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

  • Jabin Rafiq
  • Morten Duno
  • Elsebet Østergaard
  • Kirstine Ravn
  • Christoffer R. Vissing
  • Flemming Wibrand
  • John VissingEmail author
Research Report
Part of the JIMD Reports book series (JIMD, volume 25)

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.

Keywords

Muscle Biopsy Mitochondrial Myopathy Maternal Aunt Myopathic Change Rigid Spine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW (1992) Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet 51:1229–1239PubMedPubMedCentralGoogle Scholar
  2. Astrand I (1960) Aerobic work capacity in men and women with special reference to age. Acta Physiol Scand Suppl 49(169):1–92PubMedGoogle Scholar
  3. Jeppesen TD, Olsen D, Vissing J (2003) Cycle ergometry is not a sensitive diagnostic test for mitochondrial myopathy. J Neurol 250(3):293–299CrossRefPubMedGoogle Scholar
  4. Larsen S, Nielsen J, Hansen CN et al (2012) Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects. J Physiol 15(590):3349–3360CrossRefGoogle Scholar
  5. Ostergaard E, Hansen FJ, Sorensen N, Duno M, Vissing J, Larsen PL, Faeroe O, Thorgrimsson S, Wibrand F, Christensen E, Schwartz M (2007) Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations. Brain 130:853–861CrossRefPubMedGoogle Scholar
  6. Schapira AHV (2006) Mitochondrial disease. Lancet 368:70–82CrossRefPubMedGoogle Scholar
  7. Swain DP, Abernathy KS, Smith CS (1994) Target heart rates for the development of cardiorespiratory fitness. Med Sci Sports Exerc 26(1):112–116PubMedGoogle Scholar
  8. Taylor RW, Turnbull DM (2005) Mitochondrial DNA mutations in human disease. Nat Rev 6:389–402CrossRefGoogle Scholar
  9. Vissing CR, Duno M, Olesen JH et al (2013) Recurrent myoglobinuria and deranged acylcarnitines due to a mutation in the mtDNA MT-CO2 gene. Neurology 80(20):1908–1910Google Scholar
  10. Wong LC (2007) Pathogenic mitochondrial DNA mutations in protein-coding genes. Muscle Nerve 36:279–293CrossRefPubMedGoogle Scholar
  11. Yu-Wai-Man P, Griffiths PG, Chinnery P (2011) Mitochondrial optic neuropathies – disease mechanisms and therapeutic strategies. Prog Retin Eye Res 30:81–114CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Jabin Rafiq
    • 1
  • Morten Duno
    • 2
  • Elsebet Østergaard
    • 2
  • Kirstine Ravn
    • 2
  • Christoffer R. Vissing
    • 1
  • Flemming Wibrand
    • 2
  • John Vissing
    • 1
    Email author
  1. 1.Department of NeurologyCopenhagen Neuromuscular CenterCopenhagenDenmark
  2. 2.Department of Clinical Genetics, RigshospitaletUniversity of CopenhagenCopenhagenDenmark

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