distinct mutant HTT fragments, which they termed cp-A and cp-B, differentially build up nuclear and cytoplasmic inclusions in HD brain and in a cellular model for HD. Cp-A is released by cleavage of HTT in a 10-amino acid domain and is the major fragment that aggregates in the nucleus. The authors determined that cp-A and cp-B are most likely generated by aspartic endopeptidases acting in concert with the proteasome to ensure the normal turnover of HTT. They suggested that these proteolytic processes are thus potential targets for therapeutic intervention in HD.
To examine the role of aggregation of expanded polyglutamine-containing proteins in the etiology of HD and other disorders with expanded CAG repeats, Yang et al. (2002) produced aggregates of simple polyglutamine peptides in vitro and introduced them into mammalian cells in culture. COS-7 and PC12 cells in culture readily endocytosed aggregates of chemically synthesized polyglutamine peptides. Simple polyglutamine aggregates were localized to the cytoplasm and had little impact on cell viability. However, aggregates of polyglutamine peptides containing a nuclear localization signal were localized to nuclei and led to dramatic cell death. Amyloid fibrils of a non-polyglutamine peptide were nontoxic, whether localized to the cytoplasm or nucleus. Nuclear localization of an aggregate of a short polyglutamine peptide was just as toxic as that of a long polyglutamine peptide, supporting the notion that the influence of polyglutamine repeat length on disease risk and age at onset is at the level of aggregation efficiency. Yang et al. (2002) concluded that their results supported a direct role for polyglutamine aggregates in HD-related neurotoxicity.
To investigate the biophysical basis for the relationship between longer repeat lengths and earlier ages of onset of HD, Chen et al. (2002) studied the in vitro aggregation kinetics of a series of polyglutamine peptides. The peptides, in solution at 37 degrees centigrade, underwent a random coil-to-beta-sheet transition with kinetics superimposable on their aggregation kinetics, suggesting the absence of soluble, beta-sheet-rich intermediates in the aggregation process. Details of the time course of aggregate growth confirmed that polyglutamine aggregation occurs by nucleated growth polymerization. In contrast to conventional models of nucleated growth polymerization of proteins, Chen et al. (2002) found that the aggregation nucleus is a monomer, i.e., nucleation of polyglutamine aggregation corresponded to an unfavorable protein folding reaction. In their experiments, the repeat-length-dependent differences in predicted aggregation lag times were in the same range as the length-dependent age-of-onset differences in HD, suggesting that the biophysics of polyglutamine aggregation nucleation may play a major role in determining disease onset.
Ravikumar et al. (2002) used both exon 1 of the HD gene with expanded polyQ repeats and green fluorescent protein (GFP) attached to 19 alanines as models for aggregate-prone proteins. Autophagy is involved in the degradation of these model proteins, since they accumulated when cells were treated with different inhibitors acting at distinct stages of the autophagy-lysosome pathway. Rapamycin, which stimulates autophagy, enhanced the clearance of these aggregate-prone proteins and also reduced the appearance of aggregates and the cell death associated with the polyQ and polyA expansions. Both lactacystin and the specific proteasomal inhibitor epoxomicin increased soluble protein levels of the polyQ constructs, suggesting that these are also cleared by the proteasome. However, while polyQ aggregation was enhanced by lactacystin in an inducible PC12 cell model, aggregation was reduced by epoxomicin, suggesting that some other protein(s) induced by epoxomicin may regulate polyQ aggregation.
In HeLa cells transfected with an expanded polyglutamine repeat (Q79), Sanchez et al. (2003) showed that Congo red exerted a protective effect against Q79-induced cytotoxicity. Congo red preserved normal cellular protein synthesis and degradation functions, prevented ATP and caspase activation, and decreased cell death by 60%. Although Congo red did not suppress the expression of Q79, it inhibited the oligomerization of polyglutamine aggregates and disrupted preformed aggregates, perhaps by promoting the clearance of the aggregates by increasing accessibility to cellular protein degradation machinery. Treatment of the R6/2 mouse model of Huntington disease with Congo red showed protective effects on survival, weight loss, and motor function, and disrupted and inhibited the formation of polyglutamine oligomers as shown by brain pathology. Sanchez et al. (2003) concluded that the oligomerization of expanded polyglutamine repeats plays a key role in their chronic cytotoxicity, and suggested that inhibition of polyglutamine oligomerization may be a viable therapeutic approach to such diseases.
Qin et al. (2003) explored the role of autophagy in Htt processing in clonal striatal cells, PC12 cells, and rodent cells lacking cathepsin D (CTSD; 116840). Blocking autophagy with 3-methyladenine raised levels of exogenously expressed Htt1-287 or Htt1-969, reduced cell viability, and increased the number of cells bearing mutant Htt aggregates. Stimulating autophagy by serum reduction in vitro promoted Htt degradation, including breakdown of caspase-cleaved N-terminal Htt fragments. Htt expression increased levels of the lysosomal enzyme cathepsin D by an autophagy-dependent pathway. Cells without cathepsin D accumulated more N-terminal Htt fragments, and cells with cathepsin D were more efficient in degrading wildtype Htt than mutant Htt in vitro. Qin et al. (2003) suggested that autophagy may play a critical role in the degradation of N-terminal Htt and altered processing of mutant HTT by autophagy and cathepsin D may contribute to HD pathogenesis.
In human neuroblastoma cells, Szebenyi et al. (2003) showed that huntingtin and androgen receptor (AR; 313700) polypeptides containing pathogenic polyQ repeats directly inhibited both fast axonal transport and elongation of neuritic processes. The effects were greater with truncated polypeptides and occurred without detectable morphologic aggregates.
Arrasate et al. (2004) used a novel technique in which an automated microscope followed single cells in culture to evaluate the impact of inclusion bodies on neuronal cell survival. The findings showed that the risk of death of neurons expressing mutant huntingtin was best predicted by the level of diffuse forms of the mutant protein and by the length of their polyglutamine expansions. Inclusion body formation reduced intracellular levels of diffuse mutant huntingtin and increased cell survival, indicating a protective effect of inclusion bodies and suggesting that inclusion body formation is an adaptive coping response of the cell.
A model of polyQ aggregate structure has been proposed on the basis of studies with synthetic polyQ peptides and includes an alternating beta-strand/beta-turn structure with 7 glutamine residues per beta-strand (Thakur and Wetzel, 2002). Poirier et al. (2005) tested this model in the context of the huntingtin exon-1 N-terminal fragment in HEK293 cells, mouse neuroblastoma cells, and cultured murine primary cortical neurons. The data supported this model in the huntingtin protein and provided better understanding of the structural basis of polyQ aggregation in toxicity in Huntington disease.
To understand how the presence of misfolded proteins leads to cellular dysfunction, Gidalevitz et al. (2006) employed C. elegans polyglutamine aggregation models and found that polyglutamine expansions disrupted the global balance of protein folding quality control, resulting in loss of function of diverse metastable proteins with destabilizing temperature-sensitive mutations. In turn, these proteins, although innocuous under normal physiologic conditions, enhanced the aggregation of polyglutamine proteins. Thus, Gidalevitz et al. (2006) suggested that weak folding mutations throughout the genome can function as modifiers of polyglutamine phenotypes and toxicity.
Bennett et al. (2007) exploited a mass spectrometry-based method to quantify polyubiquitin chains and demonstrated that the abundance of these chains is a faithful endogenous biomarker of ubiquitin-proteasome system (UPS) dysfunction. Lys48-linked polyubiquitin chains accumulate early in pathogenesis in brains from the R6/2 transgenic mouse model of HD, from a knockin model of HD, and from human HD patients, establishing that ubiquitin-proteasome system dysfunction is a consistent feature of HD pathology. Lys63- and Lys11-linked polyubiquitin chains, which are not typically associated with proteasomal targeting, also accumulate in the R6/2 mouse brain. Bennett et al. (2007) concluded that HD is linked to global changes in the ubiquitin system to a much greater extent than previously recognized.
Jeong et al. (2009) found that clearance of mutant human HTT via autophagy was facilitated by acetylation of HTT at lys444 (K444). Acetylation resulted in trafficking of mutant HTT into autophagosomes, significantly improved clearance of mutant protein by macroautophagy, and reversed the toxic effects of mutant HTT in rat primary striatal and cortical neurons and in a transgenic C. elegans model of HD. In contrast, mutant HTT that was resistant to acetylation accumulated and led to neurodegeneration in cultured neurons and mouse brain. Jeong et al. (2009) showed that the histone acetyltransferase domain of CREBBP acetylated mutant HTT at K444.
Woerner et al. (2016) analyzed the compartment specificity of aggregate toxicity using artificial beta-sheet proteins, as well as fragments of mutant HTT and TAR DNA binding protein-43 (TDP43; 605078). Aggregation in the cytoplasm interfered with nucleocytoplasmic protein and RNA transport. In contrast, the same proteins did not inhibit transport when forming inclusions in the nucleus at or around the nucleolus. Protein aggregation in the cytoplasm, but not the nucleus, caused the sequestration and mislocalization of proteins containing disordered and low-complexity sequences, including multiple factors of the nuclear import and export machinery. Thus, Woerner et al. (2016) concluded that impairment of nucleocytoplasmic transport may contribute to the cellular pathology of various aggregate deposition diseases.
Interactions of Mutant Huntingtin with Other Proteins
McLaughlin et al. (1996) found that cytoplasmic protein extracts from several rat brain regions, including striatum and cortex (sites of neuronal degeneration in HD), contain a 63 kD RNA-binding protein that interacts specifically with CAG repeat sequences. They noted that the protein/RNA interactions were dependent upon the length of the CAG repeat, and that longer repeats bound substantially more protein. McLaughlin et al. (1996) identified 2 CAG-binding proteins in human cortex and striatum, one of 63 kD and another of 49 kD. They concluded that these data suggest mechanisms by which RNA-binding proteins may be involved in the pathological course of trinucleotide-associated neurologic diseases.
The glutamine residues encoded by CAG repeats are involved in the formation of cross-links within and between proteins, through a reaction catalyzed by transglutaminases (TGase; see 190195). Cariello et al. (1996) speculated that TGase may be involved in the molecular process of neurodegeneration in HD since longer polyglutamine stretches may be better substrates for TGases; increased glutamine cross-linking could induce the formation of rigid supramolecular structures, with consequent neuronal death. Cariello et al. (1996) measured TGase activity in lymphocytes and found that TGase activity was above control levels in 25% of HD patients. TGase activity increased with age in HD patients, while in normal subjects it decreased with age. TGase activity was correlated with the age of the patient and inversely correlated with the CAG repeat length. Cariello et al. (1996) suggested that TGase activity may be a factor contributing to variance in the age at onset of HD and that the length of the CAG repeat expansion/TGase ratio could be important in the manifestation of HD. In human lymphoblastoid cells, Kahlem et al. (1998) showed that huntingtin is a substrate of transglutaminase in vitro and that the rate constant of the reaction increases with length of the polyglutamine over a range of an order of magnitude. As a result, huntingtin with expanded polyglutamine is preferentially incorporated into polymers. Both disappearance of huntingtin with expanded polyglutamine and its replacement by polymeric forms are prevented by inhibitors of transglutaminase. The effect of transglutaminase therefore duplicates the changes in the affected parts of the brain. In the presence of either tissue or brain transglutaminase, monomeric huntingtin bearing a polyglutamine expansion formed polymers much more rapidly than one with a short polyglutamine sequence.
Faber et al. (1998) used a yeast 2-hybrid interactor screen to identify proteins whose association with huntingtin might be altered in the pathogenic process. Although no interactors were found with internal and C-terminal segments of huntingtin, the N terminus of huntingtin detected 13 distinct proteins, 7 novel and 6 reported previously. Among these, they identified a major interactor class, comprising 3 distinct WW domain proteins, HYPA (PRPF40A; 612941), HYPB (612778), and HYPC, that bind normal and mutant huntingtin in extracts of HD lymphoblastoid cells. This interaction was mediated by the proline-rich region of huntingtin and was enhanced by lengthening the adjacent glutamine tract. Although HYPB and HYPC were novel proteins, HYPA was shown to be FBP11, a protein implicated in spliceosome function. The emergence of this class of proteins as huntingtin partners argued that a WW domain-mediated process, such as nonreceptor signaling, protein degradation, or pre-mRNA splicing, may participate in HD pathogenesis. (The WW domain is a protein motif consisting of 35 to 40 amino acids and is characterized by 4 conserved aromatic residues, 2 of which are tryptophan; see 602307.)
Pathogenesis in HD appears to include the cytoplasmic cleavage of huntingtin and release of an amino-terminal fragment capable of nuclear localization. Steffan et al. (2000) studied potential consequences to nuclear function of a pathogenic amino-terminal region of Htt (Httex1p), including aggregation, protein-protein interactions, and transcription. They found that Httex1p coaggregated with p53 (TP53; 191170) in inclusions generated in cell culture and interacted with p53 of the in vitro and in cell culture. Expanded Httex1p repressed transcription of the p53-regulated promoters p21 (CDKN1A; 116899) and MDR1 (ABCB1; 171050). They also found that Httex1p interacted in vitro with CREBBP (600140), and that CREBBP localized to neuronal intranuclear inclusions in a transgenic mouse model of HD. These findings raised the possibility that expanded repeat HTT causes aberrant transcriptional regulation through its interaction with cellular transcription factors, possibly resulting in neuronal dysfunction and cell death in HD.
Peel et al. (2001) showed that an RNA-dependent protein kinase, PKR (PRKR; 176871), preferentially bound mutant huntingtin RNA transcripts immobilized on streptavidin columns that had been incubated with human brain extracts. Immunohistochemical studies demonstrated that PKR was present in its activated form in both human Huntington autopsy material and brain tissue derived from Huntington yeast artificial chromosome transgenic mice. The increased immunolocalization of the activated kinase was more pronounced in areas most affected by the disease. The authors suggested a role for PKR activation in the Huntington disease process.
Steffan et al. (2001) demonstrated that the polyglutamine-containing domain of huntingtin directly binds the acetyltransferase domains of 2 distinct proteins: CREB-binding protein (CREBBP, CBP; 600140) and p300/CBP-associated factor (P/CAF; 602303). In cell-free assays, the polyglutamine-containing domain of huntingtin also inhibited the acetyltransferase activity of at least 3 enzymes: p300 (602700), P/CAF, and CBP. Expression of huntingtin exon 1 protein in cultured cells reduced the level of acetylated histones H3 and H4, and this reduction was reversible by administration of inhibitors of histone deacetylase (HDAC; see 601241). In vivo, HDAC inhibitors arrest ongoing progressive neuronal degeneration induced by polyglutamine repeat expansion, and they reduced lethality in 2 Drosophila models of polyglutamine disease. Steffan et al. (2001) suggested that their findings raise the possibility that therapy with HDAC inhibitors may slow or prevent the progressive neurodegeneration seen in Huntington disease and other polyglutamine repeat diseases, even after the onset of symptoms.
Using the yeast 2-hybrid system, Singaraja et al. (2002) isolated a novel Htt-interacting protein, HIP14 (607799). The interaction of HIP14 with Htt was inversely correlated to the poly(Q) length in Htt. The HIP14 protein was enriched in the brain, showed partial colocalization with Htt in the striatum, and was found in medium spiny projection neurons, the subset of neurons affected in HD. The HIP14 protein has sequence similarity to Akr1p, a protein essential for endocytosis in S. cerevisiae. Expression of human HIP14 resulted in rescue of the temperature-sensitive lethality in akr1-delta yeast cells and, furthermore, restored their defect in endocytosis, demonstrating a possible role for HIP14 in intracellular trafficking. The authors suggested that decreased interaction between Htt and HIP14 could contribute to the neuronal dysfunction in HD by perturbing normal intracellular transport pathways in neurons.
Humbert et al. (2002) found that IGF1 (147440) and AKT (164730) inhibited mutant huntingtin-induced cell death and formation of intranuclear inclusions of polyQ huntingtin. AKT phosphorylated serine-421 of huntingtin with 23 glutamines, and this phosphorylation reduced mutant huntingtin-induced toxicity in primary cultures of rat striatal neurons. Western blot analysis of cerebellum, cortex, and striatum from Huntington disease patients detected the 60-kD full-length AKT protein and a caspase-3 (CASP3; 600636)-generated 49-kD AKT product. In contrast, normal control brain areas expressed little to no 49-kD AKT. Humbert et al. (2002) concluded that phosphorylation of huntingtin through the IGF1/AKT pathway is neuroprotective, and they hypothesized that the IGF1/AKT pathway may have a role in Huntington disease.
Gervais et al. (2002) found that huntingtin-interacting protein-1 (HIP1; 601767) binds to the HIP1 protein interactor (HIPPI; 606621), which has partial sequence homology to HIP1 and similar tissue and subcellular distribution. The availability of free HIP1 is modulated by polyglutamine length within huntingtin, with disease-associated polyglutamine expansion favoring the formation of proapoptotic HIPPI-HIP1 heterodimers. This heterodimer can recruit procaspase-8 (601763) into a complex of HIPPI, HIP1, and procaspase-8, and launch apoptosis through components of the extrinsic cell death pathway. Gervais et al. (2002) proposed that huntingtin polyglutamine expansion liberates HIP1 so that it can form a caspase-8 recruitment complex with HIPPI, possibly contributing to neuronal death in Huntington disease.
