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Abstract

Mutations in the gene encoding the catalytic subunit of polymerase gamma (POLG1) are a major cause of human mitochondrial disease. More than 150 different point mutations in the gene have been reported to be disease causing, resulting in a large range of clinical symptoms. Depending on the mutation or combination of mutations, disease onset can occur in early infancy or late in adult life. Here, we describe the use of multiplex ligation-dependent probe amplification (MLPA) analysis to detect deletions within POLG1, which could otherwise go undetected by solely sequencing of the gene. We present a case where an entire POLG1 allele is deleted, with a known pathogenic mutation (W748S) on the remaining allele. The deletion was found in a boy with Alpers syndrome, presenting at 18 months of age with slightly retarded motor development, balance problems, and seizures. Administration of valproic acid (VPA) led to rapidly progressive fatal liver failure in our patient, and we would like to highlight the need to carry out complete POLG1 gene analysis before administration of VPA in cases of pediatric seizure disorders of unknown origin. Debut and severity of the disease in this patient was unique when compared to homozygous or heterozygous patients with the W748S mutation, leading to the conclusion that gene dosage plays a role in the clinical phenotype of this disease.