POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined long before their molecular basis was known. These phenotypes exemplify the diversity that can result from mutations in a given gene. Most affected individuals have some, but not all, of the features of a given phenotype; nonetheless, the following nomenclature can assist the clinician in diagnosis and management. Onset of the POLG-related disorders ranges from early childhood to late adulthood. Alpers-Huttenlocher syndrome (AHS), one of the most severe phenotypes, is characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and hepatic failure. Childhood myocerebrohepatopathy spectrum (MCHS) presents between the first few months of life up to about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other findings can include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Myoclonic epilepsy myopathy sensory ataxia (MEMSA) now describes the spectrum of disorders with epilepsy, myopathy, and ataxia without ophthalmoplegia. MEMSA now includes the disorders previously described as spinocerebellar ataxia with epilepsy (SCAE). The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). About 90% of persons in the ANS have ataxia and neuropathy as core features. Approximately two thirds develop seizures and almost one half develop ophthalmoplegia; clinical myopathy is rare. Autosomal recessive progressive external ophthalmoplegia (arPEO) is characterized by progressive weakness of the extraocular eye muscles resulting in ptosis and ophthalmoparesis (or paresis of the extraocular muscles) without associated systemic involvement; however, caution is advised because many individuals with apparently isolated arPEO at the onset develop other manifestations of POLG-related disorders over years or decades. Of note, in the ANS spectrum the neuropathy commonly precedes the onset of PEO by years to decades. Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, Parkinsonism, hypogonadism, and cataracts (in what has been called "chronic progressive external ophthalmoplegia plus," or "CPEO+").
Establishing the diagnosis of a POLG-related disorder relies on clinical findings and identification of two disease-causing POLG mutations for all phenotypes except adPEO, for which identification of one disease-causing POLG mutation is diagnostic. POLG molecular genetic testing is available on a clinical basis.
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 disease-causing mutations 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 mutation. For pregnancies at increased risk for all phenotypes, prenatal diagnosis is possible if the disease-causing mutation(s) in the family are known.