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The 13042GA/ND5 mutation in mtDNA is pathogenic and can be associated also with a prevalent ocular phenotype

¹ Dipartimento di Scienze Neurologiche, Università di Bologna, Bologna, Italy
² Centro Oftalmologia Salus, Bologna, Italy
³ Dipartimento di Genetica e Microbiologia, Università di Pavia, Pavia, Italy
⁴ Dipartimento di Medicina Clinica e Biotecnologia Applicata "D Campanacci", Università di Bologna, Bologna, Italy

Correspondence to:
Dr Valerio Carelli
Dipartimento di Scienze Neurologiche, Università di Bologna, Via Ugo Foscolo 7, 40123, Bologna, Italy; carelli{at}neuro.unibo.it] Background: Overlapping phenotypes including LHON, MELAS, and Leigh syndrome have recently been associated with numerous mtDNA point mutations in the ND5 gene of complex I, now considered a mutational hot spot.

Objective: To identify the mtDNA defect in a family with a prevalent ocular phenotype, including LHON-like optic neuropathy, retinopathy, and cataract, but characterised also by strokes, early deaths, and miscarriages on the maternal line.

Results: Sequencing of the entire mitochondrial genome from the proband’s muscle DNA identified the heteroplasmic 13042GA transition, which was previously described only once in a patient with a different mitochondrial disease. This mutation fulfils the major pathogenic criteria, inducing an amino acid change (A236T) at an invariant position in a highly conserved domain of the ND5 gene. Phosphorus magnetic resonance spectroscopy in the proband disclosed an in vivo brain and skeletal muscle energy metabolism deficit.

Conclusions: These findings conclusively establish the pathogenic role of the 13042GA mutation and underscore its variable clinical expression.

Abbreviations: FID, free induction decay; LHON, Leber’s hereditary optic neuropathy; MELAS, mitochondrial encephalomyopathy, lactic acidosis, stroke-like syndrome; MERRF, myoclonic epilepsy, ragged red fibres; mtDNA, mitochondrial DNA; PCr, phosphocreatine

Keywords: LHON; complex I; mtDNA; ND5; mitochondria

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