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

Abstract

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.

A Novel Variation in the Mitochondrial Complex I Assembly Factor NDUFAF5 Causes Isolated Bilateral Striatal Necrosis in Childhood

“…It can be familial or sporadic in origin. BSN pathology may also involve globus pallidus, tegmental nucleus, and substantia nigra brain regions under various diseased conditions ( 2 ). The most commonly associated pyramidal symptoms include spasticity, hyperreflexia, and weakness primarily related to upper motor neuron degeneration, leading to developmental regression or cognitive as well as motor deficits ( 3 ).…”

Genetic diagnosis of basal ganglia disease in childhood

“…All mtDNA variants had been associated with Leigh syndrome except the m.3700G>A variant reported in Leber hereditary optic neuropathy 19 . Other variants initially described in this neuropathy have later been recognized in families with Leigh syndrome, such as m.13513G>A, m.3697G>A, and 4171C>A20 20,21 …”

“…19 Other variants initially described in this neuropathy have later been recognized in families with Leigh syndrome, such as m.13513G>A, m.3697G>A, and 4171C>A20. 20,21 Most children with BBG T2-hyperintensity had Leigh syndrome, half of them caused by oxidative phosphorylation system structural subunits or assembly factor defects. 3,18 Other mitochondrial defects involved pyruvate dehydrogenase E1-α (PDHA1), mtDNA maintenance (SUCLG1), mitochondrial thiamine pyrophosphate carrier (SCL25A19), valine metabolism (ECHS1 and HIBCH), and mitochondrial lipoic acid synthesis (MECR).…”

Mitochondrial DNA abnormalities and metabolic syndrome

“…The last group of through direct sequencing of PCR fragments of a 14-year-old index male hypertrophic cardiomyopathy (hCMP) patient, it was found that m.14757T> a, m.15236A>G, m.15314G> a resulted in amino acid residues in the Cyt b gene replace, Cyt b is very likely to be related to cardiomyopathy (Zarrouk-Mahjoub et al, 2015). The 3697G>A mutation can cause to isolated severe complex I defects, leading to lactic acidosis, central nervous system dysfunction and other metabolic syndromes (Zhong et al, 2019). Modification of proteins encoded by mtDNA is still a technical bottleneck at present.…”