POLG-Related Disorders

Clinical characteristics.

POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined before the molecular basis was known. POLG-related disorders can therefore be considered an overlapping spectrum of disease presenting from early childhood to late adulthood. The age of onset broadly correlates with the clinical phenotype.

In individuals with early-onset disease (prior to age 12 years), liver involvement, feeding difficulties, seizures, hypotonia, and muscle weakness are the most common clinical features. This group has the worst prognosis.

In the juvenile/adult-onset form (age 12-40 years), disease is typically characterized by peripheral neuropathy, ataxia, seizures, stroke-like episodes, and, in individuals with longer survival, progressive external ophthalmoplegia (PEO). This group generally has a better prognosis than the early-onset group.

Late-onset disease (after age 40 years) is characterized by ptosis and PEO, with additional features such as peripheral neuropathy, ataxia, and muscle weakness. This group overall has the best prognosis.

Diagnosis/testing.

Establishing the diagnosis of a POLG-related disorder relies on clinical findings and the identification of biallelic POLG pathogenic variants on molecular genetic testing for all phenotypes except autosomal dominant progressive external ophthalmoplegia (adPEO), for which identification of a heterozygous POLG pathogenic variant on molecular genetic testing is diagnostic.

Management.

Treatment of manifestations: Clinical management is largely supportive and involves standard approaches for associated complications including occupational, physical, and speech therapy; nutritional support; respiratory support; and standard treatment of liver failure, epilepsy, movement abnormalities, sleep disorders, vision, and hearing issues.

Surveillance: Evaluations by a multidisciplinary team of health care providers based on clinical findings; routine evaluation of growth, nutrition, oral intake, and respiratory status; monitoring of liver enzymes every three months or as clinically indicated; monitoring of epilepsy with repeat liver function tests after introduction of any new anti-seizure medication.

Agents/circumstances to avoid: Valproic acid (Depakene^®) and sodium divalproate (divalproex) (Depakote^®) because of the risk of precipitating and/or accelerating liver disease.

Genetic counseling.

Early-onset and juvenile/adult-onset POLG-related disorders are typically caused by biallelic pathogenic variants and inherited in an autosomal recessive manner. Late-onset PEO may be caused by a heterozygous POLG pathogenic variant and inherited in an autosomal dominant manner.

Autosomal recessive inheritance: If both parents are known to be heterozygous for a POLG pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial POLG pathogenic variants. Heterozygous sibs of a proband with an autosomal recessive POLG-related disorder are typically asymptomatic. Once the POLG pathogenic variants have been identified in an affected family member, testing for at-risk family members is possible.

Autosomal dominant inheritance: Most individuals with PEO caused by a heterozygous POLG pathogenic variant (i.e., adPEO) have an affected parent, although age of onset and severity of presentation can vary greatly from generation to generation. Each child of an individual with POLG-related adPEO has a 50% chance of inheriting the pathogenic variant.

Once the POLG pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for POLG-related disorders is possible.

Suggestive Findings

POLG-related disorders comprise a continuum of overlapping phenotypes. A POLG-related disorder should be suspected in individuals with combinations of the following clinical features and laboratory and neuroimaging findings.

Clinical features. Clinical features form a continuum but vary in their age of onset. Apart from progressive external ophthalmoplegia (PEO) / ptosis, other features could present at any time from infancy to adulthood. The most common clinical features by age of onset are:

• Prior to age 12 years (early-onset disease):
  • Liver involvement (See Laboratory Findings.)
  • Feeding difficulties
  • Seizures
  • Hypotonia and muscle weakness that can evolve into corticospinal tract dysfunction (spasticity and dystonia)
• Between age 12 and 40 years (juvenile/adult-onset disease):
  • Ataxia
  • Peripheral neuropathy
  • Seizures
  • Stroke-like episodes
  • PEO (in individuals with longer survival)
• After age 40 years (late-onset disease):
  • Ptosis
  • PEO
  • Ataxia
  • Muscle weakness
• Other features
  • Developmental delay, especially in childhood-onset disease
  • Movement disorder (e.g., myoclonus, dysarthria, choreoathetosis, parkinsonism)
  • Myopathy (e.g., proximal > distal limb weakness with fatigue and exercise intolerance)
  • Episodic psychomotor regression
  • Psychiatric illness (e.g., depression, mood disorder), more commonly reported in adult-onset phenotypes
  • Endocrinopathy (e.g., premature ovarian failure)