Kita et al. (2002) developed stable cell lines expressing exon 1 fragments of the huntingtin gene driven by an inducible promoter (HD-23Q or HD-74Q). The authors studied expression levels of 1,824 genes between 0 and 18 hours after induction, using adaptor-tagged competitive PCR (ATAC-PCR). A total of 126 genes exhibited statistically significant alterations in the HD-74Q cell lines but no changes in the HD-23Q lines. Eleven genes were tested for their ability to modulate polyglutamine-induced cell death in transiently transfected cell models. Five genes (glucose transporter-1, 138140; phosphofructokinase muscle isozyme, 610681; prostate glutathione-S-transferase 2, 138380; RNA-binding motif protein-3 300027; and KRAB-A interacting protein-1, 601742) significantly suppressed cell death in both neuronal precursor and nonneuronal cell lines, suggesting that these transcriptional changes were relevant to polyglutamine pathology.
Jiang et al. (2003) confirmed that nuclear inclusions containing polyQ-expanded Htt recruit the transcriptional cofactor CREBBP. In a hippocampal cell line, they found that toxicity within individual cells induced by polyQ-expanded Htt (as revealed by a TUNEL assay) was associated with the localization of the mutant Htt within either nuclear or perinuclear aggregates. However, in addition to CREBBP recruitment, CREBBP ubiquitylation and degradation were selectively enhanced by polyQ-expanded Htt. Jiang et al. (2003) concluded that selected substrates may be directed to the ubiquitin/proteasome-dependent protein degradation pathway in response to polyQ-expanded Htt within the nucleus.
Willingham et al. (2003) performed genomewide screens in yeast to identify genes that enhance the toxicity of a mutant huntingtin fragment or of alpha-synuclein (163890). Of 4,850 haploid mutants containing deletions of nonessential genes, 52 were identified that were sensitive to a mutant huntingtin fragment, 86 that were sensitive to alpha-synuclein, and only 1 mutant that was sensitive to both. Genes that enhanced toxicity of the mutant huntingtin fragment clustered in the functionally related cellular processes of response to stress, protein folding, and ubiquitin-dependent protein catabolism, whereas genes that modified alpha-synuclein toxicity clustered in the processes of lipid metabolism and vesicle-mediated transport. Genes with human orthologs were overrepresented in their screens, suggesting that they may have discovered conserved and nonoverlapping sets of cell-autonomous genes and pathways that are relevant to Huntington disease and Parkinson disease.
Modregger et al. (2002) reported that PACSIN1 (606512), a neurospecific phosphoprotein with a presumptive role in synaptic vesicle recycling, interacts with huntingtin via its C-terminal SH3 domain. The interaction was repeat-length-dependent and was enhanced with mutant huntingtin, possibly causing the sequestration of PACSIN1. PACSIN2 (604960) and PACSIN3 (606513), isoforms which show a wider tissue distribution including the brain, did not interact with huntingtin despite a highly conserved SH3 domain. Normally, PACSIN1 is located along neurites and within synaptic boutons, but in HD patient neurons there was a progressive loss of PACSIN1 immunostaining in synaptic varicosities, beginning in presymptomatic and early-stage HD. Further, PACSIN1 immunostaining of HD patient tissue revealed a more cytoplasmic distribution of the protein, with particular concentration in the perinuclear region coincident with mutant huntingtin. The authors hypothesized a role for PACSIN1 during early stages of the selective neuropathology of HD.
Tang et al. (2003) used protein-binding experiments to identify a protein complex containing Htt, HAP1A (see 600947), and the type 1 inositol 1,4,5-triphosphate (IP3) receptor (ITPR1; 147265) in neurons from rat brain. Both wildtype and Htt with expanded polyglutamine repeats bound to the C terminus of ITPR1, but only expanded Htt caused increased sensitization of the ITPR1 receptor to activation by IP3. Expression of the expanded Htt protein in medium spiny striatal neurons, those affected in HD, resulted in an increase in intracellular calcium levels which may be toxic to neurons.
Goehler et al. (2004) generated a protein-protein interaction network for HD and identified GIT1 (608434) as a protein that interacts directly with huntingtin. Using a cell-based assay, they found that coexpression of GIT1 and HD169Q68, an aggregation-prone N-terminal Htt fragment with a 68-residue polyglutamine tract, increased the amount of Htt aggregates 3-fold compared with expression of HD169Q68 alone. N-terminally truncated GIT1 was a more potent enhancer of Htt aggregation than the full-length protein. Mutation analysis indicated that the C terminus of GIT1 interacted with the N terminus of Htt. HD169Q68 distributed to the cytoplasm of transfected human embryonic kidney cells, but coexpression with GIT1 resulted in relocalization of HD169Q68 to membranous structures and accumulation of protein aggregates. In wildtype mice, Git1 distributed diffusely in neurons throughout the brain, but in a mouse model of HD, Git1 immunoreactivity was also present in large nuclear and cytoplasmic puncta containing Htt aggregates. In normal human brain, GIT1 migrated at an apparent molecular mass of 95 kD. However, in HD brains, expression of the 95-kD protein was reduced, and prominent GIT1 C-terminal fragments of 25 to 50 kD were also detected. Goehler et al. (2004) concluded that accumulation of C-terminal GIT1 fragments in HD may contribute to disease pathogenesis.
Using human embryonic kidney and mouse neuroblastoma cell lines, Bae et al. (2006) showed that nuclear translocation and associated neurotoxicity of mutant huntingtin was mediated by a ternary complex of huntingtin, GAPDH, and SIAH1 (602212), a ubiquitin E3 ligase that provided the nuclear translocation signal. Overexpression of GAPDH or SIAH1 enhanced nuclear translocation of mutant huntingtin and cytotoxicity, whereas GAPDH mutants unable to bind SIAH1 prevented translocation. Depletion of GAPDH or SIAH1 by RNA interference diminished nuclear translocation of mutant huntingtin.
Luo et al. (2008) identified PAK1 (116899) as an HTT-interacting protein that bound both wildtype and mutant HTT proteins. Binding of PAK1 mediated soluble wildtype HTT-wildtype HTT, mutant HTT-wildtype HTT, and mutant HTT-mutant-HH interactions and enhanced aggregation of mutant HTT independent of PAK1 kinase activity. Overexpression of PAK1 enhanced HTT toxicity in cell models and neurons that paralleled increased aggregation, whereas PAK1 knockdown suppressed both aggregation and toxicity. PAK1 colocalized with mutant HTT in human neuroblastoma cells and rat cortical and striatal neurons and in human brains from HD patients. Luo et al. (2008) suggested that pathology in HD may be at least partly dependent on soluble mutant HTT-mutant HTT interaction.
Paul et al. (2014) showed a major depletion of cystathionine gamma-lyase (CTH; 607657), the biosynthetic enzyme for cysteine, in Huntington disease tissues, which may mediate Huntington disease pathophysiology. The defect occurs at the transcriptional level and seems to reflect influences of mutant HTT on specificity protein-1 (SP1; 189906), a transcriptional activator for CTH. Consistent with the notion of loss of CTH as a pathogenic mechanism, supplementation with cysteine reversed abnormalities in cultures of Huntington disease tissues and in intact mouse models of Huntington disease, suggesting therapeutic potential.
Through biochemical and live cell imaging studies, Marcora and Kennedy (2010) showed that wildtype Htt stimulated the transport of NFKB (see NFKB1, 164011) out of dendritic spines (where NFKB is activated by excitatory synaptic input) and supported a high level of active NFKB in neuronal nuclei (where NFKB stimulates the transcription of target genes). This novel function of Htt was impaired by polyQ expansion; the authors suggested that this impairment may contribute to the etiology of HD.
Apoptosis and Neurodegeneration
Portera-Cailliau et al. (1995) among others presented evidence that apoptosis is a mode of cell death in Huntington disease. Apopain (600636), a human counterpart of the nematode cysteine protease death-gene product (CED-3), has a key role in proteolytic events leading to apoptosis. Goldberg et al. (1996) showed that apoptotic extracts, and apopain itself, specifically, cleave huntingtin. The rate of cleavage increased with the length of the huntingtin polyglutamine tract, providing an explanation for the gain of function associated with CAG expansion. The results suggested to the investigators that HD may be a disorder of inappropriate apoptosis.
Saudou et al. (1998) investigated the mechanisms by which mutant huntingtin induces neurodegeneration by use of a cellular model that recapitulates features of neurodegeneration seen in Huntington disease. When transfected into cultured striatal neurons, mutant huntingtin induced neurodegeneration by an apoptotic mechanism. Antiapoptotic compounds or neurotrophic factors protected neurons against mutant huntingtin. Blocking nuclear localization of mutant huntingtin suppressed its ability to form intranuclear inclusions and to induce neurodegeneration. However, the presence of inclusions did not correlate with huntingtin-induced death. The exposure of mutant huntingtin-transfected striatal neurons to conditions that suppress the formation of inclusions resulted in an increase in mutant huntingtin-induced death. These findings suggested that mutant huntingtin acts within the nucleus to induce neurodegeneration. However, intranuclear inclusions may reflect a cellular mechanism to protect against huntingtin-induced cell death.
Clarke et al. (2000) studied the kinetics of neuronal death in 12 models of photoreceptor degeneration, hippocampal neurons undergoing excitotoxic cell death, a mouse model of cerebellar degeneration, and in Parkinson (168600) and Huntington diseases. In all models the kinetics of neuronal death were exponential and better explained by mathematical models in which the risk of cell death remains constant or decreases exponentially with age. These kinetics argue against the cumulative damage hypothesis; instead, the time of death in any neuron is random. Clarke et al. (2000) argued that their findings are most simply accommodated by a '1-hit' biochemical model in which mutation imposes a mutant steady state on the neuron and a single event randomly initiates cell death. This model appears to be common to many forms of neurodegeneration and has implications for therapeutic strategies in that the likelihood that a mutant neuron can be rescued by treatment is not diminished by age, and therefore treatment at any stage of illness is likely to confer benefit.
Using a cellular model of HD, Wyttenbach et al. (2002) identified heat-shock protein HSP27 (see 602195) as a suppressor of polyQ-mediated cell death. In contrast to HSP40 and HSP70 chaperones, HSP27 suppressed polyQ death without suppressing polyQ aggregation. While polyQ-induced cell death was reduced by inhibiting cytochrome c release from mitochondria, protection by HSP27 was regulated by its phosphorylation status and was independent of its ability to bind to cytochrome c. However, mutant huntingtin caused increased levels of reactive oxygen species (ROS) in neuronal and nonneuronal cells. ROS contributed to cell death because both N-acetyl-L-cysteine and glutathione in its reduced form suppressed polyQ-mediated cell death. HSP27 decreased ROS in cells expressing mutant huntingtin, suggesting that this chaperone may protect cells against oxidative stress. The authors proposed that a polyQ mutation may induce ROS that directly contribute to cell death, and that HSP27 may be an antagonist of this process.
Mitochondrial Dysfunction
Horton et al. (1995) used serial dilution PCR to demonstrate an 11-fold increase of the common 4977 nucleotide mitochondrial DNA deletion in temporal lobes of Huntington disease patients compared to normal controls. Huntington disease frontal lobes have 5-fold greater levels, whereas occipital lobe and putamen deletion levels were comparable with control levels. The authors hypothesized that the increased rate of mitochondrial DNA deletions could be caused by elevated oxygen radical production by mitochondria in Huntington disease patients. Gu et al. (1996) demonstrated marked deficiency of the mitochondrial respiratory chain in the caudate nucleus but not the platelets from patients with Huntington disease.
Relative to the mechanisms by which the mutant huntingtin protein cause neurodegeneration, Panov et al. (2002) showed that lymphoblast mitochondria from patients with HD have a lower membrane potential and depolarize at lower calcium loads than do mitochondria from controls. They found a similar defect in brain mitochondria from transgenic mice expressing full-length mutant huntingtin, and this defect preceded the onset of pathologic or behavioral abnormalities by months. By electron microscopy, they identified N-terminal mutant huntingtin on neuronal mitochondrial membranes, and by incubating normal mitochondria with a fusion protein containing an abnormally long polyglutamine repeat, they reproduced the mitochondrial calcium defect seen in human patients and transgenic animals. Thus, mitochondrial calcium abnormalities occur early in HD pathogenesis and may be a direct effect of mutant huntingtin on the organelle.
Trushina et al. (2004) found that expression of full-length mutant Htt impaired vesicular and mitochondrial trafficking in mouse neurons in vitro and in whole mice in vivo. Particularly, mitochondria became progressively immobilized and stopped more frequently in neurons from transgenic animals. These defects occurred early in development, prior to the onset of measurable neurologic or mitochondrial abnormalities. Consistent with a progressive loss of function, wildtype Htt, trafficking motors, and mitochondrial components were selectively sequestered by mutant Htt in human HD-affected brain. Trushina et al. (2004) concluded that mutant Htt aggregates sequester Htt and components of trafficking machinery, leading to loss of mitochondrial motility and eventually to mitochondrial dysfunction.
In STHdh(Q111) knockin striatal cells, Seong et al. (2005) found that a juvenile-onset HD CAG repeat was associated with low mitochondrial ATP and decreased mitochondrial ADP-uptake. This metabolic inhibition was associated with enhanced Ca(2+)-influx through NMDA receptors, which when blocked resulted in increased cellular ATP/ADP. In 40 human lymphoblastoid cell lines bearing non-HD CAG lengths (9 to 34 units) or HD-causing alleles (35 to 70 units), there was an inverse association of ATP/ADP with the longer of the 2 allelic HD CAG repeats in both the non-HD and HD ranges. Thus, the polyglutamine tract in huntingtin appeared to regulate mitochondrial ADP-phosphorylation in a Ca(2+)-dependent process, fulfilling the genetic criteria for the HD trigger of pathogenesis. Seong et al. (2005) hypothesized that aberration in cellular energy status may contribute to the exquisite vulnerability of striatal neurons in HD.
Using striatal neuronal cell lines from wildtype mice and HD-knockin mice, Cui et al. (2006) showed that mutant huntingtin disrupted mitochondrial function by inhibiting expression of the transcriptional coactivator Pgc1a (604517). Mutant huntingtin repressed Pgc1a transcription by associating with the promoter and interfering with the Creb (123810)/Taf4 (601796)-dependent transcriptional pathway critical for regulation of Pgc1a expression. Crossbreeding of Pgc1a-knockout mice with HD-knockin mice led to increased neurodegeneration of striatal neurons and motor abnormalities in the HD mice. Expression of Pgc1a partially reversed the toxic effects of mutant huntingtin in cultured rat striatal neurons, and lentiviral-mediated delivery of Pgc1a in striatum provided neuroprotection in transgenic HD mice. Cui et al. (2006) concluded that PGC1A has a key role in controlling energy metabolism in the early stages of HD pathogenesis.
Greenamyre (2007) reviewed the hypothesis that in patients with HD, gene transcription regulated by PGC1A is defective, resulting in reduced expression of mitochondrial and antioxidant genes regulated by PGC1A. In this way, PGC1A provides a plausible link between what were previously unrelated mechanisms: transcriptional dysregulation and mitochondrial impairment. These studies underscored the role of PGC1A and neurodegeneration and raised the possibility that increasing PGC1A expression or function might be therapeutic in HD and other neurodegenerative disorders.
Sassone et al. (2015) noted that mutant HTT causes mitochondrial depolarization and fragmentation and promotes activation of proapoptotic proteins, including BNIP3 (603293), BAX (600040), and BAK (BAK1; 600516). They found that mouse embryonic fibroblasts lacking Bnip3, but not those lacking both Bax and Bak, were resistant to mitochondrial depolarization, fragmentation, and cell death induced by expression of mutant human HTT. Expression of a dominant-negative Bnip3 mutant lacking the transmembrane domain required for mitochondrial localization and function partially rescued mitochondrial pathology and cell death in a mouse striatal neuron HD model. Sassone et al. (2015) concluded that mitochondrial dysfunction induced by mutant HTT depends on BNIP3, but not BAX or BAK.
Other Disease Mechanisms
Schwarcz et al. (1988) demonstrated increased activity of quinolinate's immediate biosynthetic enzyme, 3-hydroxyanthranilate oxygenase (EC 1.13.11.6), in HD brains as compared to control brains. The increment was particularly pronounced in the striatum, which is known to exhibit the most prominent nerve-cell loss in HD. Thus, the HD brain has a disproportionately high capacity to produce the endogenous 'excitotoxin' quinolinic acid, a tryptophan metabolite.
Miller et al. (2003) stated that rat Csp binds heterotrimeric G proteins (see 139320) and promotes G protein inhibition of N-type calcium channels (see 601012). They showed that an N-terminal fragment of human huntingtin with an expanded polyglutamine tract blocked association of Csp with G proteins and eliminated Csp's tonic G protein inhibition of N-type calcium channels. In contrast, an N-terminal huntingtin fragment without an expanded polyglutamine tract did not alter association of Csp with G proteins and had no effect on channel inhibition by Csp.
