Clinical characteristics.

POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined long before their molecular basis was known. 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 and 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 biallelic POLG pathogenic variants for all phenotypes except adPEO, for which identification of a heterozygous POLG pathogenic variant is diagnostic.

Management.

Treatment of manifestations: Clinical management is largely supportive and involves conventional approaches for associated complications including occupational, physical, and speech therapy; nutritional interventions; and standard respiratory support, treatment for liver failure and disorders of arousal and sleep, 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 health care 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.

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 findings.

Clinical features

• Hypotonia
• Developmental delay
• Seizures
• Movement disorder (e.g., myoclonus, dysarthria, choreoathetosis, parkinsonism)
• Myopathy (e.g., ptosis, ophthalmoplegia, proximal > distal limb weakness with fatigue and exercise intolerance)
• Ataxia
• Peripheral neuropathy
• Episodic psychomotor regression
• Psychiatric illness (e.g., depression, mood disorder)
• Endocrinopathy (e.g., diabetes mellitus, premature ovarian failure)

Laboratory findings

• Liver dysfunction or failure, which may follow exposure to certain anti-seizure medication. This could result in elevations in the liver enzymes ALT, AST, and GTT as well as synthetic liver dysfunction causing hypoglycemia, hyperammonemia, elevated glutamine, hyperbilirubinemia, prolonged bleeding times (INR, PT, PTT), hypoalbuminemia, and low cholesterol.
• Respiratory chain defect and/or a defect of mitochondrial (mt) DNA (depletion or multiple deletions). This could result in respiratory chain dysfunction, identified by either enzymatic assays or polarographic assays. Depletion of mtDNA can be measured by comparing the value of mtDNA content in an affected tissue (e.g., liver) with the nuclear DNA content. The use of Southern blot or long-range PCR of the mtDNA can detect deletions or multiple deletions in some individuals. Note: Biochemical findings on muscle biopsy can be normal, and normal respiratory chain function or absence of mtDNA depletion should not rule out consideration of a POLG-related disorder.
• Cerebrospinal fluid (CSF) protein is generally elevated in individuals with Alpers-Huttenlocher syndrome (AHS).

Radiographic features

• Brain computerized tomography (CT) or magnetic resonance imaging (MRI) 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.

Establishing the Diagnosis

Clinical diagnostic criteria do not exist. 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 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 variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any 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 serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Serial single-gene testing. Sequence analysis of POLG is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  Sequence analysis of TWNK (formerly C10orf2 or PEO1) may be considered in persons with a suspected autosomal recessive POLG-related disorder but in whom only one POLG pathogenic variant was identified by single-gene testing, to investigate the possibility of digenic inheritance (see Differential Diagnosis). Digenic inheritance has been reported in autosomal recessive progressive external ophthalmoplegia (arPEO) in a simplex case with pathogenic variants in POLG and TWNK [Van Goethem et al 2003a].
  Note: 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 a de novo POLG pathogenic variant.
• A multigene panel that includes POLG, TWNK (formerly C10orf2 or PEO1), and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing, mtDNA sequencing, and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

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. 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 pathogenic variants is ongoing, knowledge of their associated phenotypes continues to evolve.

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 clinical phenotype.

Genotype-Phenotype Correlations

Genotype-phenotype correlations are not possible because all combinations of pathogenic variant type and location have been associated with the entire phenotypic spectrum and with 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 and founder variants occur in some populations, the frequency may vary greatly by ethnicity.

The sum frequency of the most common autosomal recessive pathogenic variants can be used to estimate disease frequency at 1:10,000:

• p.Ala467Thr. ~0.2%-0.6% (up to 1% in Norway)
• p.[Trp748Ser;Glu1143Gly]. ~0.1%-0.8%
• p.Gly848Ser. ~0.05%-0.1%
• p.Pro587Leu. ~0.05%

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

Mitochondrial DNA Depletion (MDD) Disorders

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

Mitocondrial DNA depletion syndromes, a genetically and clinically heterogeneous group of autosomal recessive disorders, are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs.

