Following recent reports of this same mutation in a single case and in a family with late-onset LS and NARP-like features, our paper emphasises the role of MTATP6 in LS and expands the associated clinical phenotype further.
The diagnosis of Leigh syndrome was subsequently confirmed by genetic study which showed a novel mutation at 8597T>C of the mitochondrial ATPase6 gene.
The archetypal NARP syndrome is almost exclusively associated with the m.8993T>C/G mutation in the sixth subunit of the mitochondrial ATP synthase, whereas other mutations in the MT-ATP6 gene primarily associate with Leigh syndrome or Leber's hereditary optic neuropathy (LHON).
We report a new case of Leigh disease (subacute necrotizing encephalomyelopathy) in a girl with mitochondrial DNA (mtDNA) mutation in the ATPase6 gene at nucleotide position 8993.
Pathogenic mutations in MT-ATP6 are associated with the Leigh syndrome, the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP), as well as with non-classical phenotypes, while MT-ATP8 is less frequently mutated in patients with mitochondrial disease.
The first patient with a limb-girdle-type myopathy carried an A3302G substitution in the tRNA(Leu(UUR)) gene (70% heteroplasmy), the second patient with mitochondrial myopathy and cardiomyopathy carried a T3271C mutation in the tRNA(Leu(UUR)) gene (80% heteroplasmy) and the third patient with Leigh syndrome carried a T9176C mutation in the ATPase6 gene (93% heteroplasmy).
The result of mutational analysis revealed the absence of mitochondrial mutations in MT-ATP6 gene and the presence of a known homozygous splice site mutation c.516-517delAG in sibling patients added to the presence of a novel double het mutations in LS patient (c.752-18 A > C/c. c.751 + 16G > A).
Mutations in encoding genes of oxidative phosphorylation complexes have been frequently reported, of which, MTATP6 was one of the most frequently reported genes for Leigh syndrome.
Mutations in the human mitochondrial ATP6 gene encoding ATP synthase subunit a/6 (referred to as Atp6p in yeast) are at the base of neurodegenerative disorders like Neurogenic Ataxia and Retinitis Pigmentosa (NARP), Leigh syndrome (LS), Charcot-Marie-Tooth (CMT), and ataxia telangiectasia.
MT-ATP6 is associated with some cases of Leigh disease; clinical outcomes in our cohort ranged from death from neurodegenerative disease in early childhood to clinically and developmentally normal after several years of follow-up.