Neuromuscular disease presentation with three genetic defects involving two genomes

Al-Dosary, Mazhor; Whittaker, Roger G.; Haughton, Joanna; McFarland, Robert; Goodship, Judith; Turnbull, Douglass M.; Taylor, Robert W.

doi:10.1016/j.nmd.2009.10.001

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Volume 19, Issue 12 , Pages 841-844, December 2009

Neuromuscular disease presentation with three genetic defects involving two genomes

Mazhor Al-Dosary
- Mitochondrial Research Group and NCG Rare Mitochondrial Disorders of Adults and Children Service, Newcastle University, Newcastle upon Tyne, UK
Roger G. Whittaker
- Mitochondrial Research Group and NCG Rare Mitochondrial Disorders of Adults and Children Service, Newcastle University, Newcastle upon Tyne, UK
Joanna Haughton
- Regional Neurosciences Centre, Newcastle General Hospital, Newcastle upon Tyne, UK
Robert McFarland
- Mitochondrial Research Group and NCG Rare Mitochondrial Disorders of Adults and Children Service, Newcastle University, Newcastle upon Tyne, UK
Judith Goodship
- Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK
Douglass M. Turnbull
- Mitochondrial Research Group and NCG Rare Mitochondrial Disorders of Adults and Children Service, Newcastle University, Newcastle upon Tyne, 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 12 August 2009; received in revised form 16 September 2009; accepted 2 October 2009.

Abstract

An extensive range of molecular defects have been identified in the human mitochondrial genome (mtDNA), many associated with well-characterised, progressive neurological syndromes. We describe a patient who presented to a mitochondrial clinic with progressive bilateral ptosis, external opthalmoplegia and increasing difficulty with walking. He had previously been diagnosed with a dominant, demyelinating polyneuropathy due to PMP22 gene duplication and had also developed gout, presenting in acute renal failure, due to an X-linked recessive HPRT gene mutation. Muscle biopsy revealed many COX-deficient fibres which we show contain high levels of a third genetic defect – a novel, mitochondrial tRNA^Leu(CUN) (MTTL2) gene mutation.

Keywords: PEO, Mitochondrial DNA, tRNA mutation, Single fibre analysis, Segregation