Using quantitative single-cell analysis and time-lapse imaging, Trushina et al. (2003) followed the subcellular location of mutant huntingtin. At first, the mutant protein was localized to the cytoplasm. As affected cells lost neurites and began to lose their morphology and prepare for apoptosis, the mutant protein and its N-terminal fragments were localized to the nucleus. However, neither blocking of nuclear accumulation nor nuclear entry prevented cell death, suggesting that nuclear entry was not the initiating event in toxicity. Further analysis indicated that full-length mutant huntingtin bound to and disrupted microtubules in the cytoplasm; stabilization of microtubules with taxol resulted in increased cell survival. Trushina et al. (2003) postulated that cytoplasmic dysfunction involving microtubules is a primary event in neuronal toxicity in HD, resulting in the disruption of cellular processes such as vesicle trafficking, disintegration of the nucleus, and cell death.
Bezprozvanny and Hayden (2004) reviewed the role of disrupted calcium signaling in the pathogenesis of HD. Postulated mechanisms have included disrupted mitochondrial calcium homeostasis, potentiation of certain NMDA receptors which cause calcium influx, and increased sensitization of ITPR1. Calcium overload may trigger apoptosis in medium spiny striatal neurons in HD.
Intracellular amyloid-like inclusions formed by mutant proteins result from polyglutamine expansions in HD and polyalanine expansions in polyadenylate binding protein-2 (PABP2; 602279) in oculopharyngeal muscular dystrophy (OPMD; 164300). Bao et al. (2004) found further parallels between these diseases: as had been observed in HD, they demonstrated that HSP70 (601113) and HDJ1 colocalized with PABP2 aggregates in muscle tissue from patients with OPMD and overexpression of HSP70 reduced mutant PABP2 aggregate formation.
Charvin et al. (2005) demonstrated that low doses of dopamine acted synergistically with mutated huntingtin to activate the proapoptotic c-Jun (165160)/JNK (see 601158) pathway in cultured mouse striatal cells. Dopamine also increased aggregate formation of mutant huntingtin via the D2 receptor (DRD2; 126450). These effects were blocked by a selective inhibitor of the JNK pathway and a DRD2 antagonist, respectively. Charvin et al. (2005) suggested that increased autooxidation of dopamine with the resultant increase in reactive oxygen species in the striatum during aging could potentiate mutant huntingtin-induced activation of the c-Jun/JNK pathway that becomes manifest in adulthood.
Petersen et al. (2005) described a dramatic atrophy and loss of orexin (HCRT; 602358)-producing neurons in the lateral hypothalamus of R6/2 Huntington mice and in Huntington patients. Similar to animal models and patients with impaired orexin function, the R6/2 mice were narcoleptic. Both the number of orexin neurons in the lateral hypothalamus and the levels of orexin in the cerebrospinal fluid were reduced by 72% in end-stage R6/2 mice compared with wildtype littermates, suggesting that orexin could be used as a biomarker reflecting neurodegeneration.
By neuropathologic study of human brain tissue from patients with HD, Shelbourne et al. (2007) found greater somatic instability of the mutant HTT allele in neurons compared to glial cells. Striatal neurons were particularly affected. Greater somatic mutation length gains were observed from patients with more advanced stage disease. Similar findings were observed in a mouse model of HD. In mice, striatal interneurons tended to have smaller mutation length gains than pan-striatal neurons. The findings demonstrated that there are tissue- and cell-type differences in vulnerability to repeat expansion length, and that the somatic repeat expansions in brain tissue can be 2 to 3 times greater than the inherited allele. The evidence also supported the hypothesis that somatic increases of mutation length may play a role in the progressive nature of the disorder.
Jain and Vale (2017) showed that repeat expansions create templates for multivalent basepairing, which causes purified RNA to undergo a sol-gel transition in vitro at a similar critical repeat number as observed in Huntington disease (143100), spinocerebellar ataxia (e.g., 164400), myotonic dystrophy (e.g., 160900), and FTDALS1 (105550). In human cells, RNA foci form by phase separation of the repeat-containing RNA and can be dissolved by agents that disrupt RNA gelation in vitro. Jain and Vale (2017) concluded that, analogous to protein aggregation disorders, their results suggested that the sequence-specific gelation of RNAs could be a contributing factor to neurologic disease.
Prenatal Diagnosis
Harper and Sarfarazi (1985) pointed out that predictive testing can be done in prenatal diagnosis without determining the status of the at-risk parent. For example, if the affected grandparent of the fetus is deceased, the other grandparent is genotype BB, and the parent at risk is AB married to a CC individual, the fetus is unlikely to have inherited HD if it is BC, while the risk is 50% if the fetus is AC. The likelihood of the BC fetus being affected is a function of recombination. Bloch and Hayden (1987) pointed out that this 'no news' or 'good news' option has some important consequences. The 'no news' outcome increases the risk of the fetus's having inherited the gene for HD from 25% to about 50%; thus, persons given this information may need long-term support. Also, the implication of linking the status of an at-risk child to that of the at-risk parent may be more serious than realized.
Quarrell et al. (1987) suggested the usefulness of the G8 marker in exclusion testing for HD. They cited studies of 52 families from various parts of the world, indicating a maximum total lod score of 75.3 at a recombination fraction of about 5 cM. The 95% confidence intervals were 2.4 and 6.5 cM, with no evidence of multilocus heterogeneity. The marker could be applied either for presymptomatic predictive testing or for exclusion testing in pregnancy, where the estimated risk to the parent is not altered. The requirements for family structure were much less stringent in the case of exclusion testing. In South Wales they found that nearly 90% of couples have the minimum structure required for an exclusion test, whereas for a presymptomatic predictive test only 15% have the ideal 3-generation family structure and only 10% have a suitably extended 2-generation family. The distribution of G8 haplotypes presented the same difficulty whichever test was being considered; only about two-thirds of couples would be informative. If the fetus acquired the G8 haplotype of the affected grandparent, then the risk to the fetus was the same as that of the parent, i.e., 50%. If the fetus has the G8 haplotype of the unaffected grandparent, then the risk to the fetus became 2.5%. If termination of pregnancy was unacceptable despite an adverse result of the test and HD subsequently developed in the parent in generation 2, it would be immediately known that HD would also be likely to arise in the offspring since their risks are the same (apart from the possibility of recombination). To prevent this complication, Quarrell et al. (1987) told couples that if termination of pregnancy was unacceptable for whatever reason, then an exclusion test would be inappropriate.
Millan et al. (1989) pointed out the importance of not acquiring more information than necessary to exclude or include the diagnosis of HD in a fetus. In a family they studied, the probability of the fetus being affected, approaching 50%, could be deduced from the genotype of the fetus, the 2 parents, and the unaffected paternal grandfather of the conceptus. Genotyping of the unaffected maternal grandmother of the father refined downward somewhat (from 47 to 42%) the risk of HD in the conceptus; however, it ran the risk of making the diagnosis of HD in the father and the information was really unnecessary for genetic counseling. Information about the prenatal exclusion test for HD was given to an unselected series of couples who attended a genetic counseling clinic in Glasgow from 1986 onwards. Ten couples underwent 13 prenatal tests during this period with expressed intention of stopping a pregnancy if the results indicated a high risk (almost 50%) that the fetus carried the HD gene. Although 9 fetuses at nearly 50% risk of carrying the HD gene were identified, only 6 such pregnancies were terminated. In each of the 3 high-risk pregnancies that continued, the mother made a 'final hour' decision not to undergo the scheduled, first-trimester termination.
Bloch and Hayden (1990) opposed the testing of children at risk for Huntington disease and questioned the usefulness of DNA tests to support a diagnosis of HD in either adulthood or childhood. They opposed testing in adoption cases because of the negative effects on the child's upbringing and education as well as the necessity to adhere to the principle of autonomy on the part of the individual tested. Prenatal testing was undertaken in their practice only if the parents were prepared to make a decision about continuing the pregnancy on the basis of the outcome of the prenatal testing. The parents were given to understand that prenatal testing is similar to testing a minor child. In the program of Bloch and Hayden (1990), 8 exclusion prenatal tests had been performed, with 5 resulting in an increased risk for the fetus. In 4 of these, the parents decided to terminate the pregnancy.
In the experience of Tolmie et al. (1995), late reversal of a previous decision to undergo first-trimester pregnancy termination for a genetic indication was frequent among couples who had undergone the prenatal exclusion test for HD.
Testing in Adults
Early results of predictive testing using D4S10 RFLPs were reported by Meissen et al. (1988). MacDonald et al. (1989) characterized genetically 5 highly informative multiallele RFLPs of value in the presymptomatic diagnosis of HD. Morris et al. (1989) and Craufurd et al. (1989) outlined problems associated with programs for presymptomatic predictive testing for HD.
Positron-emission tomography (PET scanning) demonstrating loss of uptake of glucose in the caudate nuclei may be a valuable indication of affection in the presymptomatic period (Hayden et al., 1986). Hypometabolism of glucose precedes tissue loss and caudate nucleus atrophy. Mazziotta et al. (1987) used PET studies of cerebral glucose metabolism in 58 clinically asymptomatic persons at risk for HD, 10 symptomatic patients with HD, and 27 controls. They found that 31% of the persons at risk showed metabolic abnormalities of the caudate nuclei, qualitatively identical to those in the patients. Taking into account the age of each at-risk subject and the sex of the affected parent, they averaged individual risk estimates of the members of the asymptomatic group and estimated the probability of having the clinically unexpressed HD gene at 33.9% for the group--a remarkably good agreement with the percentage of metabolic abnormalities found.
Wiggins et al. (1992) reported on the psychologic consequences of predictive testing for HD on the basis of observations in 135 participants in the Canadian program of genetic testing. The participants were in 3 groups according to their test results: the increased-risk group (37 persons); the decreased-risk group (58 persons); and the group with no change in risk (40 persons). They showed that predictive testing had benefits for the psychologic health of persons who received results that indicated either an increase or a decrease in the risk of inheriting the gene. In an accompanying editorial, Catherine V. Hayes (1992), president of the Huntington's Disease Society of America, described what it meant to grow up as an 'at-risk' person and to have genetic testing.
Read (1993) commented that the problems arising in connection with HD testing resembled those of HIV testing. The 10 years during which testing for HD required family studies have given clinical geneticists an opportunity to work out proper procedures. A great deal of effort has gone into ensuring that presymptomatic testing is always voluntary and is undertaken only after due consideration by fully informed patients. Testing of children has been firmly discouraged. It is vital that these practices should be continued.
Kremer et al. (1994) reported a worldwide study assessing the sensitivity and specificity of the CAG expansion as a diagnostic test. The study covered 565 families from 43 national and ethnic groups containing 1,007 patients with signs and symptoms compatible with the diagnosis of HD. Of these, 995 had an expanded CAG repeat that included from 36 to 121 repeats; sensitivity = 98.8%, with 95% confidence limits = 97.7-99.4. Included among those contributing to the sensitivity estimate were 12 patients with previously diagnosed HD in whom the number of CAG repeats was in the normal range. Reevaluation of these established that 11 had clinical features atypical of HD. In 1,581 of 1,595 control chromosomes (99.1%), the number of CAG repeats ranged from 10 to 29. The remaining 14 control chromosomes had 30 or more repeats, with 2 of these chromosomes having expansions of 37 and 39 repeats. An estimate of specificity was made from 113 subjects with other neuropsychiatric disorders with which HD is frequently confused. The number of repeats found in these disorders was similar to the number found on normal human chromosomes and showed no overlap with HD; specificity = 100%, with 95% CI = 95.5-100. The study confirmed that CAG expansion is the molecular basis of HD worldwide.
Decruyenaere et al. (1996) examined the psychologic effects of HD predictive testing on 53 patients after 1 year. The authors found that the test result had a definite impact on reproductive decision making and that the single best predictor of the patient's post-test ego strength was the patient's pre-test ego strength. They concluded that persons who opt for HD testing are themselves a self-selected group with good ego strength and positive coping strategies.
Gellera et al. (1996) reported that ideally a series of 3 PCR reactions should be performed to rule out Huntington disease. They reviewed the evidence that the huntingtin gene contains an unstable polyglutamine-encoding (CAG)n repeat which is located in the N-terminal portion of the protein beginning 18 codons downstream of the first ATG codon (613004.0001). The unstable (CAG)n repeat lies immediately upstream from a moderately polymorphic polyproline encoding (CCG)n repeat. Gellera et al. (1996) noted further that a number of reports in the literature indicated that in normal subjects the number of (CAG)n polyglutamine repeats ranges from 10 to 36, while in HD patients it ranges from 37 to 100. The (CCG)n polyproline repeat may vary in size between 7 and 12 repeats in both affected and normal individuals. They reported the occurrence of a CAA trinucleotide deletion (nucleotides 433-435) in HD chromosomes in 2 families that, because of its position within the conventional antisense primer hd447, hampered HD mutation detection if only the (CAG)n tract were amplified. Therefore, Gellera et al. (1996) stressed the importance of using a series of 3 diagnostic PCR reactions: one that amplified the (CAG)n tract alone, one that amplified the (CCG)n tract alone, and one that amplified the whole region.
The first predictive testing for HD was based on analysis of linked polymorphic DNA markers. Limitations to accuracy included recombination between the markers and the mutation, pedigree structure, and availability of DNA samples from family members. With availability of direct tests for the HD mutation, Almqvist et al. (1997) assessed the accuracy of results obtained by linkage approaches when requested to do so by the test individuals. For 6 such individuals, there was significant disparity between the tests: 3 went from a decreased risk to an increased risk, while in another 3 the risk was decreased.
Harper et al. (2000) reviewed data on presymptomatic testing over a 10-year period in the U.K. A total of 2,937 tests had been performed, 2,502 based on specific mutation testing: 93.1% of these individuals were at 50% prior risk, with 58.3% of them female; 41.4% were abnormal or high risk, including 29.4% in subjects aged 60 or over. Almost all of the tests were performed in National Health Service genetic centers, with a defined genetic counseling protocol.
Lindblad (2001) discussed some of the ethical issues that arise when an adult child at 25% risk for HD wishes to have the test, but the parent(s) at 50% risk refuses to have one. If the child tests positive, the genetic status of the parent will also be disclosed. No matter what course of action is chosen in this situation, the ethically legitimate interests of either child or parent might be violated (the same dilemma arises in connection with prenatal testing). Lindblad (2001) concluded that in this situation one should start with an exclusion test by the linkage principle. In this way, she believed, less harm would be caused than by direct mutation analysis.
By analysis of diffusion tensor MRI data from 25 presymptomatic HD gene carriers using a multivariate support vector machine, Kloppel et al. (2008) identified a pattern of structural brain changes in the putamen and anterior parts of the corpus callosum that differed significantly from controls. The pattern enabled correct classification of 82% of scans as that of either mutation carrier or control. In addition, probabilistic fiber tracking detected changes in connections between the frontal cortex and the caudate, a large proportion of which play a role in the control of voluntary saccades. Voluntary saccades are specifically impaired in presymptomatic mutation carriers and are an early clinical sign of motor abnormalities. In 14 carriers, there was a correlation between impairment of voluntary saccades and fewer fiber tracking streamlines connecting the frontal cortex and caudate body, suggesting selective vulnerability of these white matter tracts.
Kloppel et al. (2009) used T1-weighted MRI scans to evaluate whole brain structural changes in 96 presymptomatic mutation carriers in whom the estimated time to clinical manifestation was based on age and CAG repeat length. Individuals with at least a 33% chance of developing signs of HD in 5 years were correctly assigned to the mutation carrier group 69% of the time. This accuracy was below that reported by Kloppel et al. (2008) using diffusion-weighted analysis. However, accuracy in the study of Kloppel et al. (2009) improved to 83% when regions affected by the disease (i.e., the caudate head) were selected a priori for analysis. The results were no better than chance when the probability of developing symptoms in 5 years was less than 10%. Kloppel et al. (2009) noted that T1-weighted MRI scans are more readily available than diffusion-weighted imaging as used in the study by Kloppel et al. (2008).
Differential Diagnosis
Warner et al. (1994) searched for possible missed cases of Huntington disease in a set of 368 patients with psychiatric disorders, including schizophrenia, presenile dementia, and senile dementia. One schizophrenic patient, who died at age 88, had a CAG repeat size of 36; a 68-year-old patient, who died of presenile dementia of Alzheimer disease type, had a CAG repeat size of 34. Neither patient had neuropathologic or clinical evidence of Huntington disease.
Peyser et al. (1995) found no beneficial effect in treatment with d-alpha-tocopherol in a cohort of 73 patients with Huntington disease. However, postoperative analysis suggested possible beneficial effect on neurologic symptoms for patients early in the course of the disease.
