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POLG-Related Disorders

, MD, , MD, FRCP, FMedSci, and , PhD.

Author Information
, MD
NeuroDevelopmental Science Center
Children’s Hospital Medical Center of Akron
Northeast Ohio Medical University
Akron, Ohio
, MD, FRCP, FMedSci
Wellcome Trust Centre for Mitochondrial Research
Insitute of Genetic Medicine
Newcastle University
Newcastle upon Tyne, United Kingdom
, PhD
Mitochondrial DNA Replication Group
Laboratory of Molecular Genetics
National Institute of Environmental Health Sciences / NIH
Research Triangle Park, North Carolina

Initial Posting: ; Last Update: December 18, 2014.

Summary

Clinical characteristics.

POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined long before their molecular basis was known. These phenotypes exemplify the diversity that can result from mutation of a given gene. Most affected individuals have some, but not all, of the features of a given phenotype; nonetheless, the following nomenclature can assist the clinician in diagnosis and management. Onset of the POLG-related disorders ranges from infancy to late adulthood.

  • Alpers-Huttenlocher syndrome (AHS), one of the most severe phenotypes, is characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and hepatic failure.
  • Childhood myocerebrohepatopathy spectrum (MCHS) presents between the first few months of life up to about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other findings can include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss.
  • Myoclonic epilepsy myopathy sensory ataxia (MEMSA) now describes the spectrum of disorders with epilepsy, myopathy, and ataxia without ophthalmoplegia. MEMSA now includes the disorders previously described as spinocerebellar ataxia with epilepsy (SCAE).
  • The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). About 90% of persons in the ANS have ataxia and neuropathy as core features. Approximately two thirds develop seizures and almost one half develop ophthalmoplegia; clinical myopathy is rare.
  • Autosomal recessive progressive external ophthalmoplegia (arPEO) is characterized by progressive weakness of the extraocular eye muscles resulting in ptosis and ophthalmoparesis (or paresis of the extraocular muscles) without associated systemic involvement; however, caution is advised because many individuals with apparently isolated arPEO at the onset develop other manifestations of POLG-related disorders over years or decades. Of note, in the ANS spectrum the neuropathy commonly precedes the onset of PEO by years to decades.
  • Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, Parkinsonism, hypogonadism, and cataracts (in what has been called “chronic progressive external ophthalmoplegia plus,” or “CPEO+”).

Diagnosis/testing.

Establishing the diagnosis of a POLG-related disorder relies on clinical findings and identification of two (biallelic) POLG pathogenic variants for all phenotypes except adPEO, for which identification of one POLG pathogenic variant is diagnostic.

Management.

Treatment of manifestations: Clinical management is largely supportive and involves conventional approaches for associated complications including physiotherapy, speech therapy, nutritional interventions, respiratory support, and management of seizures and movement disorders.

Prevention of secondary complications: Dose reductions of medications metabolized by hepatic enzymes to avoid toxicity.

Surveillance: Evaluations by a multidisciplinary team of healthcare providers based on clinical findings; monitoring of liver enzymes every two to four weeks after introduction of any new anticonvulsant.

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.

The POLG-related disorders in the spectrum of AHS, MCHS, MEMSA, ANS, and arPEO are inherited in an autosomal recessive manner. Autosomal dominant PEO (adPEO) is inherited in an autosomal dominant manner. For autosomal recessive phenotypes: heterozygotes (carriers) are generally believed to be asymptomatic; the offspring of carrier parents have a 25% chance of being affected, a 50% chance of being carriers, and a 25% chance of being unaffected and not carriers; carrier testing for at-risk family members is possible if the pathogenic variants in the family are known. For the autosomal dominant phenotype: most affected individuals have an affected parent; each child of an affected individual has a 50% chance of inheriting the pathogenic variant. For pregnancies at increased risk for all phenotypes, prenatal diagnosis is possible if the pathogenic variant(s) in the family are known.

GeneReview Scope

POLG-Related Disorders: Included Disorders
  • Alpers-Huttenlocher syndrome
  • Childhood myocerebrohepatopathy spectrum disorders
  • Myoclonic epilepsy myopathy sensory ataxia
  • POLG-related ataxia neuropathy spectrum disorders
  • Autosomal recessive progressive external ophthalmoplegia
  • Autosomal dominant progressive external ophthalmoplegia

For synonyms and outdated names see Nomenclature.

Diagnosis

Clinical Diagnosis

POLG-related disorders comprise a continuum of overlapping phenotypes that were originally thought to be distinct clinical entities [Van Goethem et al 2001, Lamantea et al 2002, Van Goethem et al 2003b, Luoma et al 2004, Naviaux & Nguyen 2004, Ferrari et al 2005, Luoma et al 2005, Horvath et al 2006, Tzoulis et al 2006, Wong et al 2008].

Description of the phenotypes associated with POLG pathogenic variants is ongoing; thus, it is likely that neither the full spectrum nor the extent to which the recognized phenotypes overlap is yet known.

Clinical diagnostic criteria do not exist. Establishing the diagnosis of a POLG-related disorder requires identification of two (biallelic) POLG pathogenic variants for each of the following phenotypes except adPEO, for which identification of one dominant POLG pathogenic variant is diagnostic.

Alpers-Huttenlocher syndrome (AHS)

  • Onset usually between ages two and four years and up to age 25-35
  • Often preexisting developmental delays of variable severity
  • Seizures
  • Episodic psychomotor regression
  • Liver dysfunction or failure, which may follow exposure to certain antiepileptic drugs

Childhood myocerebrohepatopathy spectrum (MCHS)

  • Myopathy or hypotonia
  • Developmental delay or encephalopathy
  • Liver dysfunction

Myoclonic epilepsy myopathy sensory ataxia (MEMSA); includes disorders previously referred to as spinocerebellar ataxia with epilepsy (SCAE)

  • Epilepsy
  • Myoclonus
  • Myopathy
  • Sensory ataxia

Ataxia neuropathy spectrum (ANS); includes disorders previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO)

  • Cerebellar ataxia
  • Sensory ataxia
  • Axonal peripheral sensorimotor neuropathy
  • Sensory neuropathy and dorsal root ganglionopathy
  • Encephalopathy with seizures (in some cases)
  • Ophthalmoplegia (in some cases)
  • Dysarthria (in some cases)

Autosomal recessive progressive external ophthalmoplegia (arPEO)

Autosomal dominant progressive external ophthalmoplegia (adPEO)

  • PEO: ptosis (drooping of the eyelids) and ophthalmoplegia (paralysis of the extraocular muscles)
  • Other features variably present: limb weakness, parkinsonism, premature ovarian failure, and depression (mood disorder); often referred to as “chronic progressive external ophthalmoplegia plus” (CPEO+)

Testing

Biochemical analysis of an affected tissue may reveal a respiratory chain defect and/or a defect of mitochondrial DNA (depletion or multiple deletions). However, biochemical findings on muscle biopsy can be completely normal in children [de Vries et al 2008] and adults with a POLG-related disorder and in clinically unaffected tissue. Thus, these enzymatic defects are not sufficiently sensitive or specific in the diagnosis of POLG-related disorders and normal respiratory chain function or absence of mtDNA depletion should not be used to eliminate consideration of a POLG-related disorder.

Molecular Genetic Testing

Gene. POLG is the only gene in which pathogenic variants are known to cause POLG-related disorders.

Clinical testing

Table 1.

Summary of Molecular Genetic Testing Used in POLG-Related Disorders

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
POLGTargeted mutation analysis 2, 3100% for the indicated pathogenic variants only 4
Sequence analysis 5/ mutation scanning 6>95% 7
Sequence analysis of select exons 8Unknown
Deletion/duplication analysis 9Rare
1.

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Targeted mutation analysis refers to testing for specific common POLG pathogenic variant(s).

3.

The p.Ala467Thr pathogenic variant is the most common POLG pathogenic variant associated with AHS and is found in almost half of all affected individuals. Two other specific pathogenic variants tested are p.Trp748Ser and p.Gly848Ser. The p.Ala467Thr and p.Trp748Ser pathogenic variants are most often associated with AHS in European studies. The targeted pathogenic variants that are tested may vary by laboratory.

4.

Although collectively the p.Ala467Thr, p.Trp748Ser, and p.Gly848Ser pathogenic variants may be found in up to 70% of affected individuals, the need to detect two mutant alleles in an individual with this autosomal recessive disorder usually requires full sequence analysis.

5.

Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6.

Sequence analysis and mutation scanning of the entire gene can have similar variant detection frequencies; however, variant detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.

7.

Because of the difficulty of detecting microdeletions by conventional sequence analysis, mutation frequency is less than 100%.

8.

Generally detects sequence variants in and flanking exon 7, 13, and 16, although the exons sequenced may vary by laboratory.

9.

Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Interpretation of test results

  • Establishing the diagnosis of a POLG-related disorder requires identification of two (biallelic) POLG pathogenic variants for each of the phenotypes except adPEO, for which identification of one POLG pathogenic variant is diagnostic.
  • In the 5% of simplex cases of PEO in which only a single pathogenic variant is identified, it can be difficult to distinguish between autosomal recessive inheritance and autosomal dominant inheritance caused by de novo mutation. For example, the mother of a child with an MIRAS/ANS phenotype and compound heterozygosity for p.[Ala467Thr];[Trp748Ser] was herself heterozygous for the p.Trp748Ser pathogenic variant; she developed epilepsy at age 55 years and was found to have an axonal neuropathy, ataxia, mild PEO, and mild parkinsonism [Tzoulis et al 2006]. The significance of this finding is unknown.

Testing Strategy

To confirm/establish the diagnosis in a proband. Standard clinical investigations can identify findings that, in the context of an appropriate family history, can suggest one of the POLG-related phenotypes.

Confirmation of the diagnosis of a POLG-related disorder requires identification of POLG pathogenic variants by molecular genetic testing.

One genetic testing strategy is single gene molecular genetic testing of POLG.

  • One of the following two approaches can be used:
  • In persons meeting the diagnostic criteria of an autosomal recessive POLG-related disorder but in whom sequence analysis identifies only one disease-causing POLG allele, further testing may be considered to search for a second pathogenic variant in regulatory regions (e.g., the POLG promoter) or in related mitochondrial DNA replication genes such as C10orf2 (formerly PEO1; (encodes the twinkle helicase) and POLG2 to investigate the possibility of digenic inheritance (see Differential Diagnosis).
    • Digenic inheritance has been reported in arPEO in a simplex case with pathogenic variants in POLG and C10orf2 [Van Goethem et al 2003a].
    • Oligonucleotide array should be strongly considered as microdeletions involving intragenic regions of POLG are reported and therefore relevant in a symptomatic individual with a single heterozygous pathogenic variant [Naess et al 2010, Compton et al 2011].

An alternative genetic testing strategy is use of a multi-gene panel that includes POLG and other genes of interest (see Differential Diagnosis).

Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Genomic testing. If single gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of a POLG-related disorder, genomic testing may be considered. Such testing may include whole exome sequencing (WES), whole genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq).

Notes regarding WES and WGS: (1) False negative rates vary by genomic region; therefore, genomic testing may not be as accurate as targeted single gene testing or multi-gene molecular genetic testing panels; (2) most laboratories confirm positive results using a second, well-established method; (3) nucleotide repeat expansions and epigenetic alterations can not be detected; (4) deletions/duplications larger than 8-10 nucleotides are not detected effectively [Biesecker & Green 2014].

Notes regarding WmitoSeq: (1) Pathogenic mtDNA variants present at low levels of heteroplasmy in blood may not be detected in DNA extracted from blood and may require DNA extracted from skeletal muscle; (2) mtDNA deletions/duplications may not be detected effectively.

Clinical Characteristics

Clinical Description

POLG-related disorders comprise a continuum of broad and overlapping phenotypes that can be distinct clinical entities or consist of a spectrum of overlapping phenotypes [Van Goethem et al 2001, Lamantea et al 2002, Van Goethem et al 2003b, Luoma et al 2004, Naviaux & Nguyen 2004, Ferrari et al 2005, Luoma et al 2005, Horvath et al 2006, Tzoulis et al 2006, Wong et al 2008]. Presentations within a given family are usually similar. Although almost any organ system can be involved, evidence to date suggests that diabetes and cardiomyopathy are not common in POLG-related disorders, distinguishing them from other multisystem mitochondrial diseases.

Table 2 summarizes the clinical findings in POLG-related disorders. Because the description of new POLG mutations is ongoing, knowledge of their associated phenotypes continues to evolve.

Table 2.

Clinical Findings in POLG-Related Disorders

FindingManifestationNotes/References
Psychiatric illnessDepressionLuoma et al [2004]
PsychosisHakonen et al [2005], Horvath et al [2006]
DementiaVan Goethem et al [2004], Horvath et al [2006]
Seizure disorderMyoclonusCommon in children [Horvath et al 2006] and adults with ataxia [Van Goethem et al 2004, Hakonen et al 2005, Tzoulis et al 2006]
Focal motor seizuresTzoulis et al [2006]
Generalized seizuresHakonen et al [2005], Winterthun et al [2005], Horvath et al [2006]
Status epilepticusTzoulis et al [2006]
Extrapyramidal movement disorderParkinsonism Responds to levodopa [Luoma et al 2004, Mancuso et al 2004]
ChoreaHakonen et al [2005]
Cerebellar involvementAtaxiaVan Goethem et al [2004], Hakonen et al [2005], Winterthun et al [2005], Horvath et al [2006]
“Cerebrovascular” involvementMigraine May precede other features by many years [Hakonen et al 2005, Tzoulis et al 2006]
Stroke-like episodesUsually asymptomatic in children, diagnosed on imaging [Horvath et al 2006]
Special sensorySensorineural deafnessDi Fonzo et al [2003], Filosto et al [2003], Hakonen et al [2005], Horvath et al [2006]
RetinopathyDi Fonzo et al [2003], Luoma et al [2004], Hakonen et al [2005]
MyopathyPtosis and external ophthalmoplegiaMay be isolated ptosis [Luoma et al 2005]
Proximal myopathyDistal myopathy reported [Horvath et al 2006]
Exercise intoleranceDi Fonzo et al [2003], Luoma et al [2004], Hakonen et al [2005]
Peripheral neuropathySensory neuronopathy / ganglionopathyCorresponds to the acronym SANDO [Van Goethem et al 2003b]; profound sensory ataxia
Axonal sensorimotor neuropathyDavidzon et al [2006], Horvath et al [2006]
Endocrine/gonadal systemDiabetes mellitusHorvath et al [2006]
Primary ovarian failureLuoma et al [2004], Hakonen et al [2005]
Ovarian dysgenesisBekheirnia et al [2012]
Primary testicular failureFilosto et al [2003]
Gastrointestinal systemLiver failureSpontaneous or precipitated by sodium valproate in children [Naviaux & Nguyen 2004, Nguyen et al 2005, Horvath et al 2006]; also in adults with ataxia [Van Goethem et al 2004, Tzoulis et al 2006]
Gastrointestinal dysmotilityFilosto et al [2003]
HeartCardiomyopathyVan Goethem et al [2004], Horvath et al [2006]
OcularCataractBekheirnia et al [2012]

Reproduced and modified from Hudson & Chinnery [2006]

Although some affected individuals present with a classic syndrome, many have some, but not all, of the features of one or more of the recognized phenotypes. POLG-related disorders can therefore be considered as an overlapping spectrum of disease presenting from early childhood to late adulthood. The age of onset broadly correlates with the major clinical pattern seen in individual cases.

Alpers-Huttenlocher Syndrome (AHS)

AHS, one of the most severe phenotypic manifestations in the spectrum of POLG-related disorders, is characterized by a progressive and ultimately severe encephalopathy with intractable epilepsy, neuropathy, and hepatic failure. Although AHS is usually fatal, the age of onset, the rate of neurologic degeneration, the presence of hepatic failure, and the age of death vary [Naviaux et al 1999, Gauthier-Villars et al 2001, Davidzon et al 2005, Naviaux & Nguyen 2005, Davidzon et al 2006, Nguyen et al 2006].

Children with AHS appear healthy at birth and may develop normally over the first few weeks to years of life. Some have variable degrees of developmental delay prior to the onset of the recognition of neurodegeneration. Onset is usually between ages two and four years, but ranges from one month to 36 years.

Preexisting and apparently static developmental delays of variable severity have been noted, although some children who later develop manifestations appear initially to be developmentally normal.

Seizures are the first sign of AHS in about 50% of affected children. Seizures may be simple focal, primary generalized, or myoclonic. The most common early seizure types are partial seizures and secondary generalized tonic-clonic seizures. In some instances the first seizure type is epilepsia partialis continua (EPC), a classic seizure type in which the motor seizure involves only one portion of the body (e.g., a limb) with a constant and repetitive myoclonic jerking, continuing for hours or days with or without dramatic effects on consciousness. EPC is not always apparent as an abnormality on electroencephalogram (EEG) and can be mistaken for a conversion reaction. Other seizure types include apparent myoclonic seizures. In some children the first seizure presents with status epilepticus. Over time the seizures can evolve into a complex epileptic disorder such as focal status epilepticus, epilepsia partialis continua, or multifocal myoclonic epilepsy [Naviaux et al 1999, Gauthier-Villars et al 2001, Hakonen et al 2005, Naviaux & Nguyen 2005, Winterthun et al 2005, Horvath et al 2006, Tzoulis et al 2006].

In some children the seizures initially are controlled with usual dosages of anticonvulsants; in others the seizures, such as EPC, are refractory from the onset. Over time the seizures become increasingly resistant to anticonvulsant therapy. See Treatment of Manifestations for further information about management of seizures. Of note, valproic acid (Depakene®) and sodium divalproate (divalproex) (Depakote®) can precipitate the liver dysfunction in AHS and should be avoided [Saneto et al 2010].

