By Michael Rubin, MD

Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Rubin reports no financial relationships relevant to this field of study.

Synopsis: Mutations of the polymerase-gamma (POLG) subunit in mitochondrial DNA is a common cause of adult mitochondrial syndromes, such as myopathies, encephalopathies, epilepsy, and ataxias.

Source: Tchikviladzé M, et al. A diagnostic flow chart for POLG-related diseases based on signs, sensitivity and specificity. J Neurol Neurosurg Psychiatry 2015;86:646-654.

Mutation of polymerase motif B, the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase γ (POLG), which maps to 15q25, was first associated with progressive external ophthalmoplegia with multiple mtDNA deletions in 2001. Since then, many diverse syndromes have been associated with these mutations, responsible for up to 25% of adult mitochondrial disease, including mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS); mitochondrial recessive ataxia syndrome; myoclonus, epilepsy, myopathy, sensory ataxia; and sensory ataxic neuropathy with dysarthria and ophthalmoplegia. What is the sensitivity and specificity of signs that would be indicative of POLG-related diseases?

Among 311 patients who underwent sequencing of the POLG gene in the Department of Metabolic Biochemistry of La Salpêtrière Hospital, Paris, between 2003-2012, follow-up data were available on 154 patients, representing diverse neurological conditions for “plausible” POLG mutations. Of these, 122 were followed at the National Reference Center for Neuromuscular and/or Rare Neurogenetic Diseases at La Salpêtrière Hospital, and 32 in various neurology departments of other Paris hospitals. Data collected included clinical information, brain magnetic resonance imaging (MRI), nerve conduction studies, electromyography, and muscle histochemistry and enzymatic assays, including respiratory chain assays, and search for multiple deletions. Statistical analysis encompassed the Fisher exact or χ2 test with the Yates correction, and the Mann–Whitney analysis of variance.

Among the 154 patients, 34 demonstrated deleterious mutations on both POLG alleles, and 10 demonstrated deleterious mutations on only one POLG allele, of which only two recognized dominant mutations were known to be pathogenic, and thus this group was omitted from comparison. One hundred ten patients had a normal POLG sequence. All groups had similar gender, age of onset, and disease duration. Comparing those with mutations on both alleles to those with normal alleles, peripheral neuropathy, ptosis, ophthalmoplegia, dysphagia, axial or limb muscle weakness, or both, psychiatric symptoms were significantly more frequent in the former. Sensory neuronopathy associated with either ophthalmoplegia, dysphagia, and axial or limb weakness was the only highly specific and sensitive association for POLG mutation. No patient had a demyelinating neuropathy, although all patients with mutations on both alleles had abnormal nerve conduction studies, compared to 55% without mutations. Solitary findings, such as weakness, cerebellar or movement disorders, or sensory neuropathy, were sensitive but not specific, unless associated with seizures, psychiatric issues, or cognitive impairment. Neither brain MRI nor mitochondrial studies, including muscle histology, lactate measurement, respiratory chain complex activity, or multiple mtDNA deletions in muscle, allowed for specific diagnosis.


With an estimated prevalence of more than 1 in 5000, mitochondrial diseases result from more than 200 different mtDNA mutations and 100 nuclear mutations, the most frequent gene affected being POLG, with more than 80 mutations described. Leber hereditary optic neuropathy is the most common mitochondrial disease due to mtDNA mutations, followed by MELAS. Resting serum lactate and pyruvate, frequently increased, are the most important laboratory measurements, with creatine kinase often normal or mildly elevated, and electromyography studies spanning the spectrum from normal to neurogenic, myopathic, or nonspecific. Ragged red fibers, usually without cytochrome C oxidase (COX) activity, are always found on muscle biopsy.