Laboratory findings

• Elevated serum lactate in serum and cerebrospinal fluid (CSF) is common throughout the spectrum of phenotypes but is more common in early-onset disease (however, normal values do not eliminate the likelihood of a POLG-related disorder).
• CSF protein levels are generally elevated in individuals with Alpers-Huttenlocher syndrome (AHS) and other POLG-related disorders, but absence of this finding does not exclude a POLG-related disorder.
• Evidence of liver dysfunction or failure can be present, which may occur following exposure to certain anti-seizure medications. This could result in elevation of liver enzymes (alanine transaminase, aspartate transaminase, and gamma-glutamyl transferase) as well as synthetic liver dysfunction, causing hypoglycemia, hyperammonemia, elevated glutamine, hyperbilirubinemia, prolonged bleeding times (international normalized ratio, prothrombin time, partial thromboplastin time), hypoalbuminemia, and low cholesterol levels.
• Respiratory chain defect and/or a defect of mitochondrial DNA (mtDNA) (depletion or multiple deletions) can be present. This could result in respiratory chain dysfunction, identified by either enzymatic assays or polarographic assays. Depletion of mtDNA can be measured by comparing mtDNA to nuclear DNA content in an affected tissue (e.g., liver). Normal respiratory chain function or absence of mtDNA depletion does not rule out a POLG-related disorder.
• In muscle biopsy samples, ragged-red fibers, COX-negative fibers, excessive lipid deposits, and abnormal respiratory chain activities can be present. However, biochemical findings on muscle biopsy can be normal.

Neuroimaging features

• Brain computerized tomography (CT) or magnetic resonance imaging (MRI) may be normal early in the course of AHS.
• As AHS evolves, neuroimaging shows gliosis (initially more pronounced in occipital lobe regions) and generalized brain atrophy. These findings are also reported in some individuals with adult-onset POLG-related disorders.
• Cortical focal lesions manifesting as T₂/FLAIR hyperintensities in cortical and subcortical areas can be seen. These findings are typical in AHS but have also been reported in sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO) and ataxia neuropathy spectrum (ANS) [Parada-Garza et al 2020, García-Cabo et al 2023].

Other diagnostic studies

• Abnormal epileptiform activity over the occipital lobes in individuals with epilepsy
• Abnormal nerve conduction studies (NCVs)

Establishing the Diagnosis

The diagnosis of most POLG-related disorders is established in a proband by identification of biallelic pathogenic (or likely pathogenic) variants in POLG by molecular genetic testing (see Table 1). The diagnosis of autosomal dominant progressive external ophthalmoplegia (adPEO) is established in a proband by identification of a heterozygous pathogenic (or likely pathogenic) variant in POLG by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 2

Comprehensive genomic testing including exome sequencing, mtDNA sequencing, and genome sequencing may be considered.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in POLG-Related Disorders

Clinical Description

POLG-related disorders comprise a continuum of broad and overlapping phenotypes that range from fatal neonatal-onset disease to mild late-onset disease with myopathy and progressive external ophthalmoplegia (PEO).

Although some affected individuals present with one of the clinical entities caused by POLG pathogenic variants, many have some, but not all, of the features of one or more of the recognized phenotypes. Although clinical phenotypes in affected individuals from the same family are often similar, ages of onset, specific features, and rate of progression may differ. POLG-related disorders can therefore be considered an overlapping spectrum of disease presenting from early childhood to late adulthood. The age of onset broadly correlates with the clinical phenotype [Rahman & Copeland 2019, Hikmat et al 2020]. Table 2 summarizes the clinical findings in POLG-related disorders.

Table 2.