Headaches, another common first presenting symptom, typically are associated with visual sensations or visual auras that reflect early occipital lobe dysfunction [Hakonen et al 2005, Tzoulis et al 2006]. Stroke and stroke-like episodes may occur in this disorder as well [Horvath et al 2006].

Movement disorders, primarily myoclonus and choreoathetosis, are common [Horvath et al 2006].

Myoclonus can be difficult to distinguish from myoclonic seizures and EPC. Palatal myoclonus resulting from involvement of the inferior olivary nuclei can be seen as well. Some develop parkinsonism, which may temporarily respond to levodopa [Luoma et al 2004, Mancuso et al 2004].

Neuropathy and ataxia develop in all persons with AHS unless the disease process is so rapid that it results in early death. All neurologic signs and symptoms, including ataxia and nystagmus, may worsen during infections or with other physiologic stressors.

Areflexia (resulting from neuropathy) and hypotonia (possibly the result of generalized weakness as part of systemic illness or pyramidal or extrapyramidal dysfunction) are often both present early in the disease course. They are later followed by complete loss of motor function due to spastic paraparesis resulting from progressive loss of cortical neuronal function.

Episodic psychomotor regression is variably present at the time of initial consideration of the diagnosis. The major motor manifestation is a progressive spastic paraparesis that evolves over months to years. Progressive spasticity involving all motor functions occurs universally; onset occurs at variable stages of the illness.

Loss of cognitive function occurs throughout the course of the disease, but the time of onset and rate of progression are variable. Significant sudden or rapid regression is often seen during infectious illnesses. The clinical manifestations may include somnolence, loss of concentration, loss of language skills (both receptive and expressive), irritability with loss of normal emotional responses, and memory deficits. In addition to the dementia caused by loss of brain tissue and the refractory seizures, the high dosages of medication used to treat those seizures can lead to significant cognitive impairment.

Cortical visual loss leading to blindness may appear months to years after the onset of other neurologic manifestations. Retinopathy (retinitis pigmentosa) may also play a less important role in vision loss [Di Fonzo et al 2003, Luoma et al 2004, Hakonen et al 2005]. Hearing loss is variable [Di Fonzo et al 2003, Filosto et al 2003, Hakonen et al 2005, Horvath et al 2006].

Liver involvement can progress rapidly to end-stage liver failure within a few months, although this is highly variable. End-stage liver disease is often heralded by hypoalbuminemia and prolonged coagulation time, followed shortly thereafter by fasting hypoglycemia and hyperammonemia. Rapid onset of liver failure is described when valproic acid (Depakene®) and sodium divalproate (divalproex) (Depakote®) have been used to treat seizures, although the introduction of other anticonvulsants, including phenytoin, may also play a role in onset of hepatic failure. Longer survival in AHS through improved care for those with profound dementia and motor dysfunction results in the occurrence of late-onset hepatic involvement in a higher percentage of children with AHS now than previously noted.

Disease progression is variable in timing and rapidity. Loss of neurologic function culminates in dementia, spastic quadriparesis from corticospinal tract involvement, visual loss, and death. The rate of neurodegeneration varies and is marked by periods of stability. The degree of dementia is often difficult to assess because of the frequent seizures and high therapeutic doses of anticonvulsants, which can cloud the sensorium. The typical life expectancy from onset of first symptoms ranges from three months to 12 years.

EEG findings include high-amplitude slow activity with smaller polyspikes or intermittent continuous spike-wave activity [Worle et al 1998].

Note: Although not specific, this EEG pattern in the setting of the clinical history may be helpful in the diagnosis. As in many cases of epilepsia partialis continua, the EEG may not show epileptic spikes over the involved hemisphere, but may be normal or show only focal slowing of the background rhythm. The diversity of EEG patterns in AHS is increasingly recognized [Boyd et al 1986, Saneto et al 2010].

Cerebrospinal fluid (CSF) protein is generally elevated in individuals with AHS. Aside from Kearns-Sayre syndrome, the PEO+ presentations of MELAS, and possibly pathogenic variants in other genes involved in mtDNA maintenance, the CSF protein is usually normal in mitochondrial disorders [Hirano & DiMauro 2001, Nguyen et al 2005].

Neuroimaging. Computerized tomography (CT) or magnetic resonance imaging (MRI) of the brain may be normal early in the course of AHS. As the illness evolves neuroimaging shows gliosis (initially more pronounced in the occipital lobe regions) and generalized brain atrophy.

Note: In 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.

FLAIR and T2 sequence images demonstrate high signal intensity in deep gray matter nuclei, especially in the thalamus and cerebellum [Smith et al 1996]. Lesions described in the inferior olivary nuclei may also be a part of AHS and are associated with palatal myoclonus.

Pathophysiology. Depletion of mitochondrial DNA (mtDNA) develops in clinically affected tissues causing a mitochondrial oxidative-phosphorylation defect resulting in the clinical findings of AHS.

Brain. The gross appearance of the brain varies from normal to severe atrophy, depending on the state of disease progression. The central nervous system regions affected in AHS are the same as those affected by Leigh syndrome but typically evolve in the reverse order. For example, in AHS the gliosis is most severe and occurs earliest in the cerebral cortex, followed by the cerebellum, basal ganglia, and brain stem. Involved regions demonstrate neuronal degeneration, characteristic spongiform or microcystic degeneration, and, as seen in Leigh syndrome, gliosis, necrosis, and capillary proliferation. The cortical ribbon shows patchy lesions, but the calcarine cortex, which is characteristically involved early in the course of the disease, is usually narrowed, granular, and discolored.

Microscopic abnormalities, present throughout the cerebral cortex, evolve as the disease progresses. Early in the course of the disease spongiosis, astrocytosis, and neuronal loss are prevalent in the superficial cortex. Later the deeper laminae are affected. In the most advanced stage the entire cortex becomes a thin dense gliotic scar. Usually the striate cortex is the most affected part of the brain followed by the thalamus, hippocampus, and cerebellum. These pathologic features differ from those resulting from hypoxic injury, recurrent seizures, or other causes of hepatic failure.

Liver. Liver histology may demonstrate macro- and microvesicular steatosis, centrilobular necrosis, disorganization of the normal lobular architecture, hepatocyte loss with or without bridging fibrosis or cirrhosis, regenerative nodules, bile duct proliferation, or mitochondrial proliferation with a vivid eosinophilic cytoplasm (oncocytic change). Florid cirrhosis occurs late in the disease. This pathology differs from that seen in chemically induced or toxic hepatopathies.

Childhood Myocerebrohepatopathy Spectrum (MCHS)

MCHS presents between the first few months of life up to about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other features of a mitochondrial disorder that may be present include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Seizures are not present, at least early in the disease course [Wong et al 2008].

Myoclonic Epilepsy Myopathy Sensory Ataxia (MEMSA)

Previously referred to as spinocerebellar ataxia with epilepsy (SCAE), MEMSA now describes the spectrum of disorders with myopathy, epilepsy, and ataxia without ophthalmoplegia. Cerebellar ataxia, generally the first sign, begins in young adulthood as a subclinical sensory polyneuropathy. Epilepsy develops in later years, often beginning focally in the right arm and then spreading to become generalized. The seizures may be refractory to conventional therapy, including anesthesia. Recurrent bouts of seizure activity are accompanied by progressive interictal encephalopathy. The myopathy in MEMSA may be distal or proximal, and, as in the other POLG spectrum disorders, it also may present as exercise intolerance.

Ataxia Neuropathy Spectrum (ANS)

ANS includes mitochondrial recessive ataxia syndrome (MIRAS) and a separate entity known as sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO) [Fadic et al 1997]. ANS is characterized by ataxia, neuropathy, and in most, but not all affected individuals, an encephalopathy with seizures. The encephalopathy is similar to that seen in AHS but tends to be more slowly progressive and can even be mild. The neuropathy may be sensory, motor, or mixed and can be severe enough to contribute to ataxia — so-called sensory ataxia. About 25% of affected individuals have cramps, but clinical myopathy is rare.

Other features may include myoclonus, blindness, and liver dysfunction [Wong et al 2008]. Liver findings range from no dysfunction to elevated enzymes and mild synthetic dysfunction to florid liver failure on occasion [Tzoulis et al 2006, Wong et al 2008]. Psychiatric illness including depression is common. Headache, generally migrainous, is also common and may precede other symptoms by many years.

Although muscle pathology may show COX-negative fibers, there may be no pathologic findings.

Autosomal Recessive Progressive External Ophthalmoplegia (arPEO)

Progressive PEO without systemic involvement is the hallmark of arPEO. Caution needs to be exercised, however, when making the diagnosis of arPEO, as some POLG pathogenic variants associated with arPEO are also associated with ANS and other POLG-related disorders with systemic involvement. Thus, many individuals who have no other clinical findings at the time of diagnosis with isolated arPEO develop other manifestations of POLG-related disorders over subsequent years or decades [Van Goethem et al 2001, Lamantea et al 2002, Van Goethem et al 2003b]. In the past these findings were designated “PEO+” or “PEO+” disease.

