Other entities represented in this entry:
SNOMEDCT: 1208412003; ORPHA: 275872, 803; DO: 0060201;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.22 | Amyotrophic lateral sclerosis 10, with or without FTD | 612069 | Autosomal dominant | 3 | TARDBP | 605078 |
| 1p36.22 | Frontotemporal lobar degeneration, TARDBP-related | 612069 | Autosomal dominant | 3 | TARDBP | 605078 |
A number sign (#) is used with this entry because amyotrophic lateral sclerosis-10 with or without frontotemporal dementia (ALS10) is caused by heterozygous mutation in the TARDBP gene (605078), which encodes the TDP43 protein, on chromosome 1p36.
For a general phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis (ALS), see ALS1 (105400).
Some patients with mutations in the TARDBP gene develop frontotemporal dementia with TDP43-positive inclusions: see GRN-related FTLD-TDP (607485) for a general phenotypic description of FTLD with TDP43 inclusions. Patients with TARDBP mutations and frontotemporal dementia may or may not have associated signs of motor neuron disease.
Tagawa et al. (2007) described a Japanese family in which 4 members in 2 generations had adult onset of amyotrophic lateral sclerosis characterized by relatively rapid progression of bulbar symptoms. Autopsy of one of the patients showed neuropathology of the classic form, with degenerative changes restricted to the upper and lower motor neuron systems. In addition, Bunina bodies and ubiquitin-positive skein-like inclusions were found in the remaining lower motor neurons, and ubiquitin-positive intracytoplasmic inclusions were also found in the putaminal small neurons. The authors noted that these findings were typical of patients with sporadic ALS. Autosomal dominant inheritance was proposed, but no mutations were identified in the SOD1 gene (147450).
Sreedharan et al. (2008) described a Caucasian family of English descent segregating autosomal dominant amyotrophic lateral sclerosis with male-to-male transmission. Four of the affected individuals had definite ALS by the El Escorial criteria, and another recently symptomatic individual had probable ALS. Three had limb-onset ALS and 2 had bulbar-onset ALS. The mean age of symptoms onset was 47 years (range 44 to 52). Mean disease duration was 5.5 years (range 4 to 7) from symptom onset to death. The obligate carrier (who died aged 54 from severe coronary atheroma) was reported by family members to have had gait disturbance and declining upper limb strength consistent with ALS. There was no history of dementia or any atypical features in the kindred. Sreedharan et al. (2008) also reported a man who developed limb-onset ALS at age 72 with a disease duration of 3 years, and in a man who developed limb-onset ALS at age 65, with a disease duration of 5 years and no atypical features.
Van Deerlin et al. (2008) reported a Caucasian father and daughter with rapidly progressive ALS inherited in an autosomal dominant pattern. The daughter presented with dysarthria and dysphagia at age 51 years and had a rapidly progressive course involving the limbs and respiration. She died after 13 months. Her father had presented with arm weakness at age 47 years and died after 16 months. Postmortem examination showed findings consistent with ALS. Van Deerlin et al. (2008) also reported a Chinese family in which 5 members spanning 2 generations had ALS with onset between ages 41 and 60 years. Most showed rapid progression with death within 1 or 2 years. Both spinal and bulbar onset were reported. Postmortem examination of 2 patients showed changes consistent with ALS as well as TDP43-positive inclusions in upper and lower motor neurons and in various brain regions.
Kuhnlein et al. (2008) reported a German family with ALS10 confirmed by genetic analysis (G348C; 605078.0007). The proband presented at age 55 years with paresis of the right hand, which progressed rapidly to involve the arms and lower limbs and left her wheelchair-bound within 2.5 years. She died of respiratory insufficiency 3 years after disease onset. The patient's mother had died of respiratory insufficiency due to a similar disorder. There were no clinically relevant bulbar symptoms and no cognitive impairment.