Clinical Findings in POLG-Related Disorders

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Nomenclature

In a study of 155 individuals with POLG-related disorders in which the age of onset of features was analyzed by median age rather than age range, Hikmat et al [2020] observed that age of onset broadly correlates with clinical phenotype (see GeneReview Scope) and prognosis. Based on this observation, Hikmat et al [2020] proposed the following system of classification that differs from the classic descriptions of POLG-related phenotypes and provides alternate nomenclature:

• Early-onset disease refers to individuals with onset prior to age 12 years. This classification encompasses Alpers-Huttenlocher syndrome (AHS) and childhood myocerebrohepatopathy spectrum (MCHS) and is associated with the worst prognosis.
• Juvenile/adult-onset disease refers to individuals with onset at age 12-40 years. This classification encompasses myoclonic epilepsy myopathy sensory ataxia (MEMSA) / spinocerebellar ataxia with epilepsy (SCAE) and ataxia neuropathy spectrum (ANS) and generally has a better prognosis than the early-onset disease group.
• Late-onset disease refers to individuals with onset after age 40 years. This classification encompasses autosomal recessive progressive external ophthalmoplegia (arPEO), autosomal dominant progressive external ophthalmoplegia (adPEO), and progressive external ophthalmoplegia plus (PEO-plus) and has the best prognosis overall.

Prevalence

AHS is reported to affect approximately 1:51,000 people [Darin et al 2001].

The combined frequency of the most common autosomal recessive pathogenic variants in POLG can be used to estimate disease frequency at 1:10,000. Common POLG variants include those in Table 3.

Table 3.

Frequency of the Most Common POLG Pathogenic Variants

Pathogenic variants in POLG, identified in nearly 50% of individuals with adPEO in one study [Lamantea et al 2002], may be the most frequent cause of adPEO.

Other Disorders to Consider

Leigh syndrome is a progressive neurodegenerative disorder characterized by hypotonia, spasticity, dystonia, muscle weakness, hypo- or hyperreflexia, seizures, movement disorders, cerebellar ataxia, and peripheral neuropathy. In individuals with Leigh syndrome, MRI changes most often occur initially in the brain stem, and the gliosis "migrates" over time to involve the deep gray masses and cortex, whereas in AHS the initial lesions form in the cerebral cortex (usually the occipital lobes), followed by the cerebellum, basal ganglia, thalamus, and brain stem. Epilepsia partialis continua (EPC), seen in Alpers-Huttenlocher syndrome (AHS), has been described in individuals with Leigh syndrome [Mameniškienė & Wolf 2017]. Most individuals with Leigh syndrome have an autosomal recessive or X-linked disorder of mitochondrial energy generation (see Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview); Leigh syndrome can also be caused by genetic alternations in mitochondrial DNA (see Mitochondrial DNA-Associated Leigh Syndrome and NARP and Single Large-Scale Mitochondrial DNA Deletion Syndromes).

For additional disorders to consider in the differential diagnosis of individuals presenting with ataxia, see Hereditary Ataxia Overview.

For additional disorders to consider in the differential diagnosis of individuals presenting with peripheral neuropathy, see Charcot-Marie-Tooth Hereditary Neuropathy Overview.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with POLG-related disorder, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to diagnosis) are recommended. Evaluation should always include measures of functional neurologic status.

Table 5.

POLG-Related Disorders: Recommended Evaluations Following Initial Diagnosis

Treatment of Manifestations

There is no cure for POLG-related disorders. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6).

Table 6.

POLG-related disorders: Treatment of Manifestations

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, evaluations by a multidisciplinary team including neurologist, biochemical geneticist, hepatologist or gastroenterologist, physiatrist, psychiatrist, neuropsychologist and/or psychologist, ophthalmologist, and pulmonologist are recommended. No standard-of-care guidelines regarding the recommended frequency of evaluations exist; surveillance should be guided by clinical features, and the schedule should be modified if the clinical course is stable. For those with the most severe phenotypes, the recommendations in Table 7 can be considered.

Table 7.

POLG-related disorders: Recommended Surveillance

Agents/Circumstances to Avoid

Valproic acid (Depakene^®) and sodium divalproate (divalproex) (Depakote^®) should be avoided because of the risk of precipitating and/or accelerating liver disease [Saneto et al 2010].

