Exercise Intolerance and Myoglobinuria Associated with a Novel Maternally Inherited MT-ND1 Mutation

Abstract

The most common clinical phenotype caused by a mtDNA mutation in complex I of the mitochondrial respiratory chain is Leber hereditary optic neuropathy. We report a family with a novel maternally inherited homoplasmic mtDNA m.4087A>G mutation in the ND1 gene (MT-ND1) associated with isolated myopathy, recurrent episodes of myoglobinuria, and rhabdomyolysis. DNA from blood in seven family members and muscle from four family members were PCR amplified and sequenced directly and assessed for the m.4087A>G variation in MT-ND1. Mitochondrial enzyme activity in all muscle biopsies was measured. PCR and direct sequencing of the MT-ND1 genes from blood showed that all seven family members were homoplasmic for the m.4087A>G mutation (NC_012920.1:c.781A>G). The mutation predicts a threonine to alanine substitution at position 261 (p.T261A). The same mutation was found in muscle of all four family members available for muscle biopsy, and biochemical analyses revealed an isolated complex I defect in muscle of all family members (range 22-52% of normal). Muscle morphology showed severe myopathic changes with internal nuclei in multiple fibers of all family members. Monosymptomatic myopathy with recurrent myoglobinuria is a rare phenotype of mitochondrial myopathies. We report this phenotype in a family affected by a novel homoplasmic mutation in MT-ND1. It is the first time such a phenotype has been associated with complex I gene mutations and a homoplasmic mutation of mtDNA.

Molecular Genetics Overview of Primary Mitochondrial Myopathies

“…F: female; M: male; NA: not available yo: years old; * truncation; CR: case report; CS: cohort study. All the mtDNA mutations were heteroplasmic except for one (Rafiq J et al, 2015).…”

“…Mutations affecting MT-ND1 have been described both in homoplasmic and heteroplasmic form: for example, Rafiq J et al described a family carrying a new homoplasmic mtDNA m.4087A>G mutation in the ND1 gene (MT-ND1), associated with isolated myopathy, recurrent episodes of myoglobinuria, and rhabdomyolysis [31]; conversely, Gorman GS et al reported two novel heteroplasmic mutations (m.3365T>C predicting p.Leu20Pro and m.4175G>A predicting p.Trp290*) in the MT-ND1 gene of two different adults with considerable fatigue and dyspnea induced by progressive exertion, persistent hyperlactatemia and severe muscle-restricted, isolated CI deficiency [32].…”