Mitochondrial DNA depletion syndromes occur as a result of defects in mtDNA maintenance caused by pathogenic variants in nuclear genes that function in either mitochondrial nucleotide synthesis (e.g., TK2, SUCLA2, SUCLG1, RRM2B, DGUOK, and TYMP) or mtDNA replication (e.g., POLG and TWNK).

Mitochondrial DNA depletion syndromes are phenotypically classified into myopathic, encephalomyopathic, hepatocerebral, and neurogastrointestinal forms (see Table 3) [El-Hattab & Scaglia 2013].

• Myopathic forms present in infancy or early childhood with hypotonia, proximal muscle weakness, and feeding difficulty. Cognition is usually spared. Typically, there is rapid progression of muscle weakness with respiratory failure and death within a few years of onset.
• Encephalomyopathic mtDNA depletion syndromes present in infancy with hypotonia and global developmental delay. Depending on the underlying defect, other features including deafness, movement disorders, Leigh like syndrome, and renal disease can be observed.
• Hepatocerebral forms present with early-onset liver dysfunction and neurologic involvement, including developmental delay, abnormal eye movements, and peripheral neuropathy.
• Neurogastrointestinal forms, the prototype of which is mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease, present in adolescence to early adulthood with progressive gastrointestinal dysmotility, cachexia, and peripheral neuropathy.

Table 3 classifies the mtDNA depletion syndromes by phenotypic category and associated genes.

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

Deoxyguanosine kinase deficiency (DGUOK deficiency). The two forms of DGUOK deficiency are a hepatocerebral mtDNA 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 (jaundice, cholestasis, and elevated transaminases) and neurologic manifestations (hypotonia, nystagmus, and psychomotor retardation) evident within weeks of birth. 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-related hepatocerebral mtDNA depletion syndrome (Navajo neurohepatopathy) is characterized by liver failure, severe sensory neuropathy, corneal anesthesia and scarring, cerebral leukoencephalopathy, failure to thrive, and metabolic acidosis. Homozygosity for the MPV17 pathogenic variant NP_002428.1:p.Arg50Gln (NM_002437.4:c.149G>A) is associated with Navajo neurohepatopathy, a mtDNA depletion syndrome displaying hepatic failure early in life, prevalent in the Navajo tribes in the southwestern United States.

SUCLA2-related mtDNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria is characterized by 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, and 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.

FBXL4-related encephalomyopathic mtDNA depletion syndrome is a multisystem disorder characterized primarily by congenital or early-onset lactic acidosis and growth failure, feeding difficulty, hypotonia, and global developmental delay. Other neurologic manifestations can include seizures, movement disorders, ataxia, autonomic dysfunction, and stroke-like episodes. All affected individuals alive at the time they were reported (median age: 3.5 years) demonstrated significant global developmental delay. Other findings can involve the heart (hypertrophic cardiomyopathy, congenital heart malformations, arrhythmias), liver (mildly elevated transaminases), eyes (cataract, strabismus, nystagmus, optic atrophy), hearing (sensorineural hearing loss), and bone marrow (neutropenia, lymphopenia). Survival varies; the median age of reported deaths was two years (range 2 days - 75 months), although surviving individuals as old as 36 years have been reported. To date FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals.

SUCLG1-related mtDNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria is characterized in the majority of affected newborns by hypotonia, muscle atrophy, feeding difficulties, and lactic acidosis. Affected infants commonly manifest developmental delay / cognitive impairment, growth retardation / failure to thrive, hepatopathy, sensorineural hearing impairment, dystonia, and hypertonia. Notable findings in some affected individuals include hypertrophic cardiomyopathy, epilepsy, myoclonus, microcephaly, sleep disturbance, rhabdomyolysis, contractures, hypothermia, and/or hypoglycemia. Life span is shortened, with median survival of 20 months. The phenotype may be indistinguishable from SUCLA2-related mtDNA depletion syndrome, encephalomyopathic form, with mild methylmalonic aciduria. Affected individuals have urinary excretion of MMA, combined respiratory chain enzyme deficiency, and mtDNA depletion.