Neural and stem cell transplantation is a potential treatment for neurodegenerative diseases, e.g., transplantation of specific committed neuroblasts (fetal neurons) to the adult brain. Encouraged by animal studies, a clinical trial of human fetal striatal tissue transplantation for the treatment of Huntington disease was initially undertaken at the University of South Florida. In this series, 1 patient died 18 months after transplantation from causes unrelated to surgery. Freeman et al. (2000) reported postmortem findings indicating that grafts derived from human fetal striatal tissue can survive, develop, and remain unaffected by the underlying disease process, at least for 18 months, after transplantation into a patient with Huntington disease. Selective markers of both striatal projection and interneurons showed transplant regions clearly innervated by host tyrosine hydroxylase fibers. There was no histologic evidence of immune rejection including microglia and macrophages. Notably, neuronal protein aggregates of mutated huntingtin, which is typical of HD neuropathology, were not found within the transplanted fetal tissue.
Friedlander (2003) discussed apoptosis and caspases in neurodegenerative diseases. The fact that activation of mechanisms mediating cell death may be involved in neurologic diseases makes these pathways attractive therapeutic targets. They noted that clinical trials of an inhibitor of apoptosis (minocycline) for neurodegenerative disorders (Huntington disease and ALS) were in progress (Fink et al., 1999; Chen et al., 2000).
A variety of growth factors had been shown to induce cell proliferation and neurogenesis. It was suggested by Curtis et al. (2003) that, if the potential for endogenous neural replacement can be augmented pharmacologically with the use of exogenous growth factors or pharmaceuticals that increase the rate of neural progenitor formation, neural migration, and neural maturation, then the rate of cell loss may be slowed, and clinical improvements observed.
Ravikumar et al. (2003) showed that the protective effect of GLUT1 overexpression is associated with decreased huntingtin exon 1 aggregation in cell models. Reduced aggregation and enhanced clearance of mutant huntingtin was observed when cells were cultured in raised glucose concentrations (8 g/l). These effects were mimicked by 8 g/l 2-deoxyglucose (2DOG), but not with 8 g/l 3-O-methyl glucose, suggesting that the biochemical mediator may be glucose-6-phosphate. Increased clearance of mutant huntingtin by raised glucose (8 g/l) and 2DOG correlated with increased autophagy and reduced phosphorylation of MTOR (FRAP1; 601231), S6K1 (608938), and AKT. Ravikumar et al. (2003) concluded that raised intracellular glucose/glucose-6-phosphate levels reduced mutant huntingtin toxicity by increasing autophagy via mTOR and possibly AKT.
Both animal and human studies suggest that transplantation of embryonic neurons or stem cells offers a potential treatment strategy for neurodegenerative disorders such as Parkinson disease (168600), Huntington disease, and Alzheimer disease. Curtis et al. (2003) investigated whether neurogenesis occurs in the subependymal layer adjacent to the caudate nucleus in the adult human brain in response to neurodegeneration of the caudate nucleus in HD. Postmortem control and HD human brain tissue were examined by using the cell cycle marker proliferating cell nuclear antigen (PCNA; 176740), the neuronal marker beta-III-tubulin, and the glial cell marker glial fibrillary acidic protein (GFAP; 137780). They observed a significant increase in cell proliferation in the subependymal layer and HD compared with control brains. Within the HD group, the degree of cell proliferation increased with pathologic severity and increasing CAG repeats in the HD gene. Most importantly, PCNA+ cells were shown to coexpress beta-III-tubulin or GFAP, demonstrating the generation of neurons and glial cells in the subependymal layer of the diseased human brain. The results provided evidence of increased progenitor cell proliferation and neurogenesis in the diseased adult human brain and further indicated the regenerative potential of the human brain.
Ravikumar et al. (2004) presented data that provided proof of principle for the potential of inducing autophagy to treat HD. They showed that mammalian target of rapamycin (MTOR; 601231) is sequestered in polyglutamine aggregates in cell models, transgenic mice, and human brains. Such sequestration impairs the kinase activity of mTOR and induces autophagy, a key clearance pathway for mutant huntingtin fragments. This protects against polyglutamine toxicity.
Cheng et al. (2013) reported the beneficial effects of miR196a (608632) on HD in cell, transgenic mouse models, and human induced pluripotent stem cells derived from 1 individual with HD (HD-iPSCs). In the in vitro results, a reduction of mutant HTT (613004) and pathologic aggregates, accompanying the overexpression of miR196a, was observed in HD models of human embryonic kidney cells and mouse neuroblastoma cells. In the in vivo model, HD transgenic mice overexpressing miR196a revealed the suppression of mutant HTT in the brain and also showed improvements in neuropathologic progression, such as decreases of nuclear, intranuclear, and neuropil aggregates and late-stage behavioral phenotypes. Most importantly, miR196a also decreased HTT expression and pathologic aggregates when HD-iPSCs were differentiated into the neuronal stage. Cheng et al. (2013) postulated that mechanisms of miR196a in HD might be through the alteration of ubiquitin-proteasome systems, gliosis, CREB protein pathways, and several neuronal regulatory pathways in vivo.
Tabrizi et al. (2019) reported the results of a randomized, double-blind, multiple-ascending-dose phase 1-2a trial of an antisense oligonucleotide designed to inhibit HTT mRNA, in 46 adults with early Huntington disease. Patients were randomized in a 3:1 ratio for intrathecal injections every 4 weeks for 4 doses. There were no serious adverse events, and a dose-dependent reduction in mutant huntingtin was observed in the CSF.
Li et al. (2019) hypothesized that compounds that interact with both the autophagosome protein microtubule-associated protein 1A/1B light chain-3 (LC3) (MAP1LC3A; 601242) and the disease-causing mutant huntingtin protein (mHTT) may target the latter for autophagic clearance. Li et al. (2019) used small molecule microarray-based screening to identify 4 compounds that interact with both LC3 and mHTT, but not with the wildtype HTT protein. Some of these compounds targeted mHTT to autophagosomes, reduced mHTT levels in an allele-selective manner, and rescued disease-relevant phenotypes in cells and in vivo in fly and mouse models of Huntington disease. Li et al. (2019) further showed that these compounds interact with the expanded polyglutamine stretch of mHTT and could also lower the level of mutant ataxin-3 (ATXN3; 607047), another disease-causing protein with an expanded polyglutamine tract. Li et al. (2019) concluded that their study presented candidate compounds for lowering mHTT and potentially other disease-causing proteins with polyglutamine expansions, demonstrating the concept of lowering levels of disease-causing proteins using autophagosome-tethering compounds.
Huntington disease has a frequency of 4 to 7 per 100,000 persons. Reed and Chandler (1958) estimated the frequency of recognized Huntington chorea in the Michigan lower peninsula to be about 4.12 x 10(-5) and the total frequency of heterozygotes to be about 1.01 x 10(-4). Wright et al. (1981) estimated the minimal prevalence of HD in blacks in South Carolina to be 0.97 per 100,000 persons--about one-fifth the prevalence for whites in that state. Clinical features seemed identical. Even lower prevalence has been observed in blacks in Africa. The higher prevalence in South Carolina blacks may be because of white admixture and longer life expectancy in South Carolina blacks than in African blacks. Walker et al. (1981) estimated a prevalence of 7.61 per 100,000 in South Wales. Heterozygote frequency was estimated as about 1 in 5,000. Simpson and Johnston (1989) found an unusually high prevalence of Huntington disease in the Grampian region of Scotland; they arrived at an incidence of 9.94 per 100,000. There were 46 individuals ascertained from 98 pedigrees.
New mutations are probably rare. Bundey (1983) concluded 'that it is incorrect to say that new mutations for Huntington's chorea occur in less than 0.1% of sufferers. I believe the evidence shows that the true figure is nearer 10%. I therefore consider that the absence of a known affected relative should not deter a neurologist from diagnosing Huntington's chorea in a patient who shows the characteristic clinical features of the disease.' She based her conclusion particularly on estimates of fitness and the Haldane formula for estimating proportion of new mutation cases. However, Mastromauro et al. (1989) could find no evidence of difference in fitness of HD-affected persons from their unaffected sibs or from the general population of Massachusetts.
Palo et al. (1987) estimated the frequency of HD in Finland to be 5 cases per million as contrasted with frequencies of 30 to 70 per million in most Western countries. The lowest frequencies have been found in South African blacks (0.6), in Japan (3.8), and in North American blacks (15). The findings in Finland are consistent with almost all cases having originated from a single source and illustrate founder effect, which is shown by so many other diseases in that country. For example, PKU (261600) has been found in only 5 cases over all time, whereas aspartylglycosaminuria (208400) has been identified in almost 200 living cases in a population of 4.9 million. The part of Finland that is an exception to the above statement is the Aland archipelago where the frequency of HD is high, but this is an exception that proves the rule: the islands have been exposed to other populations (including the British) for centuries.
Quarrell et al. (1988) presented data suggesting that there has been a steady decline in births at risk for HD in both North Wales and South Wales in the period between 1973 and 1987. Lanska et al. (1988) determined an overall mortality rate for HD in the U.S. of 2.27 per million population per year. Age-specific mortality rates peaked around age 60. Lanska et al. (1988) suggested from their experience that the risk of suicide may have been overstated.
Stine and Smith (1990) studied the effects of mutation, migration, random drift, and selection on the changes in the frequency of genes associated with HD, porphyria variegata (176200), and lipoid proteinosis (247100) in the Afrikaner population of South Africa. By limiting analyses to pedigrees descendant from founding families, it was possible to exclude migration and new mutation as major sources of change. Calculations which overestimated the possible effect of random drift demonstrated that drift did not account for the changes. Therefore, these changes must have been caused by natural selection, and a coefficient of selection was estimated for each trait. A value of 0.34 was obtained for the coefficient of selection demonstrated by the HD gene, indicating a selective disadvantage rather than advantage suggested by some other studies.
In Finland, Ikonen et al. (1992) reported further studies by RFLP haplotype analysis in combination with genealogic study of all the Finnish HD families. They found that a high percentage (28%) of the families had foreign ancestors. Furthermore, most of the Finnish ancestors were localized to border regions or trade centers of the country, following the old postal routes. The observed high-risk haplotypes formed with markers from the D4S10 and D4S43 loci were evenly distributed among the HD families in different geographic locations. Ikonen et al. (1992) concluded that the HD gene(s) probably arrived in Finland on several occasions via foreign immigrants.
On the basis of a review of the epidemiology of Huntington disease, Harper (1992) predicted that molecular studies in the future would show that more than 1 mutation has occurred at the HD locus. A very small number of mutations, possibly a single common one, will be found to account for most HD cases in populations of European origin. Any predominant mutation will probably have an extremely ancient origin, possibly dating back millennia. No single focus in northern Europe will be found as the point of origin of such a principal mutation. Phenotype will correlate poorly with specific mutations.
Leung et al. (1992) stated that the prevalence of HD in Hong Kong Chinese for the period 1984-1991 was 3.7 per million. They traced the ancestral origin of the patients mainly to the coastal provinces and proposed that Chinese HD had a European origin. They found a male preponderance: 63 males to 26 females. They made no comment on the provinces of origin of the Hong Kong Chinese population generally.
Almqvist et al. (1994) constructed haplotypes for 23 different HD families, 10% of the 233 known HD families in the Swedish Huntington disease register. Ten different haplotypes were observed. Analysis of 2 polymorphic markers within the HD gene indicated that there are at least 3 origins of the HD mutation in Sweden. One of the haplotypes accounted for 89% of the families, suggesting descent from a single ancestor.
Rubinsztein et al. (1994) investigated the evolution of HD by typing CAG alleles from 5 different human populations and 10 different species of primates. Using computer simulations, they found that human alleles have expanded from a shorter primate ancestor and exhibit unusual asymmetric length distributions. Suggesting that the key element in HD evolution is a simple length-dependent mutational bias toward longer alleles, they predicted that, in the absence of interference, expansion of trinucleotide repeats will continue and accelerate, leading to an ever-increasing incidence of HD. Masuda et al. (1995) demonstrated that the size of the CAG repeat in Japanese HD patients ranges from 37 to 95 repeats, as compared with a range from 7 to 29 in normal controls. Whereas HD chromosomes in the west are strongly associated with the (CCG)7 repeat, immediately 3-prime adjacent to the CAG repeat, Japanese HD chromosomes were found to be in strong linkage disequilibrium with the (CCG)10 repeat. The frequency of HD in Japan is less than one-tenth of the prevalence in western countries. It had been suggested that the low frequency reflected western European origin with spread to Japan by immigration. The haplotype findings concerning the association of the CAG repeat and the CCG repeat suggest a separate origin with founder effect in the Japanese cases.
Morrison et al. (1995) achieved virtually complete ascertainment of HD in Northern Ireland which, with a population of 1.5 million, showed a 1991 prevalence rate of 6.4/100,000. Estimates of heterozygote frequency gave values between 10 and 11 x 10(-5). The direct and indirect mutation rates were 0.32 x 10(-6) and 1.05 x 10(-6), respectively. Genetic fitness was increased in the affected HD population but decreased in the at-risk population. Fertility in HD was not reduced, but it appeared that at-risk persons had actively limited their family size. Factors responsible for this included, among others, the fear of developing HD and genetic counseling of families.
Scrimgeour et al. (1995) described a case of apparently typical HD in a 40-year-old Sudanese man from Khartoum, in whom the HD gene showed 51 CAG repeats. It was suspected that his mother and his deceased 16-year-old son were also affected.
Silber et al. (1998) described Huntington disease with proven expansions of the HD gene in 5 black South African families of different ethnic origins.
Falush et al. (2001) described a new approach for analysis of the epidemiology of progressive genetic disorders that quantifies the rate of progression of the disease in the population by measuring mutational flow. They applied the method to HD. The disease is 100% penetrant in individuals with 42 or more repeats of the CAG trinucleotide sequence. Measurement of the flow from disease alleles provided a minimum estimate of the flow in the whole population and implied that the new mutation rate for HD in each generation is 10% or more of currently known cases (95% confidence limits 6-14%). Analysis of the pattern of flow demonstrated systematic underascertainment for repeat lengths less than 44. Ascertainment fell to less than 50% for individuals with 40 repeats and to less than 5% for individuals with 36 to 38 repeats. Falush et al. (2001) stated that clinicians should not assume that HD is rare outside of known pedigrees or that most cases have onset at less than 50 years of age.
In a study of Huntington disease in British Columbia based on referrals for testing the CAG expansion, Almqvist et al. (2001) found that of the 141 subjects with a CAG expansion of at least 36, almost one-quarter did not have a family history of HD. An extensive chart review revealed that 11 patients had reliable information on both parents (who lived well into old age) and therefore could possibly represent new mutations for HD. This indicated a new mutation rate 3 to 4 times higher than previously reported. The findings also showed that the yearly incidence rate for HD was 6.9 per million, which was 2 times higher than previous incidence studies performed before identification of the HD mutation. They identified 5 persons with a clinical presentation of HD but without CAG expansion, i.e., genocopies.
Garcia-Planells et al. (2005) analyzed the genetic history of the HD mutation in 115 HD patients from 83 families from the Valencia region of eastern Spain. They identified a haplotype H1 (based on allele A of marker rs1313770, allele 7 of the CCG triplet, and allele A of marker rs82334) that was found in 47 of 48 phase-known mutant chromosomes and in 120 of 166 chromosomes constructed using the PHASE program. By constructing extended haplotypes, Garcia-Planells et al. (2005) determined that the H1-associated CAG expansion originated between 4,700 and 10,000 years ago. They also observed a nonhomogeneous distribution in different geographic regions associated with the different extended haplotypes of the ancestral haplotype H1, suggesting that local founder effects had occurred.
In a population-based study of 1,772 chromosomes covering all regions of Portugal, Costa et al. (2006) found that the most frequent HTT allele was 17 CAG repeats (37.9%), intermediate class 2 alleles (27 to 35 repeats) represented 3.0% of the population, and there were 2 expanded alleles (36 and 40 repeats, 0.11%). There was no evidence for geographic clustering. Among 140 Portuguese HD families, there were 3 different founder haplotypes associated with 7-, 9-, or 10-CCG repeats, suggesting different origins for the HD mutation. The haplotype carrying the 7-CCG repeat was the most frequent.
Warby et al. (2009) identified a haplogroup, haplogroup A, comprising 22 SNPs in the HTT region on chromosome 4p that was significantly associated with HD disease chromosomes (greater than 35 CAG repeats) among 65 European HD patients but not in controls. The data were confirmed in a replication cohort of 203 HD patients. The same SNPs were significantly associated with the disease chromosome, but some were not, arguing against a founder effect. In addition, chromosomes with increased CAG repeats of 27 to 35 were also associated with haplogroup A. Chromosomes with a haplotype subgroup, haplogroup A1 comprising 10 SNPs, were 6.5 times more likely to carry a CAG expansion. The specific haplogroup A variants at risk for CAG expansion were not present in the general population in China, Japan, and Nigeria, where the prevalence of HD is much lower than in Europe. The data supported a stepwise model for CAG expansion and suggested that CAG expansions occur on haplotypes that are predisposed for CAG instability, likely resulting from cis-acting elements. Warby et al. (2009) noted that the strong association between specific SNP alleles and CAG expansion may provide an opportunity for personalized therapeutics by using allele-specific gene silencing.
