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Genotype-phenotype analysis of MT-ATP6-associated Leigh syndrome

Authors
 Ji-Hoon Na  ;  Young-Mock Lee 
Citation
 ACTA NEUROLOGICA SCANDINAVICA, Vol.145(4) : 414-422, 2022-04 
Journal Title
ACTA NEUROLOGICA SCANDINAVICA
ISSN
 0001-6314 
Issue Date
2022-04
MeSH
Child ; Child, Preschool ; DNA, Mitochondrial / genetics ; Genotype ; Humans ; Leigh Disease* / diagnostic imaging ; Leigh Disease* / genetics ; Mitochondrial Proton-Translocating ATPases / genetics ; Mutation / genetics ; Phenotype
Keywords
MT-ATP6 ; Leigh syndrome ; heteroplasmic mutant load ; mitochondrial disease ; mtDNA
Abstract
Objectives: Mitochondrial DNA (mtDNA)-associated Leigh syndrome (LS) is characterized by maternal inheritance, and the heteroplasmic mutant load of mtDNA pathogenic variants is known to affect clinical phenotypes. Among mtDNA pathogenic variants, variants of the MT-ATP6 gene account for most of reported cases. In this report, we aimed to describe the clinical and genetic findings of MT-ATP6-associated LS patients diagnosed at a single tertiary institution in Korea.

Methods: Thirteen patients with genetically confirmed MT-ATP6-associated LS were selected. We reviewed each patient's clinical findings, including general characteristics, biochemical parameters, brain MR images, muscle biopsy results, and heteroplasmic mutant load over a long-term follow-up period.

Results: MT-ATP6-associated LS was of predominantly early onset (age <2 years), although we identified 2 late-onset (>60 months) LS patients. The heteroplasmic mutant load estimated by next-generation sequencing was 96%-100% in all nucleotide change groups. Compared with other forms of MT-ATP6-associated LS, the m.8993T>G point mutation elicited a significantly higher rate of symptom onset before 2 years of age. Brain MRI showed bilateral basal ganglia involvement in all patients, followed by cerebral atrophy, brainstem and thalamus involvement, and cerebellar atrophy. After follow-up (median 7.2 years, range 1.4 to 11.5 years), LS with m.8993T>G point mutations had a slightly more severe clinical progression compared with other forms of MT-ATP6-associated LS.

Conclusions: MT-ATP6-associated LS patients presented with a broad spectrum of clinical diagnoses and had a very high heteroplasmic mutant load. This study provides valuable data on MT-ATP6-associated LS that will inform subsequent studies on LS.
Full Text
https://onlinelibrary.wiley.com/doi/10.1111/ane.13566
DOI
10.1111/ane.13566
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아과학교실) > 1. Journal Papers
Yonsei Authors
Na, Ji Hoon(나지훈) ORCID logo https://orcid.org/0000-0002-3051-2010
Lee, Young Mock(이영목) ORCID logo https://orcid.org/0000-0002-5838-249X
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/188278
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