A467T variant of the polg gene: description of two clinical cases

Abstract

Introduction: Variations in the POLG gene are the most common causes of mitochondrial disease of autosomal inheritance, and may be present in about 2% of the population. Case report: Case 1. CMAM, male, 48-year-old, complaining of bilateral eyelid ptosis with onset in adolescence. Since the age of six, he has been diagnosed with epilepsy. After five years of follow-up, he developed sensory ataxia. After 10 years he began to present dysarthria, dysphagia, tremor and pyramidal syndrome. Case 2. ASB, female, 42 years old, at 20 years old presented generalized clonic tonic crisis during the second and third trimesters of pregnancy; at 35 years of age she complained of tingling in plants and legs; at 37 years she noticed bilateral eyelid ptosis and at 39 years she noticed the presence of slurred speech and fatigue on small efforts. He has 3 siblings with similar symptoms and great difficulty walking. No history of consanguinity. Propedeutics: Normal serum lactate and CPK dosage; muscle biopsy showed variation in the caliber of muscle fibers, with the presence of “ragged red fibers” in Gomori’s Trichrome stain. Cranial magnetic resonance imaging: mild cerebellar atrophy in patient 1 and normal in patient 2. Electroneuromyography reveled absence of sensory action potentials in all nerves studied in both cases. New generation sequencing myopathy panel revealed pathogenic variant in homozygosis in the POLG c.1399G>A gene (p.Ala467Thr). Results: The patients received the diagnosis of mitochondrial disease, presenting complex clinical phenotype. Conclusion: DNA polymerase gamma is the enzyme responsible for replicating and maintaining mitochondrial DNA, encoded by nuclear DNA. The c.1399G>A variant in exon7 causes a replacement of an alanine with threonine (A467T), and is one of the causes of ataxia, such as spinocerebellar ataxia with epilepsy; autosomal recessive mitochondrial ataxia, sensory neuropathy, dysarthria and ophthalmoparesis and myoclonic epilepsy, myopathy and sensory ataxia. However, most of the time, they present a continuum between the phenotypes described.