In a response to the report by Warby et al. (2009), Falush (2009) presented evolutionary modeling of the HD CAG repeat length distribution within populations and argued that the distribution of CAG repeat length and disease incidence in different haplotypes can be explained by founder events. Each haplotype examined involved expansion of repeats to lengths that are classified as normal by HD investigators (less than 28 repeats). The results were based on the assumptions that the HD CAG repeat is upwardly based (increases in length are more common than decreases) and length-dependent (longer repeats mutate more frequently than short ones), and that there is natural selection against longer disease alleles. Falush (2009) argued against a cis element having a role in the evolution of HD chromosomes. In a reply, Warby et al. (2009) found fault with some aspects of the modeling presented by Falush (2009), and asserted that cis elements do play a role in the instability of CAG repeats at the HD locus.
In 1872, George Huntington of Pomeroy, Ohio, wrote about a hereditary form of chorea 'which exists, so far as I know, almost exclusively on the east end of Long Island.' Osler (1893) wrote about this disorder as follows: 'Twenty years have passed since Huntingdon (sic), in a postscript to an every-day sort of article on chorea minor, sketched most graphically, in 3 or 4 paragraphs, the characters of a chronic and hereditary form which he, his father and grandfather had observed in Long Island.' As with many other conditions, Osler's writings about them brought the disorder to general attention. In a footnote, he stated: 'Several years ago I made an attempt to get information about the original family which the Huntingdons (sic) described, but their physician stated that, owing to extreme sensitiveness on the subject, the patients could not be seen.' Vessie (1932) traced the ancestry of the families studied by Huntington (1872). About 1,000 cases in 12 generations descendant from 2 brothers in Suffolk, England, could be identified. Uncertainty concerning the usual interpretation (Critchley, 1973; Maltsberger, 1961; Vessie, 1932) of the precise origin of the Huntington gene in England was voiced by Caro and Haines (1975).
Durbach and Hayden (1993) published a personal account of George Huntington based on unpublished sources and communications from several of his descendants. Their account provides insight into his role as a general practitioner, literally a 'horse-and-buggy doctor' as demonstrated by one of the figures, as well as indicating his avocations of sketching, hunting, and fishing.
Van der Weiden (1989) gave a biographical account of George Huntington (1850-1916) and of the American anatomist George Sumner Huntington (1861-1927), and pointed out that biographical data on the 2 have been confused repeatedly.
Huntington disease represents a classic ethical dilemma created by the human genome project, i.e., that of the widened gap between what we know how to diagnose and what we know how to do anything about. Wexler (1992) referred to the dilemma as the Tiresias complex. The blind seer Tiresias confronted Oedipus with the dilemma: 'It is but sorrow to be wise when wisdom profits not' (from Oedipus the King by Sophocles). Wexler (1992) stated the questions as follows: 'Do you want to know how and when you are going to die, especially if you have no power to change the outcome? Should such knowledge be made freely available? How does a person choose to learn this momentous information? How does one cope with the answer?'
According to the tabulation of Parrish and Nelson (1993), HD was the 21st genetic disorder of previously unknown basic biochemical defect in which the gene was isolated by positional cloning. They reviewed the methods for finding genes and tabulated the methods used in each of the 21 disorders.
Goldberg et al. (1996) produced transgenic mice containing the full-length human HD cDNA with 44 CAG repeats. By 1 year, these mice had no behavioral abnormalities; morphometric analysis at 6 months in 1 animal and at 9 months in 2 animals revealed no changes. Despite high levels of mRNA expression, there was no evidence of the HD gene product in any of these transgenic mice. In vitro transfection studies indicated that the inclusion of 120 bp of the 5-prime untranslated region into the cDNA construct and the presence of a frameshift mutation at nucleotide 2349 prevented expression of the HD cDNA. Goldberg et al. (1996) concluded that the pathogenesis of HD is not mediated through DNA-protein interaction and that presence of the RNA transcript with an expanded CAG repeat is insufficient to cause the disease. Rather, translation of the CAG is crucial for the pathogenesis of HD. In contrast to the situation in humans, the CAG repeat in these mice was remarkably stable in 97 meioses. This suggested that other genomic sequences may play a critical role in influencing repeat instability.
Mangiarini et al. (1996) generated mice transgenic for the 5-prime end of the human HD gene, including promoter sequences and exon 1 carrying (CAG)n expansions of approximately 130 residues. In 3 mouse lines, the transgene was ubiquitously expressed at both the mRNA and protein levels. Transgenic mice exhibited a progressive neurologic phenotype with many of the features of HD, including choreiform movements, involuntary stereotypic movements, tremor, and epileptic seizures, as well as nonmovement disorder components.
Mangiarini et al. (1997) examined the behavior of the CAG repeat in mice transgenic for the HD mutation. They noted that the trinucleotide repeat is unstable during transmission and somatogenesis. Similar studies of intergenerational and somatic cell instability were found with the myotonic dystrophy (DM1; 160900) CTG repeat in transgenic mice. In studies of both of these repeats, the mutability of the repeats was high, although the instability (in terms of repeat length increases) was modest, showing fluctuations of only a few repeats. The somatic instability of the repeats increased with the age of the mice and appeared to occur in different tissues (perhaps correlating with the level of expression of the transgene in particular tissues or cells). Both expansions and deletions were seen in transgenic repeats, with a tendency toward expansion upon male transmission and contraction upon female transmission.
Davies et al. (1997) observed that mice transgenic for exon 1 of the human HD gene carrying (CAG)115 to (CAG)156 repeat expansions developed pronounced neuronal intranuclear inclusions, containing the proteins huntingtin and ubiquitin, before developing a neurologic phenotype. The appearance in transgenic mice of these inclusions, followed by characteristic morphologic changes within neuronal nuclei, was strikingly similar to nuclear abnormalities observed in biopsy material from HD patients. Related observations were made by Scherzinger et al. (1997), who used exon 1 of the HD gene with expanded CAG repeats for the production of glutathione S-transferase (GST)-HD fusion proteins in E. coli. The recombinant proteins were purified by affinity chromatography. Site-specific proteolysis of the GST-HD51 fusion protein with a polyglutamine expansion in the pathologic range (51 glutamines) resulted in the formation of high molecular weight protein aggregates with a fibrillar or ribbon-like morphology. The filaments, which were not produced by proteolysis of shorter fusion proteins (20 or 30 glutamines), were similar to scrapie prions and beta-amyloid-like fibrils in Alzheimer disease, and also resembled those detected by electron microscopy in the neuronal intranuclear inclusions of mice transgenic for the HD mutation.
Ordway et al. (1997) introduced a 146-unit CAG repeat into the mouse hypoxanthine phosphoribosyltransferase gene (Hprt; 308000). Mutant mice expressed a form of the Hprt protein that contains a long polyglutamine repeat. These mice developed a phenotype similar to the human translated CAG repeat disorders. Repeat-containing mice showed a late-onset neurologic phenotype that progressed to premature death and neuronal intranuclear inclusions. The authors concluded that CAG repeats do not need to be located within one of the classic repeat disorder genes to have a neurotoxic effect.
Bates et al. (1997) reviewed transgenic models of Huntington disease.
Although the HD mRNA and protein product show widespread distribution, the progressive neurodegeneration is selective in location, with regional neuron loss and gliosis in striatum, cerebral cortex, thalamus, subthalamus, and hippocampus. Reddy et al. (1998) created an experimental animal model in transgenic mice that showed widespread expression of full-length human HD cDNA with either 16, 48, or 89 CAG repeats. Only mice with 48 or 89 CAG repeats manifested progressive behavioral and motor dysfunction with neuron loss and gliosis in striatum, cerebral cortex, thalamus, and hippocampus.
Sathasivam et al. (1999) extended their observations of polyglutamine inclusions in specific brain regions prior to the onset of a clinical phenotype and searched for polyglutamine inclusions in nonneuronal tissues. In transgenic mice, inclusions were identified outside the CNS in a variety of postmitotic cells. This was consistent with a concentration-dependent nucleation and aggregation model of inclusion formation, indicating that brain-specific factors are not necessary for this process. A detailed analysis of the timing and progression of inclusion formation in skeletal muscle showed that the formation of inclusions in non-CNS tissues could be useful with respect to in vivo monitoring of pharmaceutical agents selected for their ability to prevent polyglutamine aggregation in vitro, without the requirement that the agent can cross the blood-brain barrier in the first instance.
Schilling et al. (1999) generated transgenic mice that expressed a cDNA encoding an N-terminal fragment (171 amino acids) of huntingtin with 82, 44, or 18 glutamines. Mice expressing relatively low steady-state levels of N171 huntingtin with 82 glutamine repeats (N171-82Q) developed behavioral abnormalities, including loss of coordination, tremors, hypokinesis, and abnormal gait, before dying prematurely. In mice exhibiting these abnormalities, diffuse nuclear labeling, intranuclear inclusions, and neuritic aggregates, all immunoreactive with an antibody to the N-terminus (17 amino acids) of huntingtin, were found in multiple populations of neurons. None of these behavioral or pathologic phenotypes were seen in mice expressing N171-18Q. The authors considered these findings to be consistent with the idea that N-terminal fragments of huntingtin with a repeat expansion are toxic to neurons, and that N-terminal fragments are prone to form both intranuclear inclusions and neuritic aggregates.
Shelbourne et al. (1999) introduced an HD-like mutation (an extended stretch of 72-80 CAG repeats) into the endogenous mouse Hdh gene. Analysis of the mutation in vivo showed significant levels of germline instability, with expansions, contractions, and sex-of-origin effects in evidence. Mice expressing full-length mutant protein displayed abnormal social behavior in the absence of acute neurodegeneration. Given that psychiatric changes, including irritability and aggression, are common findings in HD patients, the findings were considered consistent with the hypothesis that some clinical features of HD may be caused by pathologic processes that precede gross neuronal cell death. This implies that effective treatment of HD may require an understanding and amelioration of these dysfunctional processes, rather than simply preventing the premature death of neurons in the brain.
The mechanism through which the widely expressed mutant HD gene mediates a slowly progressing striatal neurotoxicity is unknown. Glutamate receptor-mediated excitotoxicity has been hypothesized to contribute to HD pathogenesis. Hansson et al. (1999) showed that transgenic HD mice expressing exon 1 of the human HD gene with an expanded number of CAG repeats were strongly protected from acute striatal excitotoxic lesions. Intrastriatal infusions of quinolinic acid, the agonist of the N-methyl-D-aspartate (NMDA) receptor, caused massive striatal neuronal death in wildtype mice, but no damage in transgenic HD littermates. The remarkable neuroprotection in transgenic HD mice occurred at the stage when they had not developed any neurologic symptoms caused by the mutant HD gene. At this stage, there was no change in the number of striatal neurons and astrocytes in untreated transgenic mice, although the striatal volume was decreased by 17%. Hansson et al. (1999) proposed that the presence of exon 1 of the mutant HD gene induces profound changes in striatal neurons that render these cells resistant to excessive NMDA receptor activation.
Hodgson et al. (1999) produced yeast artificial chromosome transgenic mice expressing normal and mutant huntingtin in the developmental and tissue-specific manner identical to that observed in Huntington disease. The mutant mice showed early electrophysiologic abnormalities, indicating cytoplasmic dysfunction prior to observed nuclear inclusions or neurodegeneration. By 12 months of age, mice had a selective degeneration of medium spiny neurons in the lateral striatum associated with the translocation of N-terminal huntingtin fragments to the nucleus. Neurodegeneration could be present in the absence of macro- or microaggregates, clearly showing that aggregates are not essential to initiation of neuronal death. These mice demonstrated that initial neuronal cytoplasmic toxicity is followed by cleavage of huntingtin, nuclear translocation of huntingtin N-terminal fragments, and selective neurodegeneration.
Van Dellen et al. (2000) studied the effect of environment on the progression of Huntington disease in the mouse model developed by Mangiarini et al. (1996). They found that exposure of HD mice to a stimulating enriched environment from an early age helped to prevent the loss of cerebral volume and delayed the onset of motor disorders. Thirty male HD mice were randomized to either a normal or a stimulating environment. The normal environment was a large standard cage with routine care, which included normal feeding and bedding, whereas the cages of environmentally enriched groups also contained cardboard, paper, and plastic objects which were changed every 2 days from the age of 4 weeks. Motor coordination was tested every week by placing each mouse at the end of a suspended horizontal wooden rod; failure was defined as consistent falling or inability to turn around. At the end of testing at 22 weeks, only 1 mouse from the environmentally enriched group failed this test, whereas all of the mice from the standard environment had failed by this point. Another early sign of disease in HD mice is clasping of the rear paws when briefly suspended by the tail. The appearance of this sign was significantly delayed in mice from the environmentally enriched environment. In addition, HD mice in the enriched environment had a larger peristriatal cerebral volume when compared to those in the nonenriched environment.
Wheeler et al. (2000) studied the distribution of a mutant huntingtin gene product in Hdh-Q92 and Hdh-Q111 knockin mice, which harbor alleles with 92 and 111 glutamines, respectively. The authors observed nuclear localization of a version of the full-length protein predominant in medium spiny neurons, and subsequent formation of N-terminal inclusions and insoluble aggregate. These changes showed glutamine length dependence and dominant inheritance with recruitment of wildtype protein, suggesting to the authors 2 alternative pathogenic scenarios: the effect of the glutamine tract may act by altering interaction with a critical cellular constituent, or by depleting a form of huntingtin essential to medium spiny striatal neuron function and survival.
To understand gene expression changes mediated by polyglutamine repeat expansion in the human huntingtin protein, Luthi-Carter et al. (2000) used oligonucleotide DNA arrays to profile approximately 6,000 striatal mRNAs in the R6/2 mouse, a transgenic HD model. They found diminished levels of less than 2% of mRNAs tested; however, some encoded components of neurotransmitter, calcium, and retinoid signaling pathways at both early and late symptomatic time points (6 and 12 weeks of age). Similar changes in gene expression were also seen in another HD mouse model (N171-82Q). The authors concluded that mutant huntingtin directly or indirectly reduces the expression of a distinct set of genes involved in signaling pathways known to be critical to striatal neuron function.
Li et al. (2000) reported that in mutant mice expressing HD repeats, the production and aggregation of N-terminal huntingtin fragments preferentially occur in HD-affected neurons and their processes and axonal terminals. N-terminal fragments of mutant huntingtin form aggregates and induce neuritic degeneration in cultured striatal neurons. N-terminal mutant huntingtin also binds to synaptic vesicles and inhibits their glutamate uptake in vitro. Li et al. (2000) suggested that the specific processing and accumulation of toxic fragments of N-terminal huntingtin in HD-affected striatal neurons, especially in their neuronal processes and axonal terminals, may contribute to the selective neuropathology of HD.
Transgenic HD model mice that express a portion of the disease-causing form of human huntingtin develop a behavioral phenotype suggesting dysfunction of dopaminergic neurotransmission. Bibb et al. (2000) showed that presymptomatic mice had severe deficiencies in dopamine signaling in the striatum. The findings included selective reductions in total levels of dopamine- and cAMP-regulated phosphoprotein DARPP32 (604399), as well as other dopamine-regulated phosphoprotein markers of medium spiny neurons. HD mice also showed defects in dopamine-regulated ion channels and in the D1 dopamine (126449)/DARPP32 signaling cascade. These presymptomatic defects may contribute to HD pathology.
Hilditch-Maguire et al. (2000) surveyed 19 classes of organelle in Hdh(ex4/5)/Hdh(ex4/5) knockout compared with wildtype embryonic stem cells to identify any that might be affected by huntingtin deficiency. Although most did not differ, dramatic changes in 6 classes revealed that huntingtin's function is essential for normal nuclear (nucleoli, transcription factor-speckles) and perinuclear membrane (mitochondria, endoplasmic reticulum, Golgi, and recycling endosomes) organelles and for proper regulation of the iron pathway. Moreover, upmodulation by deferoxamine mesylate implicated huntingtin as an iron-response protein. However, excess huntingtin produced abnormal organelles that resembled the deficiency phenotype, suggesting the importance of huntingtin level to the protein's normal pathway. The authors proposed roles for the protein in RNA biogenesis, trafficking, and iron homeostasis to be explored in HD pathogenesis.
Trettel et al. (2000) compared striatal cell lines established from wildtype and Hdh(Q111) knockin mouse embryos. Alternate versions of full-length huntingtin, distinguished by epitope accessibility, were localized to different sets of nuclear and perinuclear organelles involved in RNA biogenesis and membrane trafficking. However, mutant STHdh(Q111) cells also exhibited additional forms of the full-length mutant protein and displayed dominant phenotypes that did not mirror phenotypes caused by either huntingtin deficiency or excess. These phenotypes reflected a disruption of striatal cell homeostasis by the mutant protein, suggesting an additional mechanism that is separate from its normal activity. The authors hypothesized that specific stress pathways, including elevated p53, endoplasmic reticulum stress response, and hypoxia, may be pathophysiologic processes in HD.
