Complex I is the largest of the mitochondrial respiratory chain enzyme complexes, consisting of at least 46 subunits, seven of which are encoded by mtDNA. Deficiency of complex I is the most common respiratory chain defect, and can be caused by mutations in both nuclear and mtDNA encoded genes. It has a wide range of clinical presentations, from lethal infantile mitochondrial disease to isolated myopathy.^1–3 Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is one of the syndromes associated with complex I deficiency and in approximately 80% of cases is caused by a mutation, 3243A→G, in the mitochondrial tRNA^Leu(UUR) gene (MTTL1). Other mutations in MTTL1 and other transfer RNA genes (MTTF, MTTV, MTTQ) account for most of the remainder of cases.⁴ However, a number of mutations in the mitochondrial MTND subunit genes of complex I have also been reported to cause MELAS, most notably in MTND5⁵ and to a lesser extent in MTND6.⁶

In stark contrast, there are presently no mutations in the MTND1 subunit gene associated with MELAS. There are several mutations in MTND1 associated with Leber’s hereditary optic neuropathy (LHON) which may be pathogenic, but only one, the 3460G→A mutation, that has robust evidence, including cell biology studies, for pathogenicity.^7–9 Here we report three unrelated patients with MELAS and isolated complex I deficiency in skeletal muscle and cultured fibroblasts due to previously unreported mutations in the MTND1 gene. Evidence confirming the pathogenic nature of these mutations includes data from cell fusion experiments and blue native polyacrylamide gel electrophoresis (BN-PAGE), the latter confirming a crucial role for the ND1 subunit in the assembly of complex I holoenzyme.¹⁰

PATIENTS

Patient 1

Patient 1, a white male, presented at 4 years of age with a 3 month history of increasing tiredness, clumsiness, …