Autosomal Dominant Progressive External Ophthalmoplegia (adPEO)

The universal manifestation of this adult-onset disorder is progressive weakness of the extraocular eye muscles resulting in ptosis and strabismus [van Goethem et al 2001]. A generalized myopathy is present in most affected individuals, leading to early fatigue and exercise intolerance. Some affected individuals (in what has been called “chronic progressive external ophthalmoplegia plus, or CPEO+) have variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, and cataracts [Luoma et al 2004, Pagnamenta et al 2006]. Cardiomyopathy and gastrointestinal dysmotility are less common.

Genotype-Phenotype Correlations

Genotype-phenotype correlations are not possible because all combinations of mutation type and location have been associated with the entire phenotypic spectrum and both autosomal recessive and autosomal dominant inheritance.

Nomenclature

Alpers-Huttenlocher syndrome (AHS) is named after Bernard Alpers, who first described the disease in 1931, and Peter Huttenlocher, who with his colleagues described the associated liver disease and autosomal recessive mode of inheritance [Huttenlocher et al 1976].

In the older literature, autosomal dominant progressive external ophthalmoplegia (adPEO) associated with additional findings was labeled “chronic progressive external ophthalmoplegia plus” (CPEO+).

Prevalence

AHS is reported to affect approximately one in 51,000 people [Darin et al 2001]; however, because some pathogenic variants are found at high frequencies in certain populations, the frequency may vary greatly within any population.

The frequency of the most common autosomal recessive pathogenic allelic variants (p.Ala467Thr: ~0.2%-0.6%; p.[Trp748Ser;Glu1143Gly] (indicating two variants in cis configuration on the same allele): ~0.1%-0.8%; p.Gly848Ser: ~0.05%-0.1%; and p.Pro587Leu: ~0.05%) suggests that the sum frequency of the 20 most common pathogenic variants may be about 2%, resulting in a calculated disease frequency of 1:10,000. However, the estimate is far more complicated because certain populations have high carrier rates of POLG alleles associated with AHS. For example, the frequency of the pathogenic allele p.Ala467Thr is 0.6% in Belgium and 1% in Norway. Other pathogenic alleles may have a founder effect; therefore, the incidence may vary by ethnicity.

Pathogenic variants in POLG, identified as the cause of autosomal dominant PEO (adPEO) in nearly 50% of individuals in one series [Lamantea et al 2002], may be the most frequent cause of adPEO.

Differential Diagnosis

Epilepsia Partialis Continua

The frequency of epilepsia partialis continua in Alpers-Huttenlocher syndrome (AHS) suggests that unless a structural lesion is identified on neuroimaging, consideration for AHS as a cause is warranted [Saneto et al 2010].

Mitochondrial DNA Depletion (MDD) Disorders

MDD disorders, characterized by a reduction in mtDNA copy number, have been associated with pathogenic variants in twelve nuclear genes: DGUOK, MPV17, POLG, RRM2B, SUCLA2, SUCLG1, TK2, C10orf2, SLC25A4, FBLX4, MGME1, and TYMP. The gene products are involved either in mtDNA replication or in regulation of the mitochondrial deoxyribonucleoside triphosphate (dNTP) pools needed for mtDNA replication. Inheritance for all the MDD syndromes is autosomal recessive.

MDD disorders may affect either a specific tissue (most commonly muscle or liver) or multiple organs, including the heart, brain, and kidney [Ricci et al 1992]. MDD disorders need to be distinguished from the disorders of mtDNA mutation, duplication, or deletion (see Mitochondrial Disorders Overview).

In one recent study in which 50 of 100 children with multiple electron transport chain defects had a mtDNA copy number lower than than 35% of normal controls, 18% of those with mtDNA depletion had DGUOK pathogenic variants and 18% had POLG pathogenic variants. Among those with mtDNA depletion and hepatic dysfunction, DGUOK deficiency was the most common single cause [Sarzi et al 2007].

Table 3 summarizes the clinical phenotypes associated with pathogenic variants in these genes.

Note: For some of the genes (POLG and C10orf2), other phenotypes not associated with mtDNA depletion with autosomal dominant or recessive inheritance have been reported.

Table 3.

Mitochondrial DNA Depletion Syndromes

Gene PhenotypeFunction of Gene ProductUrinary Methylmalonic Acid
DGUOKHepatocerebraldNTP poolsNormal
MPV17HepatocerebralUnknownNormal
POLGHepatocerebral/ AHSmtDNA replicationNormal
RRM2BEncephalomyopathic with renal tubulopathydNTP poolsNormal
SUCLA2EncephalomyopathicdNTP pools
SUCLG1Fatal infantile lactic acidosisdNTP pools
TK2MyopathicdNTP poolsNormal
C10orf2 (previously known as PEO1)HepatocerebralmtDNA replicationNormal
SLC25A4Hypertrophic cardiomyopathy and exercise intoleranceAdenine nucleotide, translocator, dNTP poolsUnknown/not reported 1
FBXL4Mitochondrial encephalopathyF-box and leucine-rich repeat protein 4Unknown/not reported 2, 3
MGME1MtDNA depletion and multisystemic mitochondrial diseaseExonuclease in mtDNA replicationUnknown/not reported 4
TYMPMitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE)Thymidine phosphorylase, dNTP poolsUnknown/not reported 1

dNTP = deoxyribonucleoside triphosphate

mtDNA = mitochondrial DNA

1.

Christopher & Koshy [2013]

2.

Gai et al [2013]

3.

Bonnen et al [2013]

4.

Kornblum et al [2013]

DGUOK. The two forms of deoxyguanosine kinase (DGUOK) deficiency are a hepatocerebral mitochondrial DNA depletion syndrome (multisystem disease in neonates) and isolated hepatic disease later in infancy or childhood. The majority of affected individuals have the multisystem illness with hepatic disease (cholestasis) and neurologic dysfunction evident within weeks of birth. They subsequently manifest severe hypotonia, developmental regression, and typical rotary nystagmus that evolves into opsoclonus. In contrast to AHS caused by POLG pathogenic variants, DGUOK deficiency is not characterized by seizures or brain imaging abnormalities [Dimmock et al 2008]. Those with isolated liver disease may also have renal involvement and some later develop mild hypotonia. Progressive hepatic disease is the most common cause of death in both forms. Reduced mtDNA copy number in liver or muscle can be used to confirm mtDNA depletion. Molecular genetic testing of DGUOK is necessary to establish the specific diagnosis of DGUOK deficiency [Mandel et al 2001].

MPV17. Homozygosity for the MPV17 pathogenic variant NP_002428.1:p.Arg50Gln (NM_002437.4:c.149G>A) is associated with a mitochondrial DNA depletion syndrome displaying hepatic failure early in life: Navajo neurohepatopathy, a disorder found in the Navajo tribes in southwestern United States [Spinazzola et al 2006]. Navajo neurohepatopathy is characterized by the following [Karadimas et al 2006]:

  • Liver failure
  • Severe sensory neuropathy
  • Corneal anesthesia and scarring
  • Cerebral leukoencephalopathy
  • Failure to thrive
  • Metabolic acidosis

The function of MPV17 is unknown but the protein has been shown to localize to mitochondria [Spinazzola et al 2006]. Inheritance is autosomal recessive.

RRM2B. Mutation of RRM2B has been associated with severe muscle mtDNA depletion in several families [Bourdon et al 2007]. This disorder manifests as severe encephalopathy, myopathy with persistent lactic acidosis, hypotonia, renal tubular defects, seizures, respiratory distress, and diarrhea. Death occurs by age four months.

RRM2B encodes the p53-inducible small subunit of ribonucleotide reductase which comprises two subunits:

  • A large catalytic subunit, R1
  • The smaller R2 subunit. Cells have two forms of the R2 subunit:
    • A cell cycle-regulated form that is maximally expressed in S-phase;
    • A p53-inducible form known as p53R2. The p53R2 form is required for a basal level of DNA repair and mtDNA synthesis in non-proliferating cells.

Ribonucleotide reductase activity is required to produce the nucleotide precursors required for DNA replication by reduction of ribonucleoside diphosphates to deoxyribonucleoside diphosphates.