Transgenic mice expressing N-terminal mutant huntingtin show intranuclear huntingtin accumulation and develop progressive neurologic symptoms. Inhibiting caspase-1 (147678) can prolong the survival of these HD mice. Li et al. (2000) reported that intranuclear huntingtin induces the activation of caspase-3 (600636) and the release of cytochrome c from mitochondria in cultured cells. As a result, cells expressing intranuclear huntingtin underwent apoptosis. Intranuclear huntingtin increased the expression of caspase-1, which may in turn activate caspase-3 and trigger apoptosis. The authors proposed that the increased level of caspase-1 induced by intranuclear huntingtin may contribute to HD-associated cell death.
By quantifying the CAG repeat sizes of individual mutant alleles in tissues derived from an accurate genetic mouse model of HD, Kennedy and Shelbourne (2000) showed that the mutation became very unstable in striatal tissue. The expansion-biased changes increased with age, such that some striatal cells from old HD mice contained mutations that had tripled in size. The authors hypothesized that this pattern of repeat instability and the concomitant increased polyglutamine load may contribute to the patterns of selective neuronal cell death in HD, and that the expansion may increase by mechanisms that are not replication-based.
Leavitt et al. (2001) demonstrated that mutant human huntingtin causes apoptotic cell death in the testes of transgenic mice expressing no endogenous Htt. This proapoptotic effect of mutant Htt was completely inhibited by increased levels of murine wildtype Htt, providing the first evidence that wildtype Htt can reduce the toxicity of mutant Htt in vivo.
Lin et al. (2001) used gene targeting to generate mice with 150 CAG repeats in the Hdh gene. Such mice exhibited late-onset behavioral and neuroanatomic abnormalities consistent with HD, including a motor task deficit, gait abnormalities, reactive gliosis, and the formation of neuronal intranuclear inclusions predominating in the striatum. Inclusions exhibited increased glial fibrillary acidic protein immunoreactivity, suggesting to the authors that these mice had neuronal injury similar to that found early in the course of HD.
Kovtun and McMurray (2001) followed heritable changes in CAG length in male transgenic mice generated by Mangiarini et al. (1996). In germ cells, expansion was limited to the postmeiotic, haploid cell and therefore did not involve mitotic replication or recombination between a homologous chromosome or sister chromatid during meiosis. Kovtun and McMurray (2001) suggested a model in which expansion in the germ cells arises by gap repair and depends on a complex containing MSH2 (609309). Expansion occurs during gap-filling synthesis when DNA loops comprising the CAG trinucleotide repeats are sealed into the DNA strand. A shift in the repeat sizes toward expansion was observed in epididymal sperm, demonstrating that expansion is a postmeiotic event in the male germ cell that occurs late in the maturation of spermatids to mature spermatozoa. Somatic changes in expansion were age-dependent, began near 11 weeks of age, and continued throughout the lifetime of the animal. Age-dependent expansion in somatic tissues at 30 weeks was abrogated in the absence of Msh2, indicating that Msh2 is involved in the somatic expansion mutation. Absence of MSH2 also completely abolished germline expansion and age-dependent somatic expansion in transgenic cells.
Jana et al. (2001) used a mouse neuro2a cell line that expresses truncated N-terminal huntingtin with different polyglutamine length, along with mice transgenic for HD exon 1, to demonstrate that the ubiquitin-proteasome pathway is involved in the pathogenesis of HD. Proteasomal 20S core catalytic component (176843) was redistributed to the polyglutamine aggregates in both the cellular and transgenic mouse models. Proteasome inhibitor dramatically increased the rate of aggregate formation caused by N-terminal huntingtin protein with 60 glutamine repeats, but had very little influence on aggregate formation by N-terminal huntingtin protein with 150 glutamine repeats. Both normal and polyglutamine-expanded N-terminal huntingtin proteins were degraded by proteasome, but the rate of degradation was inversely proportional to the repeat length. The shift of the proteasomal components from the total cellular environment to the aggregates, as well as the comparatively slower degradation of N-terminal huntingtin with longer polyglutamine, decreased the proteasome's availability for degrading other key target proteins, such as p53. This altered proteasomal function was associated with disrupted mitochondrial membrane potential, released cytochrome c from mitochondria into the cytosol, and activated caspase-9- (602234) and caspase-3-like proteases. The authors concluded that the impaired proteasomal function may play an important role in polyglutamine protein-induced cell death.
Petersen et al. (2001) examined dissociated postnatally derived cultures of striatal neurons from transgenic mice expressing exon 1 of the human HD gene carrying a CAG repeat expansion. While there was no difference in cell death between wildtype and mutant littermate-derived cultures, the mutant striatal neurons exhibited elevated cell death following a single exposure to a neurotoxic concentration of dopamine. The mutant neurons exposed to dopamine also exhibited lysosome-associated responses including induction of autophagic granules and electron-dense lysosomes. The autophagic/lysosomal compartments colocalized with high levels of oxygen radicals in living neurons and ubiquitin. The authors suggested that the combination of mutant huntingtin and a source of oxyradical stress (such as excessive dopamine) may induce autophagy and may underlie the selective cell death characteristic of HD.
Sathasivam et al. (2001) observed that it was impossible to establish fibroblast lines from R6/2 transgenic mice (Mangiarini et al., 1996) at 12 weeks of age, although this could be achieved without difficulty at 6 and 9 weeks. Cultures derived from mice at 12 weeks contained a high frequency of dysmorphic cells, including cells with an aberrant nuclear morphology and a high frequency of micronuclei and large vacuoles. All of these features were also present in a line derived from a juvenile HD patient. Fibroblast lines derived from R6/2 mice and from HD patients were found to have a high frequency of multiple centrosomes which could account for all of the observed phenotypes, including a reduced mitotic index, high frequency of aneuploidy, and persistence of the midbody. The authors were unable to detect large insoluble polyglutamine aggregates in either the mouse or human fibroblast lines, in contrast to findings in neuronal cells.
To elucidate the role of transglutaminase-2 (TGM2; 190196) in HD, Mastroberardino et al. (2002) generated a transgenic HD mouse model (R6/1) that was also null for TGM2 (Tgm2 -/-). Comparisons of transglutaminase activity among different mouse lines showed that Tgm2 is the predominant transglutaminase active in the brain. The deletion of Tgm2 led to significant ameliorations in generalized and brain weight loss in the HD mice. Tgm2 ablation also led to a large reduction in overall cell death and to an increased number of neuronal intranuclear inclusions, suggesting that Tgm2 crosslinking is not directly involved in the assembly of inclusions. Moreover, the findings suggested a protective role for neuronal aggregates. Tgm2 -/- HD mice showed a significant improvement in motor behavior and survival. The results suggested that TGM2 plays a role in the regulation of neuronal cell death in HD.
Muchowski et al. (2002) investigated the mechanism underlying the major pathologic feature in Huntington disease neurons: the presence of detergent-insoluble ubiquitinated inclusion bodies composed of the huntingtin protein. They analyzed the effects of drugs or genetic mutations that disrupt the microtubule cytoskeleton in an S. cerevisiae model of the aggregation of an N-terminal polyglutamine-containing fragment of huntingtin exon 1 (HtEx1). Treatment of yeast with drugs that disrupt microtubules resulted in less than 2% of the inclusion bodies observed in mock-treated cells and prevented the formation of large juxtanuclear inclusion bodies. Disruption of microtubules also unmasked a potent glutamine length-dependent toxicity of HtEx1 under conditions where HtEx1 exists in an entirely detergent-soluble nonaggregated form. These results suggested that active transport along microtubules may be required for inclusion body formation by HtEx1 and that inclusion body formation may have evolved as a cellular mechanism to promote the sequestration or clearance of soluble species of HtEx1 that are otherwise toxic to cells.
To assess the consequences of mutant protein when huntingtin is limiting, Auerbach et al. (2001) studied 3 lines of compound heterozygous mice in which both copies of the HD gene were altered, resulting in greatly reduced levels of huntingtin with a normal human polyglutamine length (Q20) and/or an expanded disease-associated segment (Q111). All surviving mice in each of the 3 lines were small from birth and had variable movement abnormalities. Magnetic resonance microimaging and histologic evaluation showed enlarged ventricles in approximately 50% of the Q20/Q111 and Q20/null mice, revealing a developmental defect that does not worsen with age. Only Q20/Q111 mice exhibited a rapidly progressive movement disorder that, in the absence of striatal pathology, began at 3 to 4 months of age, progressed to paralysis of the limbs and tail and hypokinesis, and resulted in premature death, usually by 12 months of age. The authors concluded that greatly reduced huntingtin levels fail to support normal development in mice, resulting in reduced body size, movement abnormalities, and a variable increase in ventricle volume. On this sensitized background, mutant huntingtin causes a rapid neurologic disease, distinct from the HD-pathogenic process. The authors hypothesized that therapeutic elimination of huntingtin in HD patients could lead to unintended neurologic and developmental side effects.
Wheeler et al. (2002) reported late-onset neurodegeneration and gait deficits in older Hdh(Q111) knockin mice. Using the early nuclear-accumulation phenotypes as surrogate markers, the authors showed that the disease process, initiated by full-length mutant protein, was hastened by coexpression of mutant fragment; therefore, accrual of insoluble product in already compromised neurons may exacerbate pathogenesis. In contrast, timing of early disease events was not altered by normal huntingtin or by mutant caspase-1, 2 proteins shown to reduce inclusions and glutamine toxicity in other HD models.
Supporting the view that transcriptional dysregulation may contribute Yu et al. (2002) examined the expression and localization of the polyglutamine-containing or glutamine-rich transcription factors TBP (600075), CBP, and SP1 in HD mouse models. All 3 transcription factors were diffusely distributed in the nucleus, despite the presence of abundant intranuclear inclusions. There were no differences in the nuclear staining of these transcription factors between HD and wildtype mouse brains. Western blots showed that these transcription factors were not trapped in huntingtin inclusions. The authors suggested that altered gene expression may result from the interactions of soluble mutant huntingtin with nuclear transcription factors, rather than from the depletion of transcription factors by nuclear inclusions.
Luthi-Carter et al. (2002) investigated gene expression in several brain areas in the R6/2 HD mouse. They reported that although several genes exhibited differential expression compared to wildtype mice, there was no regional specificity, and comparable changes in gene expression were also seen in skeletal muscle. In comparing transgenic mice bearing either full-length atrophin-1 (DRPLA; 607462) or partial huntingtin transproteins to wildtype, Luthi-Carter et al. (2002) reported that there was considerable overlap in the alteration of gene expression between the 2 models, at least in the cerebellum. The authors concluded that polyglutamine-induced changes may be independent of their protein context. However, in a study comparing mice harboring truncated or full-length mutant huntingtin transcripts, Chan et al. (2002) reported that the full-length mutant transcript had less of an effect on gene expression than the truncated protein, suggesting that protein context may indeed play a role. Sipione et al. (2002) limited their study to cultured rat striatal cells bearing different length mutant huntingtin transcripts and reported differences in expression among genes involved in cell signaling, transcription, lipid metabolism, and vesicle trafficking.
Fossale et al. (2002) compared the gene expression pattern of Hdh(Q111) mice and wildtype mice striatal RNAs by microarray and quantitative RT-PCR analysis. The authors observed a mutant-specific increase in hybridization to Rrs1 (see Tsuno et al., 2000), which encodes a ribosomal protein from as early as 3 weeks of age. Studies of the human homolog revealed elevated Rrs1 mRNA in HD compared with control postmortem brain.
Helmlinger et al. (2002) showed that R6 transgenic mice express mutant huntingtin in the retina, leading to severe vision deficiencies and retinal dystrophy. Comparable early and progressive retinal degeneration and dysfunction have been described in R7E mice, which are transgenic mice overexpressing the human SCA7 gene (ATXN1; 607640). These abnormalities are reminiscent of other retinal degeneration phenotypes (in particular rd7/rd7 mice) where photoreceptor cell loss occurs. Helmlinger et al. (2002) suggested that the NRL (162080) pathway and photoreceptor cell fate may be altered in R6 and R7E mice retina.
By examining brains from mice expressing 150 CAG repeats in the Htt gene, Zhou et al. (2003) found evidence that accumulation of toxic Htt fragments was associated with an age-dependent decrease in proteasome activity and was exacerbated by inhibition of proteasome activity.
Wheeler et al. (2003) tested whether a genetic background deficient in Msh2 (609309) would eliminate the unstable behavior of the CAG array in Hdh(Q111) mice. Analyses of Hdh(Q111/+):Msh2(+/+) and Hdh(Q111/+):Msh2(-/-) progeny revealed that, while inherited instability involved Msh2-dependent and -independent mechanisms, lack of Msh2 was sufficient to abrogate progressive HD CAG repeat expansion in striatum. The absence of Msh2 also eliminated striatal mutant huntingtin with somatically expanded glutamine tracts and caused an approximately 5-month delay in nuclear mutant protein accumulation, but did not alter the striatal specificity of this early phenotype. The authors concluded that somatic HD CAG instability appears to be a consequence of a striatal-selective disease process that accelerates the timing of an early disease phenotype, via expansion of the glutamine tract in mutant huntingtin.
Gines et al. (2003) found that reduced cAMP-responsive element (CRE)-mediated signaling in Hdh(Q111) mouse striatum, monitored by brain-derived neurotrophic factor (BDNF; 113505) and phospho-CRE binding protein (CREB; 123810), predated inclusion formation. Furthermore, cAMP levels in Hdh(Q111) striatum declined from an early age (10 weeks), and cAMP was significantly decreased in HD postmortem brain and lymphoblastoid cells. Reduced CRE signaling in cultured STHdh(Q111) striatal cells was associated with cytosolic CREB-binding protein (600140) indicative of diminished cAMP synthesis. Mutant cells exhibited mitochondrial respiratory chain impairment, evident by decreased ATP and ATP/ADP ratio, impaired MTT conversion, and heightened sensitivity to 3-nitropropionic acid. The authors proposed that impaired ATP synthesis and diminished cAMP levels may amplify the early HD disease cascade by decreasing CRE-regulated gene transcription and altering energy-dependent processes essential to neuronal cell survival.
In Drosophila, Gunawardena et al. (2003) showed that a reduction in huntingtin expression caused axonal transport defects, suggesting a normal role for the protein in axonal transport. Cytoplasmic expression of pathogenic huntingtin with expanded polyQ repeats resulted in titration of soluble motor proteins and defects in axonal transport, while nuclear expression induced neuronal apoptosis. Gunawardena et al. (2003) suggested that pathogenic polyQ proteins cause neurodegeneration by 2 nonmutually exclusive mechanisms: one involving disruption of axonal transport, and one involving nuclear accumulation and apoptosis.
Slow et al. (2003) established a YAC mouse model of HD with the entire human HD gene containing 128 CAG repeats, designated YAC128. The strain developed motor abnormalities and age-dependent brain atrophy, including cortical and striatal atrophy associated with striatal neuronal loss. YAC128 mice exhibited initial hyperactivity, followed by the onset of a motor deficit and finally hypokinesis. The motor deficit in the YAC128 mice was highly correlated with striatal neuronal loss, providing a structural correlate for the behavioral changes. Slow et al. (2003) defined the natural history of HD-related changes in the YAC128 mice, demonstrating the presence of huntingtin inclusions after the onset of behavior and neuropathologic changes.
Marsh et al. (2003) reviewed Drosophila models of Huntington disease.
Lievens et al. (2005) targeted the expression of the polyQ-containing domain of Htt or an extended polyQ peptide alone in a subset of Drosophila glial cells, where the only fly glutamate transporter, Eaat1 (SLC1A3; 600111), is detected. This resulted in formation of nuclear inclusions, progressive decrease in Eaat1 transcription and shortened adult life span, but no significant glial cell death. Brain expression of Eaat1 was normally sustained by the EGFR (131550)-Ras (190020)-ERK1 (601795) signaling pathway, suggesting that polyQ could act by antagonizing this pathway. The presence of polyQ peptides abolished Eaat1 upregulation by constitutively active Egfr and potently inhibited Egfr-mediated Erk activation in fly glial cells. Long polyQ also limited the effect of activated Egfr on Drosophila eye development. Lievens et al. (2005) concluded that polyQ acts at an upstream step in the pathway, situated between EGFR and ERK activation, and that disruption of EGFR signaling and ensuing glial cell dysfunction could play a direct role in the pathogenesis of HD and other polyQ diseases.
Von Horsten et al. (2003) generated a transgenic rat model of HD, which carries a truncated huntingtin cDNA fragment with 51 CAG repeats under control of the native rat huntingtin promoter. The rats exhibited adult-onset neurologic phenotypes with reduced anxiety, cognitive impairments, and slowly progressive motor dysfunction as well as typical histopathologic alterations in the form of neuronal nuclear inclusions in the brain. As in HD patients, MRI demonstrated striatal shrinkage, and PET scan showed reduced brain glucose metabolism.
Li et al. (2003) reported that axonal terminals in HD mouse brains that contained huntingtin aggregates often had fewer synaptic vesicles than did normal axonal terminals. Subcellular fractionation and electron microscopy revealed that mutant huntingtin colocalized with huntingtin-associated protein-1 (HAP1; 600947) in HD mouse brain axonal terminals. Mutant huntingtin bound more tightly to synaptic vesicles than did wildtype huntingtin, and it decreased the association of HAP1 with synaptic vesicles in HD mouse brains. Brain slices from HD transgenic mice that had axonal aggregates showed a significant decrease in glutamate release, suggesting that neurotransmitter release from synaptic vesicles was impaired. The authors suggested that mutant huntingtin may have an abnormal association with synaptic vesicles that may impair synaptic function.