RRM2B mtDNA maintenance defects. Mutation of RRM2B has been associated with severe muscle mtDNA depletion in several families. This disorder manifests as severe encephalopathy, myopathy with persistent lactic acidosis, hypotonia, renal tubular defects, seizures, and diarrhea. Death has been reported to occur by age four months, but affected individuals have demonstrated longer survival [B Cohen, personal communication].

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is characterized by progressive gastrointestinal dysmotility (manifesting as early satiety, nausea, dysphagia, gastroesophageal reflux, postprandial emesis, episodic abdominal pain and/or distention, and diarrhea); cachexia; ptosis/ophthalmoplegia or ophthalmoparesis; leukoencephalopathy; and demyelinating peripheral neuropathy (manifesting as paresthesias [tingling, numbness, and pain] and symmetric and distal weakness more prominently affecting the lower extremities). The order in which manifestations appear is unpredictable. Onset is usually between the first and fifth decades; in about 60% of individuals, symptoms begin before age 20 years. The diagnosis of MNGIE disease can be established in a proband by detection of one of the following: (1) biallelic pathogenic variants in TYMP; (2) markedly reduced levels of thymidine phosphorylase enzyme activity; or (3) elevated plasma concentrations of thymidine and deoxyuridine.

TK2-related mtDNA depletion syndrome. Mitochondrial myopathy with mtDNA depletion is caused by pathogenic variants in TK2.

MGME1-related mtDNA depletion syndrome 11 (OMIM 615084) is caused by biallelic pathogenic variants in MGME1. 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.

SLC25A4-related mtDNA depletion syndrome 12B, cardiomyopathic type (OMIM 615418) is caused by biallelic pathogenic variants in SLC25A4. Affected individuals may present with the SANDO (ANS) phenotype.

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. (See Nuclear Gene-Encoded Leigh Syndrome Overview, Mitochondrial DNA-Associated Leigh Syndrome and NARP, and Mitochondrial DNA Deletion Syndromes.)

Autosomal dominant progressive external ophthalmoplegia (OMIM PS157640) is caused by pathogenic variants in DGUOK, DNA2, OPA1, POLG2, RNASEH1, RRM2B, SLC25A4, TK2, or TWNK.

Oculopharyngeal muscular dystrophy (OPMD) 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. OPMD is caused by pathogenic variants in PABPN1 and inherited in either an autosomal dominant or an autosomal recessive manner.

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 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 that 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 mtDNA (e.g., m.3243A>G).

Kearns-Sayre syndrome (KSS), a mtDNA deletion syndrome, is a multisystem disorder defined by the triad of onset before age 20 years, pigmentary retinopathy, and progressive external ophthalmoplegia (PEO). In addition, affected individuals have at least one of the following: cardiac conduction block, cerebrospinal fluid protein concentration greater than 100 mg/dL, or 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 deletion of mtDNA and, when inherited, are transmitted by maternal inheritance. Most individuals with KSS have a common deletion of 4,977 nucleotides involving 12 mitochondrial genes.

BCS1L-related disorders. Pathogenic variants in BCS1L are associated with GRACILE (growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death) syndrome (OMIM 603358), Bjørnstad syndrome (congenital profound hearing loss and pili torti) (OMIM 262000), and 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 hepatoencephalopathy 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-related disorders (OMIM 603644). Hepatic failure and severe encephalopathy have also been associated with biallelic pathogenic variants in SCO1.