SUCLA2. SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form, with mild methylmalonic aciduria is characterized by the following:

  • Onset of severe hypotonia in early infancy (birth to 5 months)
  • Severe muscular atrophy with failure to achieve independent ambulation
  • Progressive scoliosis or kyphosis
  • Dystonia and/or hyperkinesias (i.e., athetoid or choreiform movements)
  • Epilepsy (infantile spasms or generalized convulsions with onset from birth to 3 years) in a few children
  • Postnatal growth retardation
  • Severe sensorineural hearing impairment

The outcome is poor with early lethality. Metabolic findings usually include urinary excretion of methylmalonic acid (MMA), elevated plasma methylmalonic acid concentration, and elevated plasma lactate concentration. Plasma carnitine ester profiling shows increased C3-carnitine and C4-dicarboxylic-carnitine. Urinary excretion of C4-dicarboxylic carnitine is usually approximately 20 times normal. CT/MRI may show central and cortical atrophy, bilateral basal ganglia involvement (mainly the putamen and caudate nuclei), and delayed myelination. SUCLA2 is the only gene known to be associated with this disorder [Elpeleg et al 2005].

SUCLG1. (OMIM 245400) Pathogenic variants have been reported in SUCLG1, which encodes the α subunit of succinate-CoA ligase [Ostergaard et al 2007]. Affected individuals show the following:

  • Urinary excretion of MMA
  • Combined respiratory chain enzyme deficiency
  • Mitochondrial DNA depletion

The phenotype may be indistinguishable from SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form, with mild methylmalonic aciduria [Ostergaard et al 2010].

TK2. Mitochondrial myopathy with mtDNA depletion is caused by pathogenic variants in TK2, the gene encoding thymidine kinase [Saada et al 2001].

SLC25A4. Autosomal recessive mitochondrial DNA depletion syndrome is caused by biallelic pathogenic variants in SLC25A4, the gene encoding the adenine nucleotide translocator, ANT1 [Palmieri et al 2005]. Affected individuals may present with the SANDO (ANS) phenotype [Hanisch et al 2014].

FBXL4. Mitochondrial encephalopathy with mtDNA depletion is caused by pathogenic variants in FBXL4, the gene encoding F-box/LRR-repeat protein 4 [Bonnen et al 2013, Gai et al 2013]. Children from three unrelated Arabian families who presented with a fatal encephalopathy, lactic acidosis, and severe depletion in muscle mtDNA were identified to have compound heterozygous nonsense and splicing mutations in FBXL4. The children presented between birth and age six years, and (except for the child age 6 years, who was alive at the time of the report) died between a few days after diagnosis and age four years. Most of the affected individuals had developmental delay. FBXL4 is an F-box protein that colocalizes in the mitochondria and causes a respiratory chain deficiency, loss of mitochondrial membrane potential, and a disturbance of the dynamic mitochondrial network and nucleoid distribution in fibroblasts from affected individuals.

MGME1. Mitochondrial DNA depletion syndrome results from biallelic mutations in MGME1, the gene encoding mitochondrial genome maintenance exonuclease 1, a mitochondrial RecB-type exonuclease [Kornblum et al 2013]. Individuals present between ages ten and 36 years with ptosis, followed by mild PEO, diffuse skeletal muscle wasting and myopathy, profound emaciation, and respiratory failure. Intellectual disability was found in only one family of three affected individuals.

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is characterized by the following:

  • Progressive gastrointestinal dysmotility and cachexia
  • Ptosis/ophthalmoplegia or ophthalmoparesis
  • Hearing loss
  • Demyelinating peripheral neuropathy manifesting as paresthesias and symmetric and distal weakness primarily in the lower extremities

Onset is usually between the first and fifth decades; in about 60% of individuals, symptoms begin before age 20 years. Diagnosis is based on the following:

  • Plasma thymidine concentration greater than 3 µmol/L
  • Plasma deoxyuridine concentration greater than 5 µmol/L
  • Thymidine phosphorylase enzyme activity in leukocytes less than 10% of controls
  • Molecular genetic testing of TYMP (previously known as ECGF1), the only gene known to be associated with canonical MNGIE disease with elevated thymidine levels in the serum [Nishino et al 1999]
    Note: Several MNGIE-like disorders associated with pathogenic variants in POLG and mtDNA (e.g., m.3243A>G) have been described.

Other Disorders to Consider

Autosomal dominant progressive external ophthalmoplegia (adPEO) is caused by mutation of one of the following genes:

Oculopharyngeal muscular dystrophy with onset usually after age 45 years may result in progressive ptosis and bulbar dysfunction manifest as swallowing difficulty. This disorder may mimic the clinical manifestations of the POLG-related disorders in which PEO is the predominant feature.

Amish lethal microcephaly is characterized by microcephaly and early death. The occipitofrontal circumference is typically six to 12 SD below the mean; anterior and posterior fontanels are closed at birth and facial features are distorted. The average life span is between five and six months. Diagnosis is based on a tenfold increase in the levels of the urinary organic acid 2-ketoglutarate. SLC25A19 (also known as DNC or MUP1), encoding the mitochondrial deoxynucleotide carrier [Rosenberg et al 2002], is the only gene known to be associated with Amish lethal microcephaly. All affected individuals within the Old Order Amish population are homozygous for the same single-base pair substitution.

Chronic progressive external ophthalmoplegia (CPEO) in a simplex case or when there is a maternal family history can be the result of a large-scale single deletion of mtDNA which may only be detected in limited tissues (e.g., skeletal muscle). CPEO is sometimes complicated by mild proximal muscle weakness and dysphagia, and can be considered to lie on a spectrum of disease from pure CPEO to the Kearns-Sayre syndrome. Some individuals with CPEO (<20%) have a pathogenic single nucleotide variant of mitochondrial DNA (e.g., m.3243A>G).

Kearns-Sayre syndrome (KSS) is a multisystem disorder defined by the following triad:

  • Onset before age 20 years
  • Pigmentary retinopathy
  • PEO

In addition, affected individuals have at least one of the following:

  • Cardiac conduction block
  • Cerebrospinal fluid protein concentration greater than 100 mg/dL
  • Cerebellar ataxia

Onset is usually in childhood. PEO, characterized by ptosis, paralysis of the extraocular muscles (ophthalmoplegia), and variably severe proximal limb weakness, is relatively benign. Mitochondrial DNA deletion syndromes are caused by mtDNA deletions ranging in size from two to ten kilobases. Approximately 90% of individuals with KSS have a large-scale (i.e., 1.1-10 kb) mtDNA deletion that is usually present in all tissues; however, mutant mtDNA is often undetectable in blood cells, necessitating examination of muscle. When inherited, mtDNA deletion syndromes are transmitted by maternal inheritance. The mother of a proband with a mtDNA deletion syndrome is usually unaffected and does not have mtDNA deletions in her tissues; therefore, the risk to the sibs of a proband is usually extremely low. Offspring of females with KSS are usually not at risk of inheriting the mutation; however, exceptions occur.

Mutation of BCS1L is associated with

  • GRACILE syndrome (growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death) (OMIM 603358);
  • Bjørnstad syndrome (congenital profound hearing loss and pili torti) (OMIM 262000);
  • An overlapping GRACILE syndrome-Bjørnstad syndrome phenotype.

Children with the pure form of Bjørnstad syndrome have normal intellect. The BCS1L protein is an assembly factor for complex III responsible for insertion of the Fe-S core into the complex. Affected children have a biochemical defect in complex III. The clinical scenario of a hepato-encephalopathy may appear similar to AHS at a single point in time, but mtDNA depletion is not part of the pathology described in those with BCS1L pathogenic variants.

SCO1. (OMIM 603644) Hepatic failure and severe encephalopathy have also been associated with compound heterozygosity for two pathogenic variants in SCO1.

Other. The differential diagnosis of MDD disorders also includes infantile or late-infantile progressive encephalopathies with primary involvement of cortical gray matter and refractory epilepsy.

Neuronal ceroid-lipofuscinoses (NCLs) are a group of inherited, neurodegenerative, lysosomal storage disorders characterized by progressive mental and motor deterioration, seizures, and early death. Visual loss is a feature of most forms. Phenotypes included in the NCLs that overlap with AHS are: infantile neuronal ceroid-lipofuscinosis (INCL, Santavuori-Haltia) and late-infantile (LINCL, Janský-Bielschowsky). Inheritance is autosomal recessive.

  • INCL. Children with INCL are normal at birth; symptoms usually present acutely between ages six and 24 months. Initial signs include delayed development, myoclonic jerks and/or seizures, deceleration of head growth, and specific EEG changes. Affected infants develop retinal blindness and seizures by age two years, followed by progressive mental deterioration. Mutation of PPT1 is causative.
  • LINCL. The first symptoms of LINCL typically appear between age two and four years, usually starting with epilepsy, followed by regression of developmental milestones, dementia, ataxia, and extrapyramidal and pyramidal signs. Visual impairment typically appears between ages four and six years and rapidly progresses to blindness. Life expectancy ranges from age six years to greater than age 40 years. Mutation of PPT1 (encoding the enzyme palmitoyl-protein thioesterase 1), TPP1 (encoding the enzyme tripeptidyl-peptidase 1), CLN5, CLN6, and CLN8 can be causative.