Schilling et al. (2004) fused a nuclear localization signal (NLS) derived from atrophin-1 (DRPLA; 607462) to the N terminus of an N171-82Q construct. Two lines of mice that were identified expressed NLS-N171-82Q at comparable levels and developed phenotypes identical to previously described HD-N171-82Q mice. Western blot and immunohistochemical analyses revealed that NLS-N171-82Q fragments accumulated in nuclear, but not cytoplasmic, compartments. The authors suggested that disruption of nuclear processes may account for many of the disease phenotypes displayed in the mouse models generated by expressing mutant N-terminal fragments of Htt.
By comparing previously reported genetic modifiers in 3 Drosophila models of human neurodegenerative disease, Ghosh and Feany (2004) confirmed that protein folding, histone acetylation, and apoptosis are common features of neurotoxicity. Two novel genetic modifiers, the Drosophila homolog of ATXN2 (601517) and CGI7231, were identified. Cell-type specificity was demonstrated as many, but not all, retinal modifiers also modified toxicity in postmitotic neurons.
In HD(+/-)/Msh2(+/+) and HD(+/-)/Msh2(-/-) mice, Kovtun et al. (2004) showed that long CAG repeats were shortened during somatic replication early in embryonic development. Deletions arose during replication, did not depend on the presence of Msh2, and were largely restricted to early development. In contrast, expansions depended on strand break repair, required the presence of Msh2, and occurred later in development. Kovtun et al. (2004) hypothesized that deletions in early development may serve to safeguard the genome and protect against expansion of disease-range repeats during parent-offspring transmission.
Diabetes frequently develops in HD patients and in transgenic mouse models of HD such as the R6/2 mouse. Bjorkqvist et al. (2005) reported that R6/2 mice (at week 12, corresponding to end-stage HD) were hyperglycemic and hypoinsulinemic and failed to release insulin in an intravenous glucose tolerance test. In vitro, basal and glucose-stimulated insulin secretion was markedly reduced. Islet nuclear huntingtin inclusions increased dramatically over time, predominantly in beta cells, and beta-cell mass and pancreatic insulin content were 35% and 16% of that in wildtype mice, respectively. Normally occurring replicating cells were largely absent in R6/2 islets, while no abnormal cell death could be detected. Exocytosis was virtually abolished in beta cells but not in alpha cells. Bjorkqvist et al. (2005) concluded that diabetes in R6/2 mice is caused by a combination of deficient beta-cell mass and disrupted exocytosis.
Van Raamsdonk et al. (2005) generated YAC128 mice that lacked wildtype Htt (YAC128 -/-) but expressed the same amount of mutant Htt as YAC128 mice with wildtype Htt (YAC128 +/+). YAC128 -/- mice performed worse than YAC128 +/+ mice in the rotarod test of motor coordination and were hypoactive compared with YAC128 +/+ mice at 2 months. There was no significant effect of decreased wildtype Htt on striatal volume, neuronal counts, or DARPP32 (604399) expression, but a modest worsening of striatal neuronal atrophy was evident. Testes of YAC128 +/+ mice showed atrophy and degeneration, which was markedly worsened in the absence of wildtype Htt. YAC128 +/+ mice also showed a male-specific deficit in survival compared with wildtype mice, which was exacerbated by the loss of wildtype Htt. Overall, the loss of wildtype Htt influenced motor dysfunction, hyperkinesia, testicular degeneration and impaired life span in YAC128 mice.
Slow et al. (2005) reported the serendipitous development of the 'shortstop' mouse, which expresses a short human huntingtin fragment of 117 amino acids (only exons 1 and 2 of the HD gene) with an expanded 120-residue polyQ repeat. The mice showed early onset of frequent and widespread huntingtin inclusions but had no clinical evidence of neuronal dysfunction or neuronal degeneration. In contrast to YAC128 mice, which express full-length huntingtin and show enhanced toxicity to NMDA-induced excitotoxic neuronal death, shortstop mice showed relative protection from excitotoxicity. Slow et al. (2005) concluded that huntingtin inclusions are not pathogenic and that neurodegeneration in Huntington disease is mediated by excitotoxic mechanisms via the full-length mutant protein.
To dissect the impact of nuclear and extranuclear mutant Htt on the initiation and progression of disease, Benn et al. (2005) generated a series of transgenic mouse lines in which nuclear localization or nuclear export signal sequences were placed N-terminal to the Htt exon 1 protein carrying 144 glutamines. The exon 1 mutant protein was present in the nucleus as part of an oligomeric or aggregation complex. Increasing the concentration of the mutant transprotein in the nucleus was sufficient for and dramatically accelerated the onset and progression of behavioral phenotypes. Furthermore, nuclear exon 1 mutant protein was sufficient to induce cytoplasmic neurodegeneration and transcriptional dysregulation. Benn et al. (2005) further suggested that cytoplasmic mutant exon 1 Htt, if present, also contributed to disease progression.
Van Raamsdonk et al. (2005) demonstrated selective degeneration of the striatum and cortex in the YAC128 mouse model of HD. At 12 months, YAC128 mice showed significant atrophy in the striatum, globus pallidus, and cortex with relative sparing of the hippocampus and cerebellum. Similarly, neuronal loss at this age was present in the striatum and cortex of YAC128 mice but was not detected in the hippocampus. Mutant Htt expression levels were similar throughout the brain and thus failed to explain the selective neuronal degeneration. However, nuclear detection of mutant Htt occurred earliest and to the greatest extent in the striatum. In contrast to YAC128 mice, the R6/1 mouse model of HD (which expresses exon 1 of mutant Htt) exhibits nonselective, widespread atrophy along with nonselective nuclear detection of mutant Htt at 10 months of age. The authors suggested that selective nuclear localization of mutant Htt may contribute to the selective degeneration in HD.
In 2 mouse models of HD, Chiang et al. (2007) found increased blood ammonia and citrulline levels due to a defect in activity of the urea cycle. Liver samples showed low levels of Htt aggregates. A low-protein diet resulted in neurologic improvement, suggesting that urea cycle defects may contribute to the progression of HD. Further studies indicated that the deficiency was due to suppression of Cebpa (116897), a factor important for the transcription of urea cycle enzymes, such as argininosuccinate lyase (ASL: 608310). Mutant Htt was found to interfere with the ability of Cebpa to interact with its cofactor. Mutant Htt also recruited Cebpa into aggregates and suppressed gene expression.
Yang et al. (2008) reported their progress in developing a transgenic model for Huntington disease in a rhesus macaque that expresses polyglutamine-expanded HTT. Hallmark features of HD, including nuclear inclusions and neuropil aggregates, were observed in the brains of the HD transgenic monkeys. Additionally, the transgenic monkeys showed important clinical features of HD, including dystonia and chorea.
In a Drosophila model of HD with mutant human HTT, Mugat et al. (2008) found that expression of engrailed (EN1; 131290), a transcription activator, was able to prevent aggregation of polyQ-HTT by activating transcription of endogenous wildtype htt. N-terminal fragments of both wildtype human HTT and Drosophila wildtype htt were able to rescue phenotypes induced by polyQ-HTT, confirming that human and Drosophila HTT share biologic properties. The ratio between wildtype Drosophila htt and mutant polyQ-HTT was important for the onset of corresponding phenotypes, such as aggregation and eye toxicity. The protective role of wildtype HTT N-terminal parts suggested that HD may be considered a dominant-negative disease rather than solely dominant.
Quintanilla et al. (2008) found that mouse striatal cells expressing mutant huntingtin were more sensitive than wildtype to intracellular calcium overload, predominantly due to deregulated calcium handling by impaired mitochondria. Mutant cells also showed reduced Pparg expression and transcriptional activity. Pharmacologic activation of Pparg or overexpression of Pparg significantly improved mitochondrial response to intracellular calcium challenge, with restoration of mitochondrial membrane potential and calcium transport, and reduced intracellular reactive oxygen species. Activation of Pparg also increased mitochondrial mass in mutant striatal cells.
Crittenden et al. (2010) showed that CalDAG-GEFI (RASGRP2; 605577) was severely downregulated in the striatum of mouse Huntington disease models and was downregulated in HD individuals. In the R6/2 transgenic mouse model of HD, striatal neurons with the largest aggregates of mutant Htt had the lowest levels of CalDAG-GEFI. In a brain-slice explant model of HD, knockdown of CalDAG-GEFI expression rescued striatal neurons from pathology induced by transfection of polyglutamine-expanded Htt exon 1. The authors suggested that the striking downregulation of CalDAG-GEFI in HD could be a protective mechanism that mitigates HTT-induced degeneration.
Faideau et al. (2010) developed a novel mouse model in which mutant huntingtin was selectively expressed in striatal astrocytes. Astrocytes expressing the mutant protein developed a progressive phenotype of reactive astrocytes characterized by a marked decrease in expression of the glutamate transporters GLAST (SLC1A3; 600111) and GLI1 (SLC1A2; 600300) and in glutamate uptake. These effects were associated with neuronal dysfunction, as evidenced by the reduced expression of both DARPP32 (PPP1R1B; 604399) and NR2B (GRIN2B; 138252). Parallel studies in brain samples from HD subjects revealed early glial fibrillary acidic protein (GFAP; 137780) expression in striatal astrocytes from grade 0 HD cases. Astrogliosis was associated with morphologic changes that increased with severity of disease, from grades 0 through 4, and was more prominent in the putamen. Combined immunofluorescence of GFAP and mutant Htt showed colocalization in all grades of HD severity. Consistent with the findings from experimental mice, there was a significant grade-dependent decrease in striatal SLC1A2 expression from HD subjects. Faideau et al. (2010) suggested that the presence of mutant Htt in astrocytes alters glial glutamate transport capacity early in the disease process and may contribute to HD pathogenesis.
Pouladi et al. (2010) investigated the involvement of the insulin-like growth factor-1 (IGF1; 147440) pathway in mediating the effect of HTT on body weight. IGF1 expression was examined in transgenic mouse lines expressing different levels of full-length wildtype Htt (YAC18 mice), full-length mutant Htt (YAC128 and BACHD mice), and truncated mutant Htt (shortstop mice). Htt influenced body weight by modulating the IGF1 pathway. Plasma IGF1 levels correlated with body weight and Htt levels in the transgenic YAC mice expressing human HTT. The effect of Htt on IGF1 expression was independent of CAG size. No effect on body weight was observed in transgenic YAC mice expressing a truncated N-terminal Htt fragment (shortstop), indicating that full-length Htt is required for the modulation of IGF1 expression. Treatment with 17-beta-estradiol (17B-ED) lowered the levels of circulating IGF1 in mammals. Treatment of YAC128 with 17B-ED, but not placebo, reduced plasma IGF1 levels and decreased the body weight of YAC128 animals to wildtype levels. Levels of full-length Htt also influenced IGF1 expression in striatal tissues of the brain.
Yamanaka et al. (2010) performed a comprehensive analysis of altered DNA binding of multiple transcription factors using brains from R6/2 HD mice, which express an N-terminal fragment of mutant huntingtin (Nhtt). The authors observed a reduction of DNA binding of Brn2 (600494), a POU domain transcription factor involved in differentiation and function of hypothalamic neurosecretory neurons. Brn2 lost its function through 2 pathways, sequestration by mutant Nhtt and reduced transcription and expression of hypothalamic neuropeptides, leading to reduced expression of hypothalamic neuropeptides. In contrast, Brn1 (602480) was not sequestered by mutant Nhtt, but was upregulated in R6/2 brain, except in hypothalamus. Yamanaka et al. (2010) concluded that functional suppression of Brn2, together with a region-specific lack of compensation by Brn1, may mediate hypothalamic cell dysfunction by mutant Nhtt.
Jacobsen et al. (2010) developed an HD transgenic ovine model. Microinjection of a full-length human HTT cDNA containing 73 polyglutamine repeats under the control of the human promoter resulted in 6 transgenic founders, varying in copy number, of the transgene. Analysis of offspring (at 1 and 7 months of age) from 1 of the founders showed robust expression of the full-length human HTT protein in both CNS and non-CNS tissue. Immunohistochemical analysis demonstrated the organization of the caudate nucleus and putamen and revealed decreased expression of medium-sized spiny neuron marker DARPP-32 at 7 months of age.
Using CRISPR/Cas9 and somatic nuclear transfer technology, Yan et al. (2018) generated a knockin (KI) pig model of germline-transmittable HD that endogenously expressed full-length mutant huntingtin. HD KI pigs did not show obvious symptoms before the age of 4 months. Thereafter KI pigs gained less body weight than wildtype, and old HD KI pigs often displayed wrinkled and sagging skin. KI pigs showed walking abnormalities, behavior abnormalities, and respiratory difficulties or irregular breathing patterns. Some KI pigs died between the ages of 5 to 10 months, likely due to respiratory failure. KI pigs also displayed running difficulties and were susceptible to exercise stress. By analyzing the CAG repeats in different pig generations, the authors showed that the CAG repeat was unstable in KI pigs. Brain size of HD KI pigs was reduced, with thinner cortex, enlarged lateral ventricle, and smaller striatum. In HD KI pig brain, striatum had the most severe loss of NeuN (RBFOX3; 616999)-positive cells and the highest increase in glial cell numbers. Overall, severe neurodegeneration in HD KI pig brain showed a similar pattern to that in HD human brain.
Therapeutic Strategies
Ona et al. (1999) studied the effect of inhibition of caspase-1 (147678) on the progression of Huntington disease in the mouse model developed by Mangiarini et al. (1996), which they called R6/2 mice. Ona et al. (1999) crossed R6/2 mice with a well-characterized transgenic mouse strain expressing a dominant-negative mutant of caspase-1 in the brain (NSE M17Z). The neuron-specific enolase promoter targets the expression of mutant caspase-1 to neurons and glia within the central nervous system. R6/2 and R6/2-NSE M17Z mice developed normally and were indistinguishable from wildtype littermates until about 7 weeks of age. Thereafter, the double mutant mice performed better on rotarod tests of motor function and had a later onset and slower progression of deterioration. Quantitative in situ hybridization of levels of mutant huntingtin showed no differences between the R6/2 and the double mutant mice. The double mutant mice also exhibited less weight loss than the R6/2 mice. Mature IL1-beta (147720) levels are a sensitive and specific indicator of caspase-1 activation. Mature IL1-beta levels in R6/2 mice were elevated to 268% of those in wildtype controls. This increase was significantly inhibited in the R6/2-NSE M17Z mice. IL1-beta levels in the brains of human patients also exhibited significant increases, to 213% of those in normal controls. The protection conferred by M17Z expression represented a 55% increase in disease duration and a 20% prolongation of life. To rule out a strain-related epigenetic effect mediating protection, Ona et al. (1999) treated 7-week-old R6/2 mice with a caspase inhibitor by continuous intracerebroventricular infusion for 4 weeks. Mice thus treated performed better on rotarod and lived 25% longer than control mice who were treated with a vehicle drug. R6/2-NSE M17Z mice had delayed onset of the appearance of neural inclusions and neurotransmitter receptor alterations as well as of symptom onset. The authors suggested that caspase-1 inhibitors may be applicable to human Huntington disease.
Kazemi-Esfarjani and Benzer (2000) used a Drosophila model for Huntington and other polyglutamine diseases to screen for genetic factors modifying the degeneration caused by expression of polyglutamine in the eye. Among 7,000 P-element insertions, they isolated several suppressor strains, 2 of which led to the discovery of suppressor genes. The predicted product of one is HDJ1, which is homologous to human heat-shock protein-40 (DNAJB2; 604139). That of the second, TPR2, is homologous to the human tetratricopeptide repeat protein-2 (601964). Each of these molecules contains a chaperone-related J domain. The suppression of polyglutamine toxicity was verified in transgenic flies.
Data indicate that molecular chaperones can modulate polyglutamine pathogenesis. To elucidate the basis of polyglutamine toxicity and the mechanism by which chaperones suppress neurodegeneration, Chan et al. (2000) studied transgenic Drosophila disease models of Machado-Joseph disease (109150) and HD. They demonstrated that HSP70 (see 140559) and Hdj1, the Drosophila homolog of human HSP40 (see 604139), showed substrate specificity for polyglutamine proteins as well as synergy in suppression of neurotoxicity, and altered the solubility properties of the mutant polyglutamine protein.
Yamamoto et al. (2000) created a conditional model of HD by using the tetracycline-responsive system. Mice expressing a mutated huntingtin fragment (exon 1 of the Hd gene with a polyglutamine expansion of 94 repeats) demonstrated neuronal inclusions, characteristic neuropathology, and progressive motor dysfunction. Blockade of expression in symptomatic mice led to a disappearance of inclusions and an amelioration of the behavioral phenotype. Yamamoto et al. (2000) thus demonstrated that a continuous influx of the mutant protein is required to maintain inclusions and symptoms, raising the possibility that HD may be reversible. Orr and Zoghbi (2000) discussed potential therapeutic strategies based on these conclusions.
