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



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 MTATP6 gene account for most of reported cases. In this report, we aimed to describe the clinical and genetic findings of MTATP6-associated LS patients diagnosed at a single tertiary institution in Korea.


Thirteen patients with genetically confirmed MTATP6-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.


MTATP6-associated LS was of predominantly early onset (age 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 MTATP6-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 MTATP6-associated LS.


MTATP6-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 MTATP6-associated LS that will inform subsequent studies on LS.

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