Clinical and Diagnostic Features of Patients with Compound Heterozygous A467T/W748S POLG1 Mutations: A Case Report and Review of Previous Cases

Introduction Mutations in the POLG1 gene are considered to be the most common gene defect identified in autosomal recessive mitochondrial DNA depletion disorders. POLG1 is a gene encoding the 195kDa catalytic (alpha) subunit of the mitochondrial (gamma) DNA polymerase, located on chromosome 15q25 and is responsible for mtDNA replication. Mutations in POLG1 are associated with chronic progressive external ophthalmoplegia (CPEO). Other genes that have been implicated in causing syndromic and non-syndromic mitochondrial disorders have been found on both mtDNA (3243A\u3eG, 8344A\u3eG, 8993T\u3eG, and 11778A\u3eG) and nDNA (SURF1, POLG1, TWINKLE, and ANT1). We report a patient with a rare type of POLG1 gene (A467T/W748S) mutation with a wide range of neurological manifestations, including, focal parieto-occipital lobe seizures, sensory axonal neuropathy, intestinal malabsorption, and impairement of visual perception and other cognitive domains. Mitochondrial disorders can have a very insidious clinical course, which can make the diagnosis difficult especially if genetic workup for routinely tested mitochondrial disorders is negative. Treatment of the epilepsy in patients with POLG1 gene mutations, specifically the compound heterozygous A457T/W748S, can be very challenging. While some conventionally used anti-seizure medications can turn out to be ineffective, others such as volproic acid can have deleterious effects on neurological function and make the seizures worse