Geldanamycin is a benzoquinone ansamycin that binds to the heat-shock protein Hsp90 (see 140571) (Stebbins et al., 1997) and activates a heat-shock response in mammalian cells. Sittler et al. (2001) showed that treatment of mammalian cells with geldanamycin at nanomolar concentrations induced the expression of Hsp40 (see 604572), Hsp70 (see 140550), and Hsp90 and inhibited HD exon 1 protein aggregation in a dose-dependent manner. Similar results were obtained by overexpression of Hsp70 and Hsp40 in a separate cell culture model of HD. The authors proposed that this may provide the basis for the development of a novel pharmacotherapy for HD and related glutamine repeat disorders.
On the hypothesis that transglutaminase may be critical to the pathogenesis of Huntington disease via cross-linking huntingtin, Karpuj et al. (2002) administered the transglutaminase (190195) competitive inhibitor cystamine to transgenic mice expressing exon 1 of the huntingtin gene containing an expanded polyglutamine repeat. Cystamine given intraperitoneally entered the brain, where it inhibited transglutaminase activity. When treatment began after the appearance of abnormal movements, cystamine extended survival, reduced associated tremor and abnormal movements, and ameliorated weight loss. Treatment did not influence the appearance or frequency of neuronal nuclear inclusions. Unexpectedly, cystamine treatment increased transcription of 1 of the 2 genes shown to be neuroprotective for polyglutamine toxicity in Drosophila, DNAJ (DNAJB2; 604139).
Kazantsev et al. (2002) developed and tested suppressor polypeptides that bind mutant huntingtin and interfere with the process of aggregation in mammalian cell culture. In a Drosophila model, the most potent suppressor inhibited both adult lethality and photoreceptor neuron degeneration. The appearance of aggregates in photoreceptor neurons correlated strongly with the occurrence of pathology, and expression of suppressor polypeptides delayed and limited the appearance of aggregates and protected photoreceptor neurons. Kazantsev et al. (2002) concluded that targeting the protein interactions leading to aggregate formation may be beneficial for the design and development of therapeutic agents for Huntington disease.
Dunah et al. (2002) reported that huntingtin interacts with the transcriptional activator SP1 (189906) and coactivator TAFII130 (TAF4; 601796). Coexpression of SP1 and TAFII130 in cultured striatal cells from wildtype and HD transgenic mice reversed the transcriptional inhibition of the dopamine D2 receptor gene caused by mutant huntingtin, as well as protected neurons from huntingtin-induced cellular toxicity. Furthermore, soluble mutant huntingtin inhibited SP1 binding to DNA in postmortem brain tissues of both presymptomatic and affected HD patients.
Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is normally produced endogenously in humans at very low levels. Keene et al. (2001) found that TUDCA prevented striatal degeneration and ameliorated locomotor and cognitive deficits in the in vivo nitropropionic acid rat model of HD. However, the transgenic mouse models of HD result from genetic rather than chemical alterations, involve chronic versus acute pathophysiology, and therefore may more accurately reflect the true pathophysiology of HD. Keene et al. (2002) examined the effects of TUDCA in the transgenic mouse model of HD, containing a trinucleotide CAG expansion (approximately 150 repeats) of the Htt exon 1. The mice exhibited severe neuropathophysiology and associated neurodegeneration with concomitant sensorimotor deficits, and typically died at approximately 14 weeks of age. The authors found that TUDCA treatment led to a marked reduction in striatal cell apoptosis and degeneration. In addition, intracellular inclusions were significantly reduced, and the TUDCA-treated mice showed improved locomotor and sensorimotor abilities. Keene et al. (2002) suggested, therefore, that TUDCA may provide a novel and effective treatment for patients with HD.
Supporting the view that transcriptional dysregulation may contribute to the molecular pathogenesis of HD, administration of HDAC inhibitors rescued lethality and photoreceptor neurodegeneration in a Drosophila model of polyglutamine disease (Steffan et al., 2001). To further explore the therapeutic potential of HDAC inhibitors, Hockly et al. (2003) conducted trials with a potent HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), in the R6/2 HD mouse model. They found that the inhibitor crosses the blood-brain barrier and increases histone acetylation in the brain. It could be administered orally in drinking water when complexed with cyclodextrins. SAHA dramatically improved the motor impairment in the mouse model, clearly validating the pursuit of this class of compounds as HD therapeutics.
Nagai et al. (2000) identified polyglutamine binding peptide-1 (QBP1) from combinatorial peptide phage display libraries. Nagai et al. (2003) showed that a tandem repeat of the inhibitor peptide QBP1, (QBP1)2, significantly suppressed polyQ aggregation and polyQ-induced neurodegeneration in the compound eye of Drosophila polyQ disease models. In addition, (QBP1)2 expression rescued premature death of flies expressing the expanded polyQ protein in the nervous system, increasing the median life span from 5.5 to 52 days. The authors suggested that QBP1 may prevent polyQ-induced neurodegeneration in vivo either by altering the toxic conformation of the expanded polyQ stretch, or by simply competing with the expanded polyQ stretches for binding to other expanded polyQ proteins.
Ghosh and Feany (2004) identified nicotinamide, which has histone deacetylase-inhibiting activity, as a potent suppressor of polyglutamine toxicity.
The manipulation of chaperone levels has been shown to inhibit aggregation and/or rescue cell death in S. cerevisiae, C. elegans, D. melanogaster, and cell culture models of Huntington disease and other polyglutamine (polyQ) disorders. Hay et al. (2004) showed that a progressive decrease in Hdj1 (DNAJB2; 604139), Hdj2 (DNAJA1; 602837), Hsp70 (HSPA1A; 140550), alpha-SGT (SGTA; 603419), and beta-SGT brain levels likely contributes to disease pathogenesis in the R6/2 mouse model of HD. Despite a predominantly extranuclear location, Hdj1, Hdj2, Hsc70, alpha-SGT, and beta-SGT were found to colocalize with nuclear but not with extranuclear aggregates. Hdj1 and alpha-SGT mRNA levels did not change, suggesting the decrease in protein levels may be a consequence of their sequestration to aggregates or an increase in protein turnover. Ubiquitous overexpression of Hsp70 in the R6/2 mouse (as a result of crossing to Hsp70 transgenics) delayed aggregate formation by 1 week, had no effect on the detergent solubility of aggregates, and did not alter the course of the neurologic phenotype. Radicicol and geldanamycin could both maintain chaperone induction for at least 3 weeks and alter the detergent solubility properties of polyQ aggregates over this time course.
Ruan et al. (2004) treated immortalized striatal cells from HdhQ7 (wildtype) and HdhQ111 (mutant) mouse knockin embryos with 3-nitropropionic acid (3-NP), a mitochondrial complex II toxin. 3-NP treatment caused significantly greater cell death in mutant striatal cells compared with wildtype cells. In contrast, the extent of cell death induced by rotenone, a complex I inhibitor, was similar in both cell lines. Although evidence of apoptosis was present in 3-NP-treated wildtype striatal cells, it was absent in 3-NP-treated mutant cells. 3-NP treatment caused a greater loss of mitochondrial membrane potential in mutant striatal cells compared with wildtype cells. Cyclosporine A, an inhibitor of mitochondrial permeability transition pore (PTP), and ruthenium red, an inhibitor of the mitochondrial calcium uniporter, both rescued mutant striatal cells from 3-NP-induced cell death and prevented the loss of mitochondrial membrane potential. The authors concluded that mutant Htt specifically increases cell vulnerability to mitochondrial complex II inhibition, and may switch the type of cell death induced by complex II inhibition from apoptosis to a nonapoptotic form.
Choo et al. (2004) examined mitochondria in human neuroblastoma cells and clonal striatal cells established from Hdh(Q7) (wildtype) and Hdh(Q111) mutant homozygote mouse knockin embryos. Huntingtin was associated with the outer mitochondrial membrane, and recombinant mutant huntingtin proteins decreased the Ca(2+) threshold necessary to trigger mitochondrial permeability transition (MPT) pore opening. The mutant huntingtin protein-induced MPT pore opening was accompanied by a significant release of cytochrome c (CYCS; 123970), an effect completely inhibited by cyclosporine A. The authors suggested that the development of specific MPT inhibitors may be a therapeutic avenue to delay the onset of HD.
Inhibition of polyglutamine-induced protein aggregation could provide treatment options for polyglutamine diseases such as HD. Tanaka et al. (2004) showed through in vitro screening studies that various disaccharides can inhibit polyglutamine-mediated protein aggregation. They also found that various disaccharides reduced polyglutamine aggregates and increased survival in a cellular model of HD. Oral administration of trehalose, the most effective of these disaccharides, decreased polyglutamine aggregates in cerebrum and liver, improved motor dysfunction, and extended life span in a transgenic mouse model of HD. Tanaka et al. (2004) suggested that these beneficial effects are the result of trehalose binding to expanded polyglutamines and stabilizing the partially unfolded polyglutamine-containing protein. Lack of toxicity and high solubility, coupled with efficacy upon oral administration, made trehalose promising as a therapeutic drug or lead component for the treatment of polyglutamine diseases. The saccharide-polyglutamine interaction identified by Tanaka et al. (2004) thus provided a possible new therapeutic strategy for polyglutamine diseases.
Sang et al. (2005) reported that polyglutamine-induced cell death was dramatically suppressed in flies lacking Dark, the fly homolog of human APAF1 (602233). Dark appeared to play a role in the accumulation of polyglutamine-containing aggregates. Suppression of cell death, caspase activation, and aggregate formation were also observed when mutant huntingtin exon 1 was expressed in homozygous Dark-mutant flies. Expanded polyglutamine induced a marked increase in expression of Dark, and Dark colocalized with ubiquitinated protein aggregates. APAF1 colocalized with huntingtin-containing aggregates in a murine model and HD brain, suggesting a common role for Dark/APAF1 in polyglutamine pathogenesis in invertebrates, mice, and man. These findings suggest that limiting APAF1 activity may alleviate both pathologic protein aggregation and neuronal cell death in HD.
Berger et al. (2005) demonstrated in Drosophila that lithium could protect against the toxicity caused by aggregate-prone proteins with either polyglutamine or polyalanine expansions. The protective effect could be partly accounted for by lithium acting through the Wnt/Wg (604663) pathway, as a GSK3B (605004)-specific inhibitor and overexpression of Drosophila Tcf (153245) also mediated protective effects. The authors suggested that lithium may deserve consideration as a therapeutic for polyglutamine diseases.
In the R6/2 mouse model of Huntington disease, Chou et al. (2005) showed that an agonist of the ADORA2A receptor (102776), CGS21680 (CGS), attenuated neuronal symptoms of HD. Subsequently, Chiang et al. (2009) showed that A2a receptors are present in liver and that CGS also ameliorated a urea cycle deficiency by reducing mouse Htt aggregates in the liver. By suppressing aggregate formation, CGS slowed the hijacking of a crucial transcription factor (HSF1; 140580) and 2 protein chaperones, Hsp27 (HSPB1; 602195) and Hsp70 (HSPA1A; 140550), into hepatic Htt aggregates. The abnormally high levels of high-molecular-mass ubiquitin conjugates in the liver of R6/2 mouse model of HD were also ameliorated by CGS. The protective effect of CGS against mouse Htt-induced aggregate formation was reproduced in 2 cell lines and was prevented by an antagonist of the A2a receptor and a protein kinase A (PKA) inhibitor. The mouse Htt-induced suppression of proteasome activity was also normalized by CGS through PKA (PRKACA; 601639).
Borrell-Pages et al. (2006) found that Hsj1 (DNAJB2; 604139) proteins protected rat striatal neurons from polyQ-huntingtin-induced cell death. Hsj1a reduced intranuclear inclusions by acting as a typical chaperone that unfolds misfolded proteins, whereas Hsj1b had a neuroprotective effect by inhibiting cell death without any major effects in polyQ-huntingtin aggregation. Hsj1b mediated its beneficial effects by promoting release of BDNF (113505) from the Golgi apparatus in neuronal cells. Postmortem brain tissue from patients with Huntington disease showed significantly decreased levels of HSJ1b compared to controls. Treatment with cystamine, a transglutaminase inhibitor, increased Hsj1b levels and increased levels of BDNF in mouse neuronal cells and in a mouse model of Huntington disease and showed a neuroprotective effect. Treatment of rodent and primate models of HD with cystamine and cysteamine resulted in a transient increase in peripheral blood levels of BDNF in these animals.
Using two mouse models of HD, Phan et al. (2009) demonstrated that adipose tissue dysfunction was detectable at early ages and became more pronounced as the disease progressed. HD mice exhibited reduced levels of leptin (LEP; 164160) and adiponectin (ADIPOQ; 605441), which are adipose tissue-derived hormones that regulate food intake and glucose metabolism. Impaired gene expression and lipid accumulation in adipocytes could be recapitulated by expression of an inducible mutant HTT transgene in an adipocyte cell line, and mutant HTT inhibited transcriptional activity of the coactivator PPARGC1A (604517) in adipocytes, which may contribute to aberrant gene expression. Phan et al. (2009) concluded that mutant huntingtin may have a direct detrimental effects in cell types other than neurons, and that circulating adipose-tissue-derived hormones may be accessible markers for HD prognosis and progression.
In neurons from a rat model of HD, Okamoto et al. (2009) found that inhibition of synaptic NMDA receptor activity resulted in decreased mutant Htt inclusions. Stimulation of synaptic NMDAR activity induced mutant Htt inclusions via a TCP1 (186980) ring complex-dependent mechanism, which rendered neurons more resistant to mutant Htt-mediated cell death. In contrast, stimulation of extrasynaptic NMDARs increased the vulnerability of mutant Htt-containing neurons to cell death by impairing the neuroprotective CREB (123810)-PGC1A (604517) cascade and increasing the level of the small guanine nucleotide-binding protein Rhes (612842), which is known to sumoylate and disaggregate mutant Htt. Treatment of transgenic mice expressing a mutant Htt protein with low-dose memantine blocked extrasynaptic, but not synaptic, NMDARs and ameliorated neuropathologic and behavioral manifestations. In contrast, high-dose memantine, which blocks both extrasynaptic and synaptic NMDAR activity, decreased neuronal inclusions and worsened the outcome. The findings helped explain the selective vulnerability of striatal and cortical neurons in HD, and indicated that a balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin.
Becanovic et al. (2010) performed genomewide expression profiling of the YAC128 transgenic mouse model of HD at 12 and 24 months of age by use of 2 microarray platforms in parallel. The authors identified 13 genes that were differentially expressed between YAC128 and controls and the findings were validated by quantitative real-time PCR in independent cohorts of animals. The RNA levels of Wt1 (607102), Pcdh20, and Actn2 (102573) changed as early as 3 months of age, whereas Gsg1l, Sfmbt2 (615392), Acy3 (614413), Polr2a (180660), and Ppp1r9a (602468) expression levels were not affected until 12 to 24 months of age. Between human HD and control brain, altered expression levels were evident in SLC45A3 (605097), PCDH20 (614449), ACTN2, DDAH1 (604743), and PPP1R9A.
Chiang et al. (2010) reported that the transcript of the peroxisome proliferator-activated receptor-gamma (PPARG; 601487), a transcription factor that is critical for energy homeostasis, was markedly downregulated in multiple tissues of the R6/2 mouse model of HD and in lymphocytes of HD patients. Chronic treatment of R6/2 mice with an agonist of PPARG (thiazolidinedione, TZD) rescued progressive weight loss, motor deterioration, formation of mutant Htt aggregates, jeopardized global ubiquitination profiles, reduced expression of 2 neuroprotective proteins (BDNF, 113505 and BCL2, 151430) and shortened life span exhibited by these mice. By reducing HTT aggregates and, thus, ameliorating the recruitment of PPARG into HTT aggregates, chronic TZD treatment also elevated the availability of the PPARG protein and subsequently normalized the expression of 2 of its downstream genes, the glucose transporter type 4 (GLUT4; 138390) and PPARG coactivator-1 alpha (PPARGC1A; 604517). In addition, the PPARG agonist rosiglitazone protected striatal cells from mHTT-evoked energy deficiency and toxicity. The authors concluded that the systematic downregulation of PPARG may play a critical role in the dysregulation of energy homeostasis observed in HD, and that PPARG may be a potential therapeutic target for this disease.
Metabolites in the kynurenine pathway of tryptophan degradation in mammals are thought to play an important role in neurodegenerative disorders, including Huntington disease. Kynurenic acid (KYNA) had been shown to reduce neuronal vulnerability in animal models by inhibiting ionotropic excitatory amino acid receptors, and is neuroprotective in animal models of brain ischemia. Zwilling et al. (2011) synthesized a small-molecule prodrug inhibitor of kynurenine 3-monooxygenase (KMO; 603538), termed JM6, and found that oral administration of JM6 to rats increased KYNA levels and reduced extracellular glutamate in the brain. In a mouse model of Huntington disease, JM6 extended life span, prevented synaptic loss, and decreased microglial activation. These findings supported a critical link between tryptophan metabolism in the blood and neurodegeneration.
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