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 antiepileptic drugs. 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 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 variant in POLG by molecular genetic testing (see Table 1).

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 at the most reasonable cost 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 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.