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 CLN1 disease, classic infantile (previously classic infantile NCL, INCL, Santavuori-Haltia), and CLN2 disease, classic late infantile (previously late-infantile NCL, LINCL, Jansky-Bielschowsky disease). Inheritance of CLN1 disease and CLN2 disease is autosomal recessive.
  • CLN1 disease. Children with CLN1 disease 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. Pathogenic variants in PPT1 can be causative.
  • CLN2 disease. The first symptoms of CLN2 disease 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. Pathogenic variants in PPT1, TPP1, CLN5, CLN6, and CLN8 can be causative.
• MERRF (myoclonic epilepsy with ragged red fibers) is a multisystem disorder characterized by myoclonus (often the first symptom) followed by generalized epilepsy, ataxia, weakness, and dementia. Onset is usually in childhood, following normal early development. Common findings are hearing loss, short stature, optic atrophy, and cardiomyopathy with Wolff-Parkinson-White 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 (OMIM 256550), and galactosialidosis (OMIM 256540), 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 epilepsy, cerebral folate deficiency (OMIM 613068), glycine encephalopathy (also known as nonketotic hyperglycinemia), biotinidase deficiency, and disorders of biogenic amine metabolism, such as folate-responsive seizures (see Hereditary Folate Malabsorption). Pyridoxine-dependent seizures and biotinidase deficiency are treatable and on occasion reversible [Wolf 2005, Gallagher et al 2009].
• Sulfite oxidase deficiency (OMIM 272300) and Menkes disease (see ATP7A-Related Copper Transport Disorders) usually present earlier in infancy. Sulfite oxidase deficiency can be screened for by use of a commercially available sulfite oxidase urine dipstick test and Menkes disease by detection of low serum concentrations of copper and ceruloplasmin. Menkes disease is caused by pathogenic variants in ATP7A and in inherited in an X-linked manner.

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 pathogenic variants in CACNA1A, CACNB4, SCN1A, SCN2A, or SCN9A which encode for sodium and calcium channels. See SCN1A Seizure Disorders.

Both myoclonic epilepsy (OMIM PS254800) and the Lennox-Gastaut syndrome can cause dementia or pseudodementia as a result of unrelenting seizures and anticonvulsant side effects.

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 if they have not already been completed:

• 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.
• Echocardiogram and electrocardiogram
• Ophthalmology evaluation with vision assessment
• Audiology evaluation
• 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)
  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.
• Consideration of liver ultrasound examination to evaluate for presence of fibrosis
• Consultation with a biochemical geneticist and/or genetic counselor

Treatment of Manifestations

Treatment is limited to symptom management and supportive care.

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
• Biochemical geneticist
• Hepatologist or gastroenterologist
• Physiatrist
• Psychiatrist
• Neuropsychologist and/or psychologist
• Ophthalmologist
• Pulmonologist

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 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 2017 (20 years after liver transplantation), she was alive and living semi-independently, albeit with severe PEO, myopathy, and progressive CNS dysfunction, specifically failing memory with increasing ataxia, dysarthria, chorea, and hemiballismus. Although seizures were a presenting symptom, they are currently controlled.

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. The following, however, may be considered:

• 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 [Parikh et al 2009, Camp et al 2016].
• 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 [El-Hattab et al 2017].
• 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, Parikh et al 2013].

Mode of Inheritance

The following POLG-related disorders are inherited in an autosomal recessive manner:

• Alpers-Huttenlocher syndrome (AHS)
• Childhood myocerebrohepatopathy spectrum (MCHS)
• Myoclonic epilepsy myopathy sensory ataxia (MEMSA); previously referred to as spinocerebellar ataxia with epilepsy (SCAE)
• Ataxia neuropathy spectrum (ANS); includes disorders previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO)
• Autosomal recessive progressive external ophthalmoplegia (arPEO)

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

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• In general, the parents of an affected child are obligate heterozygotes (i.e., carriers of one POLG pathogenic variant). In two families reported to date, only one parent of the proband was heterozygous (i.e., the probands were compound heterozygous for one inherited and one de novo pathogenic variant) [Chan et al 2009, Lutz et al 2009].
• Heterozygotes are generally believed to be asymptomatic. However, some individuals with a heterozygous POLG pathogenic variant are reported to have partial manifestations of POLG-related disorders; the manifestation cannot be predicted [Rantamäki et al 2007]. 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

• At conception, the sibs of an individual with an autosomal recessive POLG-related disorder have a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected and not a carrier. Affected sibs may present differently in terms of age of onset and severity.
• Heterozygotes 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.