MERRF (myoclonic epilepsy associated with ragged red fibers) is a multisystem disorder characterized by myoclonus, which is often the first symptom, followed by generalized epilepsy, ataxia, weakness, and dementia. Onset is usually in childhood, occurring after normal early development. Common findings are hearing loss, short stature, optic atrophy, and cardiomyopathy with Wolff-Parkinson-White (WPW) syndrome. Occasionally pigmentary retinopathy and lipomatosis are observed. MERRF is transmitted by maternal inheritance.

MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) is a multisystem disorder with onset typically occurring in childhood. Early psychomotor development is usually normal. Onset of symptoms is often between ages two and ten years. The most common initial symptoms are generalized tonic-clonic seizures, recurrent headaches, anorexia, and recurrent vomiting. Seizures are often associated with stroke-like episodes of transient hemiparesis or cortical blindness. The cumulative residual effects of the stroke-like episodes gradually impair motor abilities, vision, and mentation, often by adolescence or young adulthood. Sensorineural hearing loss is common. MELAS is transmitted by maternal inheritance.

Storage diseases during infancy and early childhood, such as atypical hexosaminidase A deficiency, Sandhoff disease, infantile sialidosis, and galactosialidosis, can be diagnosed by testing for lysosomal enzyme activity in the appropriate tissue.

Other rare neonatal-onset causes of a progressive encephalopathy with refractory seizures include pyridoxine-dependent seizures, cerebral folate deficiency, glycine encephalopathy (also known as nonketotic hyperglycinemia), biotinidase deficiency, and disorders of biogenic amine metabolism, such as folate-responsive seizures. Pyridoxine-dependent seizures and biotinidase deficiency are treatable and on occasion reversible [Wolf 2005, Gallagher et al 2009].

Sulfite oxidase deficiency and Menkes disease (see ATP7A-Related Copper Transport Disorders) usually present earlier in infancy. Sulfite oxidase deficiency can be screened for using a commercially available sulfite oxidase urine dipstick test and Menkes disease by detecting low serum concentrations of copper and ceruloplasmin. Current molecular genetic testing can detect pathogenic variants in ATP7A, the only gene known to be associated with Menkes disease, in more than 95% of affected individuals. Inheritance of Menkes disease is X-linked.

Slow virus diseases (subacute sclerosing panencephalitis) are extremely rare at this age.

Within the differential diagnosis are also epileptic syndromes that appear to be progressive at the onset but that usually plateau into developmental arrest/delay.

The channelopathies are with a group of severe infantile epileptic disorders caused by mutation of SCN1A, SCN91, CACNB4, or CACNA1A, which encode for sodium and calcium channels. See SCN1A-Related Seizure Disorders.

Both myoclonic epilepsy and the Lennox-Gastaut syndrome can cause dementia or pseudo-dementia as a result of unrelenting seizures and anticonvulsant side effects.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to SimulConsult®, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a POLG-related disorder, evaluation should always include measures of functional neurologic status.

In order to determine the baseline function for a given affected individual, it is reasonable to conduct the following evaluations as appropriate for the phenotypic presentation:

  • Electroencephalogram (EEG) and video EEG monitoring
  • Formal developmental assessment to provide a baseline of function as well as offer insights into the need for occupational, physical, and/or speech therapy
  • Brain MRI. On occasion the first neuroimaging study may be normal, but with certain phenotypes, such as AHS, changes may be seen in a relatively short amount of time.
  • Electrocardiogram. If a mitochondrial illness is suspected and if there is not yet genetic confirmation of a POLG disease it is reasonable to consider both electrocardiogram and echocardiogram.
  • Formal assessment of vision and hearing
  • Swallowing study, if bulbar signs are present
  • Nutritional assessment
  • Baseline pulmonary function testing
  • Sleep polysomnogram specifically for the purpose of evaluating for central or obstructive apnea or hypopnea that result in either pCO2 elevation or O2 desaturation
  • Liver function tests including fasting serum glucose concentration, ALT, and AST; serum concentrations of ammonia, glutamine and tyrosine (found in an amino acid panel), bilirubin, albumin, and cholesterol; and the coagulation factors (prothrombin time or INR). Liver ultrasound examination may assist in determining the presence of fibrosis.

    Note: AST elevation, and to a lesser extent ALT elevation, may be due to muscle disease; simultaneously obtaining a serum CK level differentiates between liver and muscle involvement, although both liver and muscle disease can be seen in individuals with POLG-related disorders.
  • Medical genetics consultation

Treatment of Manifestations

Treatment is limited to symptom management and supportive care.

Alpers-Huttenlocher Syndrome

Family education is critical. It is important to address the quality of life/intensity of treatment issues frequently and when major changes occur in disease status. Once the family has started the process of accepting the diagnosis, it is important to involve the family with options for supportive care that can be offered as the illness progresses. These will include (but are not limited to) the use of a gastrostomy feeding tube and the different levels of artificial ventilation that could include less invasive treatments such as CPAP or BiPAP, assisted nasal ventilation, and/or intubation, and the use of a tracheostomy and ventilator. Involvement of palliative care services can assist the care team in these discussions, as well as in practical aspects of implementation. Although rehabilitative services are a necessary part of the treatment and care plan for these children, and rehabilitation units are often where parents of children with new gastrostomy tubes and ventilator support learn to care for their children, the global perspective of care should be palliative even if death is not imminent.

Supportive therapies. Occupational, physical, and/or speech therapy is indicated to maintain neurologic function for as long as possible and to insure comfort when deterioration begins.

Gastrointestinal. A consult with a gastroenterologist regarding feeding or nutritional issues, or evidence of liver involvement may be appropriate. Surgical placement of a gastric feeding tube when appropriate can maintain nutritional status and/or prevent aspiration of oral feeding.

Hepatic. Standard treatment for liver failure may include small frequent meals or continuous feeding to compensate for defective gluconeogenesis, reduction in dietary protein to a minimum, use of non-absorbable sugars to create an osmotic diarrhea, and use of conjugating agents to treat hyperammonemia.

Because levocarnitine may have some benefit in the setting of liver failure and because of its low toxicity, some recommend its use from the time of diagnosis.

Respiratory. Tracheostomy placement and artificial ventilation may be performed, as appropriate.

Assessment of nocturnal ventilatory function can be performed for evidence of central and/or obstructive apnea using polysomnography with measurement of pCO2 and monitoring by pulse oximetry. Treatment with CPAP or BiPAP as indicated is appropriate.

Seizures. Seizure control is a goal of treatment; however, refractory epilepsy, especially epilepsia partialis continua (EPC), may be impossible to control with any treatment. In individuals with EPC, the use of high-dose anticonvulsants may control the clinical seizures, but the associated obtundation with subsequent risk of aspiration and ventilatory failure may outweigh the benefit.

Although anticonvulsant monotherapy is preferred, treatment with more than one medication often becomes necessary as the child’s seizures worsen and as multiple types of seizures occur. If high-dose anticonvulsant therapy is not effective in improving the quality of life by reducing the seizure burden, reducing the number and/or dose of medications may improve quality of life by reducing medication side-effects.

There is no evidence that newer anticonvulsants such as felbamate, lamotrigine, topiramate, oxcarbazepine, or levetiracetam offer a better therapeutic benefit over the older medications (phenobarbital, phenytoin, carbamazepine, primidone); however, the newer medications tend to be less sedating, may require less processing by the liver, and have fewer drug-drug interactions. Intravenous magnesium, used most often to treat seizures in eclampsia, has shown efficacy in one report where affected individuals with status epilepicus were refractory to other typical anticonvulsants [Visser et al 2011].

One unpublished pathway for management of seizures is to begin with lamotrigine monotherapy, and when this is no longer effective for adequate control of seizures, add lacosamide. Adding clobazam may also help when these medications are no longer effective [RP Saneto, personal communication]. With the exception of valproate (see Note), other standard anticonvulsants are reasonable to use, although medications that are heavily metabolized by the liver, such as phenytoins or the barbiturates, should be reserved until other medications fail.

Note: Valproic acid (Depakene®) and sodium divalproate (divalproex) (Depakote®) should be avoided (see Agents/Circumstances to Avoid). Because other anticonvulsants have also been implicated in accelerating liver deterioration, it is reasonable to monitor liver enzymes every two to four weeks after introducing any new anticonvulsant [Bicknese et al1992].

Movement disorder. In addition to electroencephalographic seizures, myoclonus and other non-epileptic movement disorders occur as part of AHS and can be as disabling as seizures. These movements should not be confused with seizures, and video EEG is often the only way to differentiate a seizure from a non-epileptic movement disorder. The use of benzodiazepines often reduces the severity of these abnormal movements and also assists in seizure management and reduction of spasticity.

Chorea and athetosis [Hakonen et al 2005] may cause pain, and treatment with muscle relaxants and pain medications, including narcotics, would be advised. Some movement disorders can be treated with dopaminergic medication such as levodopa-carbidopa or tetrabenazine: a trial of either of these medications can be considered.