Clinical Variability
Benajiba et al. (2009) reported a patient with onset of semantic dementia at age 50 years. She later developed ritual behaviors, apathy, social avoidance, aggressiveness, and bulimia, consistent with frontotemporal dementia (see 600274). She also had bulbar symptoms of ALS and upper and lower motor neuron disease in all 4 limbs. Her sister had dysarthria and dysphagia at age 57, later developed upper and lower limb motor neuron disease, and died at age 60. Their father reportedly had motor neuron disease without dementia. An unrelated patient had behavior disorders at age 52 consistent with frontotemporal dementia. She developed bulbar symptoms at age 54, and later motor neuron disease in the limbs. She died at age 58. All patients were found to carry the same heterozygous mutation in the TARDBP gene (G295S; 605078.0010). The findings expanded the phenotypic spectrum associated with mutations in the TARDBP gene.
Kovacs et al. (2009) reported a Hungarian man who showed marked personality changes beginning at age 35 years. This was followed by a rapid deterioration in attention and thinking with psychomotor agitation and insomnia, consistent with FTD. Neurologic examination showed supranuclear gaze palsy, hyperkinetic choreiform movements, motor stereotypies, and primitive reflexes. Motor neuron disease signs, rigidity, and cerebellar ataxia were not present. Brain MRI showed prominent atrophy of the mesencephalic tectum and caudate nuclei. He died at age 37 years of pulmonary edema secondary to cardiac failure. There was no family history of a similar disorder. Neuropathologic examination showed moderate atrophy of the frontal lobes and caudate nuclei, severe atrophy of tectum and tegmentum, and severe depigmentation of the substantia nigra. Microscopic analysis showed mild microvacuolar changes in the superficial cortical layers of the frontal and cingulate gyri, and neuronal loss and astrogliosis in the subcortical gray matter. Phospho-TDP43-immunoreactive deposits were present in neuronal cytoplasmic inclusions in various brain regions, including the cortex, basal ganglia, thalamus, and brainstem. Genetic analysis excluded a pathologic HTT (613004) expansion and identified a heterozygous mutation in the TARDBP gene (K263E; 605078.0011). The findings indicated that TARDBP mutations can be associated with a wider clinicopathologic spectrum of disorders than originally thought.
Gitcho et al. (2009) identified a heterozygous 2076G-A transition in the 3-prime untranslated region of the TARDBP gene (605078.0012) in affected members of 2 unrelated families with either ALS10 with or without frontotemporal dementia or isolated FTLD. The first family had 2 mutation carriers with a variable phenotype: the proband was a woman with frontotemporal dementia without motor disease, whereas her brother had lower motor neuron disease without dementia. The father and mother, from whom DNA was not available, had ALS and lower motor neuron disease, respectively, and it was not clear which parent likely transmitted the TARDBP mutation. Neuropathologic analysis of the proband, who did not have motor neuron disease, showed cortical atrophy, neuronal loss in the hippocampus, hippocampal sclerosis, and TDP43-positive neuronal cytoplasmic inclusions in the cortex and hippocampus. There was no evidence of motor neuron loss from the motor nuclei of the brainstem. The brother's neuropathologic findings were consistent with ALS and showed TDP43-immunoreactivity in the anterior horn cells of the spinal cord and neuronal cytoplasmic inclusions in the hippocampus. The second family included a patient with familial ALS; no neuropathology was available for that patient. These findings suggested that a common molecular pathology can result in clinically heterogeneous phenotypes.
Synofzik et al. (2014) identified a heterozygous A382T mutation in the TARDBP gene (605078.0013) in a Sardinian man with behavioral variant frontotemporal dementia without motor signs. The patient developed rapidly progressive dementia beginning at age 31, and was severely disabled with no meaningful communication or social interaction by age 37. Brain MRI showed generalized cerebral atrophy, particularly in the anterior temporal lobe and hippocampi. The patient had no evidence of ALS. His father, who was likely a carrier based on family history, did not show signs of dementia or ALS at age 63 years. Family history was positive for ALS without dementia in 2 individuals in antecedent generations; DNA was not available from these patients. The mutation was found by massively parallel sequencing of the proband and confirmed by Sanger sequencing. The findings confirmed that TARDBP mutations can cause a pure dementia phenotype.
