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 mutations is ongoing; thus, it is likely that neither the full spectrum nor the extent to which the recognized phenotypes overlap is yet known.

Diagnostic criteria do not exist. Establishing the diagnosis of a POLG-related disorder requires identification of two disease-causing POLG mutations for each of the following phenotypes except adPEO, for which identification of one disease-causing dominant POLG mutation is diagnostic.

Alpers-Huttenlocher syndrome (AHS)

• Onset usually before age 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 medication

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)

• PEO: ptosis and ophthalmoplegia
• Other features variably present: depression (mood disorder), premature ovarian failure, parkinsonism, ataxia, and a MNGIE-like phenotype, (see Mitochondrial Neurogastrointestinal Encephalopathy Disease)

Autosomal dominant progressive external ophthalmoplegia (adPEO)

• PEO: ptosis (drooping of the eyelids) and ophthalmoplegia (paralysis of the extraocular muscles)
• Other features that can include 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.

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 disease-causing POLG mutations by molecular genetic testing. One of two approaches to molecular genetic testing can be used:

• Direct sequencing of POLG
  
  OR
• Two-tiered analysis: targeted mutation analysis for the common POLG mutations p.Ala467Thr, p.Trp748Ser, and p.Gly848Ser, followed by sequence analysis of the entire coding region if no mutations or only one mutation is found

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 disease-causing mutation 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. Digenic inheritance has been reported in arPEO in a simplex case with mutations in POLG and C10orf2 [Van Goethem et al 2003a]. See Differential Diagnosis for other disorders to consider. 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 heterozygote pathogenic mutation [Naess et al 2010, Compton et al 2011].

Carrier testing for relatives at risk for autosomal recessive phenotypes requires prior identification of the disease-causing mutations in the family.

Note: When inheritance is autosomal recessive, the heterozygotes (carriers) are not at risk of developing the disorder. Although there are reports of mild neurologic features in the carriers of single recessive alleles, these cases are rare, and the clinical significance of these findings has yet to be substantiated.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for pregnancies at risk for:

• An autosomal recessive POLG-related disorder require prior identification of the disease-causing mutations in the family.
• An autosomal dominant POLG-related disorder require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

Because the description of new POLG mutations is ongoing, knowledge of their associated phenotypes continues to evolve. POLG mutations have been shown to be associated with Charcot-Marie Tooth neuropathy type 2 [Harrower et al 2008], Leigh syndrome [Naess et al 2009, Taanman et al 2009], and a MNGIE-like illness [Tang et al 2012] — diseases that are generally associated with defects in other genes.

Alterations in the CAG repeat region have been found to be associated with idiopathic sporadic Parkinson disease [Luoma et al 2007] and Friedreich ataxia [Heidari et al 2008].

Natural History

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.

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.

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 called “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 mutations are found at high frequencies in certain populations, the frequency may vary greatly within any population.

The frequency of the most common autosomal recessive pathologic 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 mutations 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.

Mutations 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.

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 mutations in eight nuclear genes: DGUOK, MPV17, POLG, RRM2B, SUCLA2, SUCLG1, TK2, and C10orf2. 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 mutations and 18% had POLG mutations. 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 mutations 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.

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 mutations, 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 mutation 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 [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 mutations have 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:

• Onset of severe hypotonia in early infancy (birth to five 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 three 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. Mutations have recently been reported in SUCLG1, which encodes the α subunit of succinate-CoA ligase [Ostergaard et al 2007]. Affected individuals show:

• 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 mutations in TK2, the gene encoding thymidine kinase [Saada et al 2001].

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is characterized by:

• 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:

• 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 mutations 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 mutations in:

• ANT1, the gene encoding the heart/skeletal muscle isoform of adenine nucleotide translocator [Kaukonen et al 2000];
• C10orf2 encoding Twinkle, which is responsible for mtDNA integrity [Spelbrink et al 2001];
• OPA1, which affects mitochondrial fusion and fission [Hudson et al 2008, Amati-Bonneau et al 2008];
• POLG2, which codes for the accessory subunit of polymerase gamma [Longley et al 2006];
• POLG, encoding DNA polymerase gamma, which is responsible for mtDNA replication [Van Goethem et al 2001].