In most cases, not all seizures and/or non-epileptic movements can be suppressed with medication, and a balance between the adverse effects of the medication(s) and the disability created by the seizures or movements must be accepted by both the family and physician. Often a modest reduction in seizure control is offset by an improved level of alertness, although the benefit may not be lasting.

Other Phenotypes

Management is supportive and involves conventional approaches such as physiotherapy, speech therapy, and seizure management.

Gastrostomy may be required to provide adequate nutrition.

Surgery for ptosis may provide symptomatic relief for some.

Prevention of Secondary Complications

For individuals with any of the POLG-related phenotypes, dose reduction in medications metabolized by hepatic enzymes may be necessary to avoid toxicity.

Reports suggest that CSF folate may be deficient in disorders that lead to mtDNA depletion [Hasselmann et al 2010]. Therefore, testing for CSF folate deficiency and offering treatment to those with deficiency is one option; the other option is empiric therapy with folinic acid (calcium leucovorin).

Surveillance

Individuals with POLG-related disorders require frequent examination and interval evaluation by a team comprising the following:

  • Primary care provider
  • Neurologist
  • Medical geneticist
  • Hepatologist or gastroenterologist
  • Physiatrist
  • Psychiatrist
  • Ophthalmologist
  • Pulmonologist

Laboratory tests. No standard of care guidelines are available to suggest the frequency for which the following tests should be obtained. Testing should be guided by clinical features and the proposed schedule should be modified if the clinical course is stable. For those with the most severe phenotypes, the following could be considered:

  • Every three months. CBC; electrolytes, liver enzymes (AST, ALT, GGT); CK, liver function tests including: preprandial serum glucose concentration; serum concentration of ammonia, albumin, bilirubin (free and conjugated), and cholesterol; and prothrombin time or INR as a measure of coagulation factors
  • Annually. Urine analysis; serum concentration of lactic acid
  • Biannually. Plasma amino acids; urine organic acids; plasma concentration of free and total carnitine (unless treated with levocarnitine, in which case measure annually)

Imaging and diagnostic procedures

  • Liver ultrasound examination annually
  • EEG and video EEG monitoring (e.g., for suspicion of subclinical status epilepticus; presence of epilepsia partialis continua; need to determine if events are seizures or non-epileptic movements)
  • Audiogram and brain stem auditory evoked responses as clinically indicated
  • Barium swallow study as clinically indicated
  • Polysomnogram with CPAP titration as part of an evaluation of subacute mental status changes or every two to three years

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 [Bicknese et al 1992, 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 as much as 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 for access to 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 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, 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]. As of late 2012 (15 years after liver transplantation), she was alive and living semi-independently, albeit with progressive central nervous system dysfunction, specifically failing memory with increasing chorea and hemiballismus.

The use of other treatments for refractory epilepsy, such as corticotropin or prednisone, ketogenic diet, and intravenous IgG, are unproven in the treatment of AHS.

  • Vitamin and cofactor therapy with the intent to fortify mitochondrial function may be offered. There have not been formal studies of the use of these vitamins and cofactors in AHS or other POLG-related disorders [Parkih et al 2009].
  • The use of folinic acid should be strongly considered (see Prevention of Secondary Complications).
  • The use of levo-arginine has been reported 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 CSF arginine concentration is confirmed.
  • Levocarnitine, creatine monohydrate, coenzyme Q10, B vitamins, and antioxidants such as alpha lipoic acid, vitamin E, and vitamin C have been used as mitochondrial supplements. Use of all in POLG-related disorders is reasonable based on limited published evidence and their general lack of toxicity [Gold & Cohen 2001, Rodriguez et al 2007, Horvath et al 2008].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The POLG-related disorders in the spectrum of AHS, MCHS, (including SCAE), ANS (including MIRAS and SANDO), and autosomal recessive progressive external ophthalmoplegia (arPEO) are inherited in an autosomal recessive manner.

Autosomal dominant progressive external ophthalmoplegia (CPEO+) is inherited in an autosomal dominant manner with reduced penetrance.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • In general, the parents of an affected child are obligate heterozygotes and therefore carry one POLG pathogenic variant.
  • Heterozygotes (carriers) are generally believed to be asymptomatic. However, some individuals with a heterozygous POLG pathogenic variant are reported to have manifestations of POLG-related disorders. Because knowledge of these disorders is changing quickly individuals who are heterozygous should be reevaluated by history and physical examination every few years for symptoms and signs of POLG-related disorders.

Sibs of a proband

Offspring of a proband

  • Individuals with some POLG-related disorders (e.g., Alpers-Huttenlocher syndrome) do not reproduce.
  • The offspring of individuals with less severe manifestations of a POLG-related disorder will be obligate heterozygotes for a POLG pathogenic variant.

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

Carrier Detection

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

Individuals from populations with a high carrier rate for POLG pathogenic variants and/or a high rate of consanguinity should be offered genetic counseling and carrier testing.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

  • Most individuals diagnosed with an autosomal dominant POLG-related disorder have an affected parent.
  • A proband with an autosomal dominant POLG-related disorder may have the disorder as the result of a new pathogenic variant. The proportion of cases caused by de novo mutations is thought to be low (<1%); however, because simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine whether the mutation was de novo, the proportion of cases caused by de novo mutations is unknown.
  • If the pathogenic variant found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband.
  • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include performing a complete history and physical examination, focusing on the most common symptoms and/or clinical features of POLG-related disease (ophthalmoplegia, weakness, ataxia, and neuropathy). Because migraine, depression, gastrointestinal problems, and seizures are so common in the general population, their presence as isolated findings is not likely to be relevant. If there is an ophthalmoplegia, or a constellation of features suggestive of POLG-related disease, molecular genetic testing can be performed to confirm the diagnosis.

Note: (1) Although most individuals diagnosed with an autosomal dominant POLG-related disorder have an affected biological parent, the family history may appear to be negative because of 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. (2) If the parent is the individual in whom the pathogenic variant first occurred s/he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.

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, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • The sibs of a proband with clinically unaffected parents are still at increased risk (for the disorder) because of the possibility of reduced penetrance in a parent.
  • If the POLG pathogenic variant found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

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

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has a pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

At-risk family members

  • Sibs who are similar in age or younger than the proband may still be at risk and in need of diagnostic evaluation.
  • Older unaffected sibs (as well as other family members) may have only a single pathogenic variant, but need to be informed that (1) some heterozygotes have had symptoms at a later age possibly related to their carrier status, and (2) heterozygotes (i.e., those with a single pathogenic allele) are at increased risk of having a child with the disorder, particularly if their reproductive partner is of an ethnic group with high carrier frequency.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal 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, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the POLG pathogenic variant(s) have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Requests for prenatal testing for adult-onset conditions such as adPEO are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for families in which the POLG pathogenic variant(s) have been identified in an affected family member.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Epilepsy Society (AES)
  • Children's Liver Disease Foundation (CLDF)
    36 Great Charles Street
    Birmingham B3 3JY
    United Kingdom
    Phone: +44 (0) 121 212 3839
    Fax: +44 (0) 121 212 4300
    Email: info@childliverdisease.org
  • Epilepsy Foundation
    8301 Professional Place East
    Suite 200
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Email: ContactUs@efa.org
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org
  • United Mitochondrial Disease Foundation (UMDF)
    8085 Saltsburg Road
    Suite 201
    Pittsburg PA 15239
    Phone: 888-317-8633 (toll-free); 412-793-8077
    Fax: 412-793-6477
    Email: info@umdf.org
  • RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

POLG-Related Disorders: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
POLG15q26​.1DNA polymerase subunit gamma-1POLG databasePOLG

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for POLG-Related Disorders (View All in OMIM)

157640PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT, 1; PEOA1
174763POLYMERASE, DNA, GAMMA; POLG
203700MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE); MTDPS4A
258450PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE; PEOB
607459SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS; SANDO

Molecular Genetic Pathogenesis

The mitochondrion comprises almost 1500 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 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. Unlike nuclear DNA, which replicates with each cell division, mtDNA replicates continuously and independently of cell division. This task specifically requires polymerase gamma, the only DNA polymerase in humans that allows for replication and repair of mtDNA.

POLG encodes DNA polymerase gamma (pol gamma), the enzyme required for mitochondrial DNA synthesis. The three functional domains of pol gamma:

  • Polymerase, responsible for replication
  • Exonuclease, responsible for proofreading
  • Linker, the region between the other two domains

Reports suggest that pathogenic variants in each of these three regions of POLG have rather distinct clinical consequences (see Genotype-Phenotype Correlations).

Mitochondrial DNA replication requires a heterotrimer of one 140-kd catalytic subunit of pol gamma and two accessory 55-kd subunits encoded by POLG2 (located at chromosome 17q23-24) that assist in binding and processing the synthesized DNA. The twinkle protein, encoded by C10orf2, serves the important function of a 5'→3' DNA helicase.