As with some other mitochondrial diseases, physical stressors such as infection, fever, dehydration, and anorexia can result in a sudden deterioration and should be avoided if possible.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Liver transplantation is not advised in children with Alpers-Huttenlocher syndrome (AHS) because transplanting the liver does not alter the rapid progression of the brain disease [Kelly 2000].

However, liver transplantation in adults who have an acceptable quality of life may be of benefit.

• In one report, one of two individuals undergoing liver transplantation survived [Tzoulis et al 2006]. In another report of solid organ transplantation in primary mitochondrial disease, of six individuals with POLG-related disease, two survived without complications [Parikh et al 2016].
• In another report, a woman underwent liver transplantation at age 19 years, eight years after experiencing fulminant hepatic failure following onset of valproate therapy. Molecular genetic testing seven years after her liver transplantation confirmed the diagnosis of a POLG-related disorder; her phenotype fit best with SANDO [Wong et al 2008, Parikh et al 2016].

The use of other treatments for refractory epilepsy, such as corticotropin or prednisone, ketogenic diet, and intravenous immunoglobulin G, are unproven in the treatment of AHS. The following, however, may be considered:

• Vitamin and cofactor therapy with the intent to fortify mitochondrial function may be offered, yet there is insufficient evidence demonstrating objective benefit in cohorts of persons. There have not been formal studies of the use of these vitamins and cofactors in AHS or other POLG-related disorders [Parikh et al 2009, Parikh et al 2015, Camp et al 2016].
• The use of folinic acid should be considered [Hasselmann et al 2010].
• The use of levoarginine has been reported to be helpful in reducing the frequency and severity of the strokes associated with MELAS, and can be considered for use in persons with POLG-related disorders, especially if deficiency in the plasma or cerebrospinal fluid arginine concentration is confirmed [El-Hattab et al 2017].
• The use of levocarnitine should be reserved for individuals with reduced free carnitine levels in the blood, and the levels should be monitored [Parikh et al 2015].
• Creatine monohydrate, coenzyme Q₁₀, B vitamins, and antioxidants such as alpha-lipoic acid, vitamin E, and vitamin C have been used as mitochondrial supplements based on limited case reports and small series but with a lack of objective evidence based on randomized controlled trials. Use of all in POLG-related disorders is reasonable given the general lack of toxicity but is not mandatory [Gold & Cohen 2001, Rodriguez et al 2007, Horvath et al 2008, Parikh et al 2013, Parikh et al 2015].

Mode of Inheritance

Early-onset and juvenile/adult-onset POLG-related disorders are typically caused by biallelic pathogenic variants and inherited in an autosomal recessive manner. Late-onset progressive external ophthalmoplegia (PEO) may be caused by a heterozygous POLG pathogenic variant and inherited in an autosomal dominant manner.

Note: Digenic inheritance involving pathogenic variants in POLG and TWNK has been reported in two individuals with PEO [Van Goethem et al 2003a, Da Pozzo et al 2015].

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for a POLG pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a POLG pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband [Chan et al 2009, Lutz et al 2009] or as a postzygotic de novo event in a mosaic parent. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygous parents of a child with an autosomal recessive POLG-related disorder are typically asymptomatic.

Sibs of a proband

• If both parents are known to be heterozygous for a POLG pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial POLG pathogenic variants.
• The POLG-related phenotype is usually similar in affected family members; less commonly, affected sibs may present differently in terms of age of onset, specific clinical features, and severity. For example, in a family in which affected sibs were compound heterozygotes (POLG pathogenic variants p.Gly848Ser and p.Trp748Ser), one sib presented with developmental delays and status epilepticus at age three years, while the other sib presented with ataxia and myoclonus in early adolescence [Tang et al 2011].
• Heterozygous sibs of a proband with an autosomal recessive POLG-related disorder are typically asymptomatic.

Offspring of a proband

• Unless an affected individual's reproductive partner also has POLG-related pathogenic variant(s), offspring will be obligate heterozygotes (carriers) for a pathogenic variant in POLG (see Family planning).
• Individuals with early-onset POLG-related disorders (e.g., Alpers-Huttenlocher syndrome and childhood myocerebrohepatopathy spectrum) are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for a POLG pathogenic variant.

