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.
Competing interests: None declared
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Communicated by: Daniela Karall
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Synopsis
We present a novel maternally inherited MT-ND1 mutation associated with exercise intolerance and myoglobinuria.
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Dr. Vissing has received research and travel grants from Genzyme Corporation and serves on the scientific global advisory board for Pompe disease for Genzyme Corporation.
Jabin Rafiq, Morten Duno, Elsebet Østergaard, Kirstine Ravn, Christoffer Vissing, and Flemming Wibrand declare that they have no conflict of interest.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients before inclusion in the study.
Details of the Contributions of Individual Authors
Mrs. Rafiq – study concept and design, acquisition of data, and drafting of the paper
Dr. Vissing – study concept and design, acquisition of data, study supervision, and critical revision of the manuscript
Dr. Duno – analysis and interpretation and critical revision of the manuscript
Dr. Wibrand – analysis and interpretation and critical revision of the manuscript
Dr. Østergaard – acquisition of data, analysis, and interpretation of data
Mr. C.R. Vissing – acquisition of data, analysis, and interpretation of data
Dr. Ravn – acquisition of data, analysis, and interpretation of data
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Rafiq, J. et al. (2015). Exercise Intolerance and Myoglobinuria Associated with a Novel Maternally Inherited MT-ND1 Mutation. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 25. JIMD Reports, vol 25. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_459
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DOI: https://doi.org/10.1007/8904_2015_459
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