The first pathogenic variants in POLG were identified in families with autosomal dominant chronic progressive external ophthalmoplegia [Van Goethem et al 2001] followed by reports of POLG pathogenic variants associated with SANDO and ataxia-neuropathy conditions [Van Goethem et al 2003b, Van Goethem et al 2004]. The first link between a mtDNA depletion disorder and a POLG pathogenic variant was made by Naviaux & Nguyen [2004] in two probands diagnosed with Alpers-Huttenlocher syndrome (AHS).

Gene structure. POLG comprises 23 exons and is 18,476 bases in length. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. A number of POLG pathogenic variants have been found to occur in cis configuration with the benign allelic variant p.Glu1143Gly. Heterozygosity for this haplotype does not cause mitochondrial disease, with the exception of a single report of a person having ataxia, PEO, and parkinsonism [Luoma et al 2005, Tzoulis et al 2006]. The p.Glu1143Gly variant occurs in 3%-4% of the healthy population; individuals homozygous for p.Glu1143Gly are reported to be healthy (see Table 5). However, the p.Glu1143Gly normal variant does modulate the deleterious effects of the p.Trp748Ser disease-causing allele by partially rescuing activity (increasing DNA binding affinity and polymerase activity) but decreasing protein stability [Chan et al 2006]. This same variant may increase the liver’s sensitivity to valproic acid exposure [Stewart et al 2010]. As with p.Glu1143Gly, the presence of p.Gln1236His can induce liver sensitivity to valproic acid exposure. It is estimated that the presence of either the p.Glu1143Gly or p.Gln1236His variant increases valproic acid sensitivity more than 20-fold [Stewart et al 2010]. Six patients reported previously with AHS and liver failure did not have either variant [Wong, personal communication]. Rare reports describe long-term use of valproic acid exposure with POLG pathogenic variant(s) without liver failure [Tzoulis et al 2006].

The p.Gly517Val variant, a common SNP that was initially reported to be associated with various POLG phenotypes including autosomal dominant and recessive ataxia, neuropathy, myopathy and microcephaly, progressive external ophthalmoplegia, diabetes, strokes, hypotonia, and epilepsy, has been shown to have normal (80%-90%) pol gamma activity and should not be considered a pathogenic variant [Kasiviswanathan & Copeland 2011].

Because many of the reported pathogenic variants come from singleton cases without supporting data, it is important to gain a better understanding of what mutations may not ultimately be found to be pathogenic. The use of mouse models, S. cerevisiae, and the 3D-structure of the human pol gamma will help gain a better understanding over time [Stumpf & Copeland 2011].

Pathogenic allelic variants. Pathogenic variants are found throughout the gene. Almost 200 mutations in POLG are reported to cause disease. Of these, more than 75 are associated with AHS.

Both the p.Ala467Thr and the p.Trp748Ser pathogenic variants are located in the linker region of the gene.

  • The most common AHS-causing POLG pathogenic variant is p.Ala467Thr, located near the exonuclease domain in the early linker region of pol gamma.
  • The second most common POLG pathogenic variant is p.Trp748Ser, which causes AHS, the ataxia-neuropathy spectrum disorders, and PEO.

Table 4.

Frequency of the Most Common POLG Pathogenic Allelic Variants

POLG Pathogenic VariantPrevalenceReference
p.Ala467Thr0.6% BelgianVan Goethem et al [2001]
0.17%-0.69% EuropeanHorvath et al [2006]
0.69% UKCraig et al [2007]
0% ItalianCraig et al [2007]
p.Trp748Ser0.8% FinlandHakonen et al [2005]
0% ItalianCraig et al [2007]
p.Gly848Ser0.05%-0.1%
p.[Thr251Ile]+[Pro587Leu] 10.05%
1.

Indicates a different pathogenic variant on each of two alleles (see www​.hgvs.org)

An up-to-date listing of all pathogenic variants is available at the Web site tools.niehs.nih.gov/polg/index.cfm, managed by William Copeland, PhD.

Table 5.

POLG Allelic Variants Discussed in This GeneReview

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
Benignc.52T>Gp.Pro18SerNM_002693​.2
NP_002684​.1
c.578G>Ap.Arg193Gln
c.970T>Gp.Pro324Ser
c.1550G>Tp.Gly517Val
c.1636C>Tp.Arg546Cys
c.1984C>Ap.Glu662Lys
c.3424C>Tp.Arg1142Trp
c.3428A>Gp.Glu1143Gly 2
c.3436C>Tp.Arg1146Cys
c.3708G>Tp.Gln1236His
Pathogenicc.695G>Ap.Arg232His
c.752C>Tp.Thr251Ile
c.1399G>Ap.Ala467Thr
c.1760C>Tp.Pro587Leu
c.2243G>Cp.Trp748Ser
c.2542G>Ap.Gly848Ser
c.2864A>Gp.Tyr955Cys
c.3488T>Gp.Met1163Arg
c.3630dupC
(3630insC)
p.Gly1211ArgfsTer6
(Tyr1210fs1216Ter)

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

1. Variant designation that does not conform to current naming conventions

2.

Modulates activity of the p.Trp748Ser disease-causing allele (see Benign allelic variants)

Normal gene product. POLG encodes DNA polymerase gamma (pol gamma), which comprises 1239 amino acids with a molecular weight of 139 kd; pol gamma is an enzyme required for mitochondrial DNA synthesis with two functional domains and one linker domain (see Molecular Genetic Pathogenesis).

Abnormal gene product. See Molecular Genetic Pathogenesis.

The clinical features of the diseases caused by mutation of POLG most likely result from depletion over time of normal mtDNA, with resultant reduced enzymatic activity of the electron transport chain components necessary for oxidative phosphorylation. The POLG gene product is arranged such that the 3’-5’ exonuclease activity is found in the first third of the protein and the DNA polymerase active site is found in the last third of the protein. These two active sites are separated by a linker region that contacts the POLG2 accessory subunit. The adPEO-causing pathogenic variants are the only pathogenic variants that are clustered; they are found, for the most part, in the active site region of the DNA polymerase.

The effect of several pathogenic variants on the function of the gene product has been studied.

  • The effect of the p.Ala467Thr substitution is a severe reduction in DNA polymerase gamma activity (4% of wildtype pol gamma activity) as a consequence of reduced affinity for dNTPs and lower catalysis [Chan et al 2005]. In addition, the p.Ala467Thr enzyme is defective in functional association with the POLG2 accessory subunit which is critical for highly processive DNA synthesis (defined as the number of nucleotides incorporated per DNA binding event). The combined defects lead to stalling at the replication fork and depletion of mtDNA over time.
  • The p.Trp748Ser pathogenic variant results in low DNA polymerase activity, low processivity, and a severe DNA-binding defect, but interactions with the POLG2 accessory subunit are normal [Chan et al 2006]. The phenotypic effects of p.Trp748Ser are modulated when in cis with a normal variant (see Molecular Genetic Pathogenesis, Benign allelic variants). AHS results when the p.[Trp748Ser;p.Glu1143Gly] haplotype occurs in trans configuration with a different pathogenic variant on the other allele, e.g., p.Arg232His (see Table 5).
  • The p.Tyr955Cys pathogenic variant, although rare, is the most observed POLG pathogenic variant in individuals with adPEO and causes a severe reduction in DNA polymerase activity (<1% of wildtype POLG activity) [Graziewicz et al 2004]. This pathogenic variant also results in a mutator polymerase, causing a ten- to 100-fold increase in nucleotide mis-insertion errors, most likely as a consequence of a 45-fold decrease in binding affinity for the incoming nucleoside triphosphates [Ponamarev et al 2002].

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Suggested Reading

  1. Alpers BJ. Diffuse progressive degeneration of the gray matter of the cerebrum. Arch Neurol Psychiatry. 1931;25:469–505.
  2. Cohen BH, Naviaux RK. The clinical diagnosis of POLG disease and other mitochondrial DNA depletion disorders. Methods. 2010;51:364–73. [PubMed: 20558295]
  3. Copeland WC. Defects in mitochondrial DNA replication and human disease. Crit Rev Biochem Mol Biol. 2012;47:64–74. [PMC free article: PMC3244805] [PubMed: 22176657]
  4. Longley MJ, Graziewicz MA, Bienstock RJ, Copeland WC. Consequences of mutations in human DNA polymerase gamma. Gene. 2005;354:125–31. [PubMed: 15913923]
  5. Saneto RP, Cohen BH, Copeland WC, Naviaux RK. Alpers-Huttenlocher syndrome. Pediatr Neurol. 2013;48:167–78. [PMC free article: PMC3578656] [PubMed: 23419467]
  6. Spinazzola A, Zeviani M. Disorders of nuclear-mitochondrial intergenomic signaling. Gene. 2005;354:162–8. [PubMed: 15921863]
  7. Tang S, Schmitt E, Zhang VW, Wang J, Wong LJ. An ever expanding molecular and clinical spectrum of polg revealed by the study of a large patient cohort. J Inherit Metab Dis. 2011;34 Suppl 3:S166.

Chapter Notes

Revision History

  • 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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