Carrier (heterozygote) detection. Carrier testing for at-risk relatives requires prior identification of the POLG pathogenic variants in the family.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Most individuals with PEO caused by a heterozygous POLG pathogenic variant (i.e., autosomal dominant PEO or adPEO) have an affected parent, although age of onset and severity of presentation can vary greatly from generation to generation.
• Some individuals diagnosed with adPEO have the disorder as the result of a de novo POLG pathogenic variant. The proportion of probands who have a de novo pathogenic variant is unknown but thought to be low (<1%).
• If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents include molecular genetic testing for the POLG pathogenic variant identified in the proband, a complete family history, and physical examination focusing on the most common features of POLG-related disease (ophthalmoplegia, myopathy, ataxia, and neuropathy). Note: Because migraine, depression, gastrointestinal problems, fatigue, exercise intolerance, and seizures are common in the general population, their presence as isolated findings is not likely to be relevant.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation, failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. The POLG-related phenotype is generally similar in affected family members, although the age of onset can vary significantly. Data on penetrance of adPEO are not available.
• If the POLG pathogenic variant is not detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the POLG pathogenic variant but are clinically unaffected, sibs of a proband are still presumed to be at increased risk for adPEO because of the possibility of late onset in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with POLG-related adPEO has a 50% chance of inheriting the POLG pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has a POLG pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

At-risk family members. Sibs who are close in age to or younger than the proband may still be at risk and in need of diagnostic evaluation. Note: Because the age of onset, even among family members with identical POLG pathogenic variants, can vary considerably, there is no firm certainty as to how many years need to pass before there is no longer a risk of POLG-related features in a sib [Rahman & Copeland 2019].

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are at risk of having a POLG pathogenic variant.
• Carrier testing should be considered for the reproductive partners of individuals known to have a POLG pathogenic variant, particularly if consanguinity is likely and/or if both partners are of the same ancestry.

Prenatal Testing and Preimplantation Genetic Testing

Once the POLG pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for POLG-related disorders are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The mitochondrion comprises almost 1,500 proteins, but only the 13 that comprise small portions of the respiratory chain complexes I, III, IV, and V are encoded by the mitochondrial genome. The mitochondrial genome is a circular molecule that in humans contains 15,569 base pairs including 37 genes – 13 genes encoding for subunits of complexes I, III, IV, and V, as well as 22 tRNAs and 2 rRNAs – that are distinct and necessary for mitochondrial translation. The terminal portion of energy production occurs in the respiratory chain; disruption of the production and/or assembly of any component leads to a deficiency of ATP and resultant cellular energy failure. The cause of clinical symptoms likely includes insufficient ATP production, but also excessive free radical production, disturbed calcium handling, and other factors. Unlike nuclear DNA, mitochondrial DNA (mtDNA) replicates continuously and independently of cell division. Polymerase (pol) gamma is the major DNA polymerase in humans required for replication and repair of mtDNA. Replication of mtDNA requires a heterotrimer of one catalytic subunit of pol gamma and two accessory subunits, encoded by POLG2, that assist in binding and processing the synthesized DNA. The twinkle protein, encoded by TWNK, functions as the 5' → 3' DNA helicase.

POLG encodes DNA pol gamma, which has three functional domains:

• Exonuclease, responsible for proofreading (first third of the protein)
• Linker region (center of the protein)
• Polymerase, responsible for replication (last third of the protein)

The clinical features POLG-related disorders most likely result from mtDNA depletion or multiple mtDNA deletions [Lujan et al 2020] over time of normal mtDNA, with resultant reduced electron transport chain activity. The adPEO-causing pathogenic variants cluster in the active site region of the DNA polymerase.

Mechanism of disease causation. Loss of POLG function results in loss of polymerase activity – resulting in loss of mtDNA – or loss of endonuclease function – resulting in non-fidelity of mtDNA replication – or both. The loss of mtDNA results in loss of normal mitochondrial translation as well as loss of function involving mtDNA-encoded subunits found in complexes I, III, IV, and V. The result is loss of normal ATP production and elevated free radical production and other mitochondrial functions, with resultant injury to neurons and other cells.

