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.

Keywords: bilateral striatal necrosis; homoplasmy; mitochondrial DNA mutation; sex bias.

Figure 1

The pedigree of family: squares, male; circles, female; black symbols, affected; arrow, the index

Figure 2

Brain MRI findings of family individuals. Magnetic resonance images of patients showed high‐intensity signals in the bilateral putaminal areas on both T2‐weighted (T2) and fluid‐attenuated inversion recovery (FLAIR) images in male patients III2, III3, III5, and III7; unilateral putaminal areas in female patients II1 and II4; and normal cerebral structure in other female individuals II6, III1, III4, and III6

Figure 3

The homoplasmic mutation of NC_012920.1: m.3697G>A, p.(Gly131Ser) was found in the index patient (III3), his mother (II4), and his sister (III4), but not his father (II3) (a). The mutation changes a very evolutionarily conserved glycine into serine at 131 amino acid of MTND1 (b). The homoplasmy of m.3697G>A mutation was confirmed by PCR‐RFLP. The wild‐type fragment will be cleaved into two fragments of 532 bp and 300 bp, while the mutant fragment will be cut into three fragments of 532 bp, 270 bp, and 30 bp (c)

Figure 4

Blue Native PAGE blot revealed an isolated decrease of OXPHOS complex I in the male patients III3 and III5 compared with that of the female patients II4, III6, and a control; the other OXPHOS complexes were not impaired (a,b). The ATP production rate was significantly decreased in the male patients III3 and III5 compared with that of the female patients II4, III6, and a control (c). C: control; CI: complex I; CII: complex II; CIII: complex III; CIV: complex IV; CV: complex V