A novel mitochondrial MTND5 frameshift mutation causing isolated complex I deficiency, renal failure and myopathy

Alston, Charlotte L.; Morak, Monika; Reid, Christopher; Hargreaves, Iain P.; Pope, Simon A.S.; Land, John M.; Heales, Simon J.; Horvath, Rita; Mundy, Helen; Taylor, Robert W.

doi:10.1016/j.nmd.2009.10.010

« Previous Next »Neuromuscular Disorders
Volume 20, Issue 2 , Pages 131-135, February 2010

A novel mitochondrial MTND5 frameshift mutation causing isolated complex I deficiency, renal failure and myopathy

Charlotte L. Alston
- Mitochondrial Research Group and NCG Rare Mitochondrial Disorders of Adults and Children Service, Newcastle University, Newcastle upon Tyne, UK
Monika Morak
- University Hospital of the Ludwig-Maximilians-University, Campus Innenstadt, Munich, Germany
- MGZ – Center of Medical Genetics, Munich, Germany
Christopher Reid
- Department of Paediatric Nephrology, Evelina Children’s Hospital, Guys & St. Thomas’ NHS Foundation Trust, London, UK
Iain P. Hargreaves
- Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
Simon A.S. Pope
- Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
John M. Land
- Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
Simon J. Heales
- Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
- Chemical Pathology, Great Ormond Street Hospital, London, UK
Rita Horvath
- Mitochondrial Research Group and NCG Rare Mitochondrial Disorders of Adults and Children Service, Newcastle University, Newcastle upon Tyne, UK
Helen Mundy
- Centre for Inherited Metabolic Disease, Guys & St. Thomas’ NHS Foundation Trust, London, UK
Robert W. Taylor
- Mitochondrial Research Group and NCG Rare Mitochondrial Disorders of Adults and Children Service, Newcastle University, Newcastle upon Tyne, UK
- Corresponding author. Address: Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK. Tel.: +44 191 2223685; fax: +44 191 2824373.

Received 20 July 2009; received in revised form 23 October 2009; accepted 26 October 2009.

Abstract

Isolated complex I deficiency is the most commonly reported enzyme defect in paediatric mitochondrial disorders, and may arise due to mutations in nuclear-encoded structural or assembly genes, or the mitochondrial genome. We present the clinical, biochemical and molecular genetic data in a young girl whose clinical picture is dominated by chronic renal failure, myopathy and persistent lactic acidosis. An isolated complex I deficiency in muscle was identified due to a novel mutation (m.12425delA) in the MTND5 gene. This single nucleotide deletion is heteroplasmic and detectable in several tissues from the proband but not her mother, suggesting a de novo mutation event. The description of the first frameshift mutation in a mitochondrial complex I gene affirms mitochondrial DNA mutations as an important cause of isolated complex I deficiency in children and the importance of whole mitochondrial genome sequencing in the diagnostic work-up to elucidate the underlying molecular genetic abnormality and provide important genetic advice.

Keywords: Mitochondrial DNA, Complex I, Frameshift mutation, Myopathy, Heteroplasmy