Table 8.

POLG Pathogenic Variants Referenced in This GeneReview

An up-to-date listing of all pathogenic variants is available at tools.niehs.nih.gov, managed by William Copeland, PhD.

Author Notes

Bruce H Cohen is a clinician caring for children and adults with mitochondrial disease since his training starting four decades ago. He first began caring for patients with POLG disease ten years before the POLG gene was cloned and characterized by Dr Copeland and has followed the work of the coauthors over the last 25 years. He has lectured hundreds of times to medical audiences and families on the topic of mitochondrial medicine. For the last decade his focus has been on clinical trials for mitochondrial disease.

Web pages: ‪‪Google Scholar‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬ and Akron Children's

William C Copeland is a biochemist studying mitochondrial DNA replication. He has been leading the Mitochondrial DNA Replication group at the National Institute of Environmental Health Sciences for more than 30 years and is currently the Chief of the Genome Integrity and Structural Biology Laboratory. He uses biochemistry, enzyme kinetics, structural biology, and genetics to study the consequences of POLG pathogenic variants.

William C Copeland, PhD
Chief, Genome Integrity and Structural Biology Laboratory;
Principal Investigator, Mitochondrial DNA Replication Group,
National Institute of Environmental Health Sciences
111 TW Alexander Dr
Research Triangle Park, NC 27709
Phone: 984-287-4269
Email: vog.hin.shein@1nalepoc
Web page:www.niehs.nih.gov
POLG mutation database: tools.niehs.nih.gov

Patrick F Chinnery is a neurologist and clinician-scientist caring for adults with mitochondrial disorders. He runs a laboratory and clinical research group studying disease mechanisms and developing new treatments for mitochondrial disorders based at the MRC Mitochondrial Biology Unit and Department of Clinical Neurosciences, University of Cambridge, United Kingdome.

Web pages: ORCID, Cambridge Clinical Mitochondrial Research Group, and MRC Mitochondrial Biology Unit – Chinnery Group

Patrick F Chinnery, FRCP, FMedSci
Professor of Neurology, University of Cambridge
Department of Clinical Neurosciences
University Neurology Unit
Level 5 'A' Block, Box 165
Cambridge Biomedical Campus
Cambridge, CB2 0QQ, United Kingdom
Email: ku.ca.mac@52cfp

Bruce Cohen (gro.snerdlihcnorka@nehocb) and Patrick Chinnery (ku.ca.mac@52cfp) are actively involved in clinical research regarding individuals with POLG-related disorders. They would be happy to communicate with persons who have any questions regarding diagnosis of POLG-related disorders or other considerations.

Bruce Cohen (gro.snerdlihcnorka@nehocb), Patrick Chinnery (ku.ca.mac@52cfp), and Bill Copeland (vog.hin.shein@1nalepoc) are also interested in hearing from clinicians treating families affected by mitochondrial disorders in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Dr Bill Copeland (vog.hin.shein@1nalepoc) to inquire about review of POLG variants of uncertain significance.

The Mitochondrial Medicine Society (MMS) represents an international group of physicians, researchers, and clinicians working toward advancing education, research, and global collaboration in clinical mitochondrial medicine. Information about the MMS and educational resources can be found at www.mitosoc.org.

Acknowledgments

Funding: This work was funded in part by the Intramural Research Program of the NIEHS, National Institutes of Health [Z01ES065078 and Z01ES065080] to W.C.C.

P.F.C. is currently funded by a Wellcome Discovery Award (226653/Z/22/Z), a Wellcome Collaborative Award (224486/Z/21/Z), the Medical Research Council Mitochondrial Biology Unit (MC_UU_00028/7), the Biological and Biotechnology Research Council (BB/Y003209/1), and the LifeArc Centre to Treat Mitochondrial Diseases (LAC-TreatMito). His research is supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Revision History

• 29 February 2024 (gm) Comprehensive update posted live
• 1 March 2018 (sw) Comprehensive update posted live
• 18 December 2014 (me) Comprehensive update posted live
• 11 October 2012 (me) Comprehensive update posted live
• 16 March 2010 (me) Review posted live
• 9 December 2007 (bhc) Original submission

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