Open AccessBilateral striatal necrosis due to homoplasmic mitochondrial 3697G>A mutation presents with incomplete penetrance and sex bias
Author(s) -
Zhong Shanshan,
Wen Shumeng,
Qiu Yusen,
Yu Yanyan,
Xin Ling,
He Yang,
Gao Xuguang,
Fang Hezhi,
Hong Daojun,
Zhang Jun
Publication year - 2019
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.541
Subject(s) - heteroplasmy , penetrance , lactic acidosis , mitochondrial disease , genetics , leber's hereditary optic neuropathy , mitochondrial dna , biology , non mendelian inheritance , mutation , mitochondrial encephalomyopathy , medicine , endocrinology , phenotype , gene
Background Heteroplasmic mitochondrial 3697G>A 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>A 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>A, 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>A mutation could be associated with BSN, which expanded the clinical spectrum of m.3697G>A. 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.