Bilateral striatal necrosis due to homoplasmic mitochondrial 3697G\u3eA mutation presents with incomplete penetrance and sex bias

Abstract

© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. Background: Heteroplasmic mitochondrial 3697G\u3eA mutation has been associated with leber hereditary optic neuropathy (LHON), mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and LHON/MELAS overlap syndrome. However, homoplasmic m.3697G\u3eA mutation was only found in a family with Leigh syndrome, and the phenotype and pathogenicity of this homoplasmic mutation still need to be investigated in new patients. Methods: The clinical interviews were conducted in 12 individuals from a multiple-generation inherited family. Mutations were screened through exome next-generation sequencing and subsequently confirmed by PCR-restriction fragment length polymorphism. Mitochondrial complex activities and ATP production rate were measured by biochemical analysis. Results: The male offspring with bilateral striatal necrosis (BSN) were characterized by severe spastic dystonia and complete penetrance, while the female offspring presented with mild symptom and low penetrance. All offspring carried homoplasmic mutation of NC_012920.1: m.3697G\u3eA, p.(Gly131Ser). Biochemical analysis revealed an isolated defect of complex I, but the magnitude of the defect was higher in the male patients than that in the female ones. The ATP production rate also exhibited a similar pattern. However, no possible modifier genes on the X chromosome were identified. Conclusion: Homoplasmic m.3697G\u3eA mutation could be associated with BSN, which expanded the clinical spectrum of m.3697G\u3eA. Our preliminary investigations had not found the underlying modifiers to support the double hit hypothesis, while the high level of estrogens in the female patients might exert a potential compensatory effect on mutant cell metabolism