Because TAR DNA-binding protein (TDP43) is the major protein in ubiquitinated inclusions in ALS, Sreedharan et al. (2008) investigated its role in the pathogenesis of the disorder. They screened 154 index familial ALS cases for mutations in the TARDBP gene, which encodes TDP43. Mutations in other genes associated with ALS had been excluded from these cases. They identified a missense mutation in exon 6 of the TARDBP gene in the index case from kindred ALS85, a Caucasian family of English descent. The mutation was predicted to result in substitution of valine for methionine at codon 337 (M337V; 605078.0001) and resides in a strongly phylogenetically conserved region of TDP43. The mutation segregated with disease and was present in 4 other affected individuals in 3 branches and 2 generations of the extended kindred and was absent from 9 unaffected sibs. Genomewide scan confirmed that linkage was restricted to chromosome 1p36, to a region containing the TARDBP locus. Sreedharan et al. (2008) sequenced all 6 exons of TARDBP in a cohort of 200 British sporadic ALS cases and identified another missense mutation (Q331L; 605078.0002) in a man who developed limb-onset ALS at age 72 with a disease duration of 3 years. No mutation was detected in a screen of all 6 exons from 500 British Caucasian controls. In a screen of TARDBP in 2 further cohorts, 172 Australian Caucasian sporadic ALS patients and 172 controls, as well as 200 British Caucasian controls, Sreedharan et al. (2008) found a missense mutation (G294A; 605078.0003) in a man who developed limb-onset ALS at age 65 with a disease duration of 5 years and no atypical features.
In affected members of the Japanese family with ALS previously described by Tagawa et al. (2007), Yokoseki et al. (2008) identified a heterozygous mutation in the TARDBP gene (Q343R; 605078.0008).
In affected members of a European family with ALS10, Gitcho et al. (2008) identified a heterozygous mutation in the TARDBP gene (A315T; 605078.0009).
Van Deerlin et al. (2008) identified heterozygous mutations in the TARDBP gene (605078.0004; 605078.0005) in affected individuals of 2 unrelated families with autosomal dominant ALS10.
Kabashi et al. (2008) screened a panel of familial and sporadic ALS cases for TARDBP mutations and found 8 missense mutations in 9 individuals. Protein lysates from individuals with ALS expressing TDP43 mutants showed accumulation of a smaller (approximately 28 kD) TDP43 protein product, mainly in a detergent-insoluble fraction.
Kuhnlein et al. (2008) identified mutations in the TARDBP gene in 2 (6.5%) of 31 probands with non-SOD1 familial ALS.
Millecamps et al. (2010) identified 6 different missense mutations in the TARDBP gene in 7 (4.3%) of 162 French probands with familial ALS. Three of the families had been previously reported. Patients with TARDBP mutations had disease onset predominantly in the upper limb. One-third of patients had rapid disease progression, two-thirds had a medium disease course, and 1 had a slow disease course. There was evidence of incomplete penetrance. One TARDBP mutation carrier developed frontotemporal dementia 1 year after the onset of motor weakness.
Corrado et al. (2009) identified 12 different missense mutations in the TARDBP gene (see, e.g., A382T; 605078.0013) in 18 of 666 Italian probands with ALS. Six were familial, and 12 were apparently sporadic. All patients had motor neuron disease, and none had dementia. All mutations were located in exon 6 of the gene, and the most common mutation was A382T, occurring in 7 patients. Haplotype analysis of A382T carriers suggested a founder effect.
Chio et al. (2010) identified a heterozygous A382T mutation in affected members of 3 unrelated Italian families with ALS10 with frontotemporal dementia. Affected individuals developed rapidly progressive muscle atrophy and weakness associated with hyperreflexia, dysarthria, dysphagia, and respiratory insufficiency between ages 25 and 78 years. Frontotemporal dementia, characterized by disinhibition, emotional lability, apathy, and executive dysfunction, developed soon after the onset of ALS. One mutation carrier did not manifest neurologic symptoms at age 65 years.