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 (see following). Some individuals with CPEO (<20%) have a pathogenic point mutation of mitochondrial DNA (e.g., m.3243A>G).

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

• 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., 1.3-10 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.

Mutations in BCS1L are associated with

• GRACILE syndrome (growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis and early death);
• Bjørnstad syndrome (congenital profound hearing loss and pili torti);
• 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 mutations.

SCO1. Hepatic failure and severe encephalopathy have also been associated with compound heterozygosity for two mutations in SCO1.

Other. The differential diagnosis of MDD 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, Jansky-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. Mutations in PPT1 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. Mutations in 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. Pigmentary retinopathy and lipomatosis are common features that can be detected with visual electrophysiology or MRI scanning in affected individuals where not clinically obvious. 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 mutations 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 and retardation.

At least one channelopathy has been associated with a severe infantile epileptic disorder caused by mutation of SCN1A, which encodes a sodium channel protein type 1 alpha subunit. 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Evaluations Following Initial Diagnosis

To establish the extent of disease 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 in pCO₂ elevation or O₂ desaturation.
• Liver function tests including fasting serum glucose concentration; 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.
• Medical genetics consultation

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.

Recent 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 with treatment offered 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:

• 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); 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 strongly be considered (see Prevention of Secondary Complications).
• The use of levo-arginine has been reported to be helpful in reduction in 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].

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 mutant allele.
• Heterozygotes (carriers) are generally believed to be asymptomatic. However, some individuals with a heterozygous POLG mutation 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

• 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 a carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are generally asymptomatic (see discussion in Risk to Family Members—Autosomal Recessive Inheritance, Parents 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 mutation.

Other family members. Sibs of the proband’s parents are at a 50% risk of being carriers.

Carrier Detection

Carrier testing for at-risk family members is possible once the disease-causing mutations have been identified in the family.

Individuals from populations with a high carrier rate for POLG mutations 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 gene mutation. 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 disease-causing mutation 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 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, if present as isolated findings are 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 biologic 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 mutation first occurred s/he may have somatic mosaicism for the mutation 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 disease-causing mutation 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 mutation.

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 disease-causing mutation, 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 mutation, 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) have an 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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 some families in which the disease-causing mutation(s) have been identified in an affected family member.

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 are:

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

Recent reports suggest that mutations 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 mutations in POLG were identified in families with autosomal dominant chronic progressive external ophthalmoplegia [Van Goethem et al 2001] followed by reports of POLG mutations 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 mutation was made by Naviaux & Nguyen [2004] in two probands diagnosed with Alpers-Huttenlocher syndrome (AHS).

Normal allelic variants. POLG comprises 23 exons and is 18,476 bases in length. A number of POLG mutations have been found to occur in cis configuration with the normal 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 [Tzoulis 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 mutation(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 pathologic variant [Kasiviswanathan & Copeland 2011].

Because many of the reported pathogenic mutations 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].

Pathologic allelic variants. Pathologic allelic 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 pathologic variants are located in the linker region of the gene.

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

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

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 mutations in 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 mutations are the only mutations that are clustered; they are found, for the most part, in the active site region of the DNA polymerase.

The effect of several pathologic 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 mutation 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, Normal Allelic Variants). AHS results when the p.[Trp748Ser;p.Glu1143Gly] haplotype occurs in trans configuration with a different pathologic mutation on the other allele, e.g., p.Arg232His (see Table 5).
• The p.Tyr955Cys mutation, although rare, is the most observed POLG mutation in individuals with adPEO and causes a severe reduction in DNA polymerase activity (<1% of wildtype POLG activity) [Graziewicz et al 2004]. This mutation 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. Spinazzola A, Zeviani M. Disorders of nuclear-mitochondrial intergenomic signaling. Gene. 2005;354:162–8. [PubMed: 15921863]
6. 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.

Revision History

• 11 October 2012 (me) Comprehensive update posted live
• 16 March 2010 (me) Review posted live
• 9 December 2007 (bhc) Original submission