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 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.

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.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Most individuals diagnosed with an autosomal dominant POLG-related disorder have an affected parent, although age of onset and severity of presentation can vary greatly from generation to generation.
• A proband with an autosomal dominant POLG-related disorder may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by a de novo pathogenic variant 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 pathogenic variant was de novo, the proportion of cases caused by a de novo variant is unknown.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant 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.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent.
• 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 until appropriate evaluations have been performed.
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent 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%. Although in general the phenotype of the illness may be similar in families, affected sibs may present differently in terms of age of onset 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, while the other sib presented with ataxia and myoclonus in early adolescence [Tang et al 2011].
• 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 leukocyte DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the theoretic possibility of parental 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. The risk to other family members depends on the status of the proband's parents: if a parent is affected or 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.
• Older unaffected sibs (as well as other family members) may have only a single pathogenic variant, but need to be informed that:
  • Some heterozygotes have had symptoms at a later age – possibly related to their genetic status; and
  • 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/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, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

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 a POLG-related disorder 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 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, mtDNA replicates continuously and independently of cell division. Polymerase (pol) gamma is the only DNA polymerase in humans that replicates and repairs 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.

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

Benign variants. A number of POLG pathogenic variants have been found to occur in cis with the benign variant p.Glu1143Gly, which has a minor allele frequency of 3%-4%. This variant modulates the pathogenic effect of p.Trp748Ser (see Pathogenic variants).

Pathogenic variants. Pathogenic variants are found throughout the gene. Almost 200 variants 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. Of note, the p.Glu1143Gly variant modulates the deleterious effect of p.Trp748Ser by partially rescuing activity but decreasing protein stability [Chan et al 2006].
• The mother of a child with a mitochondrial recessive ataxia syndrome/ataxia neuropathy spectrum (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 had an axonal neuropathy, ataxia, mild PEO, and mild parkinsonism [Tzoulis et al 2006]. The significance of this finding is unknown.

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

Normal gene product. POLG encodes DNA pol gamma, which has three functional domains:

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

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

Abnormal gene product. See Molecular Pathogenesis.

The clinical features POLG-related disorders most likely result from depletion 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.

The effect of several common pathogenic variants has been studied.

• The p.Ala467Thr variant severely reduces DNA polymerase gamma activity (4% of wild type pol gamma activity) by reducing the affinity for dNTPs and lowering catalytic activity [Chan et al 2005]. In addition, p.Ala467Thr fails to associate 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 reduced DNA polymerase activity, low processivity, and a severe DNA binding defect, but normal POLG2 interactions [Chan et al 2006]. The phenotypic effects of p.Trp748Ser are modulated when in cis with a normal variant (see Molecular Pathogenesis, Benign 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).
• The p.Gly848Ser pathogenic variant results in <1% polymerase activity and in a defect in DNA binding function [Kasiviswanathan et al 2009].
• The rare p.Tyr955Cys pathogenic variant is the most common associated with adPEO, causing severe reduction in DNA polymerase activity (<1% of wild type 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].
• The p.Thr251Ile and p.Pro587Leu variants nearly always occur together on the same allele in affected individuals and in the general population. Individually, these variants cause an approximately 30% reduction in DNA polymerase activity, but together there is a synergistic impairment of polymerase function to levels about 5% of normal [DeBalsi et al 2017].

Revision History

• 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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