Corcia et al. (2012) identified 19 patients from 9 families with ALS10 and 9 patients with apparently sporadic ALS10. The patients were French, and all carried mutations in the TARDBP gene. The mean age at onset was 53.4 years, and the upper limb was the most common site of onset. Only 2 patients had dementia. The median disease duration was 63 months; 2 patients were alive after 8 years. This group of patients was compared to 3 cohorts: 737 patients with sporadic ALS; 192 patients with familial ALS and no mutation in the SOD1 (147450), TARDPB (605078), or FUS (137070) genes; and 58 patients with familial ALS due to SOD1 mutations. In TARDBP-positive patients, onset was earlier (p = 0.0003), upper limb onset was predominant (p = 0.002), and duration was longer (p = 0.0001) than in patients with sporadic ALS. The mean age at onset was not significantly different between TARDBP-positive and SOD1-positive groups. TARDBP-positive and SOD1-positive groups had the longest duration, but differed in site of onset: 60.7% upper limb onset for TARDBP-positive and 74.1% lower limb onset for SOD1+ (p less than 0.0001). The TARDBP-positive patients were pooled with 117 ALS10 patients reported in the literature. Among all those with TARDBP mutations, Caucasians tended to have upper limb onset, while Asians tended to have bulbar onset. Among those with TARDBP mutations, G298S (605078.0005) was associated with the shortest survival, whereas A315T (605078.0009) and M337V (605078.0001) were associated with longest duration.
Corrado et al. (2009) noted that the frequency of TARDBP mutations is not homogeneous among different populations. In particular, 26 of 39 ALS patients carrying TARDBP mutations had an Italian or French origin, suggesting higher frequency of TARDBP mutations in southern Europe (average 3.4%; 8% in France and 2.7% in Italy) than in other Caucasian populations (average 0.7%). After exclusion of the A382T (605078.0013) mutation, which is likely to be a founder mutation, the frequency of TARDBP mutations was still 3 times higher in southern European than in northern European populations.
Chio et al. (2011) identified the A382T mutation in 39 (28.7%) of 135 Sardinian patients with ALS, including 15 with familial disease and 24 with apparently sporadic disease. None of 156 ethnically matched controls carried the mutation. Haplotype analysis of 5 patients with the mutation identified a 94-SNP common risk haplotype spanning 663 kb across the TARDBP locus on chromosome 1p36.22. The findings suggested a founder effect in this population.
Wegorzewska et al. (2009) found that transgenic mice expressing a Tdp43 A315T mutation (605078.0009) developed progressive gait abnormalities at about 3 to 4 months of age and died at about 5 months of age. Postmortem examination showed accumulation of ubiquitinated proteins selectively in the cytoplasm of neurons in cortical layer 5, including the motor cortex. The inclusions did not stain for TDP43, but the changes were associated with neuronal loss and increased glial reaction. Examination of the spinal cord of mutant mice showed degeneration of descending motor axons and ubiquitin pathology in large neurons of the ventral horn; there was also loss of motor neurons. Mutant mice also showed Tdp43 C-terminal fragments in the brain and spinal cord prior to the onset of gait abnormalities. Wegorzewska et al. (2009) concluded that since cytoplasmic Tdp43 aggregates were not present in mutant mice, they are not required for neurodegeneration. These results indicated that the selective neuronal vulnerability in Tdp43-related neurodegeneration is related to altered DNA/RNA-binding protein function rather than to toxic aggregation.
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Corcia, P., Valdmanis, P., Millecamps, S., Lionnet, C., Blasco, H., Mouzat, K., Daoud, H., Belzil, V., Morales, R., Pageot, N., Danel-Brunaud, V., Vandenberghe, N., Pradat, P. F., Couratier, P., Salachas, F., Lumbroso, S., Rouleau, G. A., Meininger, V., Camu, W. Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations. Neurology 78: 1519-1526, 2012. [PubMed: 22539580] [Full Text: https://doi.org/10.1212/WNL.0b013e3182553c88]
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Millecamps, S., Salachas, F., Cazeneuve, C., Gordon, P., Bricka, B., Camuzat, A., Guillot-Noel, L., Russaouen, O., Bruneteau, G., Pradat, P.-F., Le Forestier, N., Vandenberghe, N., and 14 others. SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations. J. Med. Genet. 47: 554-560, 2010. [PubMed: 20577002] [Full Text: https://doi.org/10.1136/jmg.2010.077180]
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Yokoseki, A., Shiga, A., Tan, C.-F., Tagawa, A., Kaneko, H., Koyama, A., Eguchi, H., Tsujino, A., Ikeuchi, T., Kakita, A., Okamoto, K., Nishizawa, M., Takahashi, H., Onodera, O. TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann. Neurol. 63: 538-542, 2008. [PubMed: 18438952] [Full Text: https://doi.org/10.1002/ana.21392]