title: Respiratory chain complex I deficiency caused by mitochondrial DNA mutations.
abstract: Defects of the mitochondrial respiratory chain are associated with a diverse spectrum of clinical phenotypes, and may be caused by mutations in either the nuclear or the mitochondrial genome (mitochondrial DNA (mtDNA)). Isolated complex I deficiency is the most common enzyme defect in mitochondrial disorders, particularly in children in whom family history is often consistent with sporadic or autosomal recessive inheritance, implicating a nuclear genetic cause. In contrast, although a number of recurrent, pathogenic mtDNA mutations have been described, historically, these have been perceived as rare causes of paediatric complex I deficiency. We reviewed the clinical and genetic findings in a large cohort of 109 paediatric patients with isolated complex I deficiency from 101 families. Pathogenic mtDNA mutations were found in 29 of 101 probands (29%), 21 in MTND subunit genes and 8 in mtDNA tRNA genes. Nuclear gene defects were inferred in 38 of 101 (38%) probands based on cell hybrid studies, mtDNA sequencing or mutation analysis (nuclear gene mutations were identified in 22 probands). Leigh or Leigh-like disease was the most common clinical presentation in both mtDNA and nuclear genetic defects. The median age at onset was higher in mtDNA patients (12 months) than in patients with a nuclear gene defect (3 months). However, considerable overlap existed, with onset varying from 0 to >60 months in both groups. Our findings confirm that pathogenic mtDNA mutations are a significant cause of complex I deficiency in children. In the absence of parental consanguinity, we recommend whole mitochondrial genome sequencing as a key approach to elucidate the underlying molecular genetic abnormality.
authors.affiliation: Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Swalwell
authors.forename: Denise M
authors.initials: DM
authors.lastname: Kirby
authors.forename: Emma L
authors.initials: EL
authors.lastname: Blakely
authors.forename: Anna
authors.initials: A
authors.lastname: Mitchell
authors.forename: Renato
authors.initials: R
authors.lastname: Salemi
authors.forename: Canny
authors.initials: C
authors.lastname: Sugiana
authors.forename: Alison G
authors.initials: AG
authors.lastname: Compton
authors.forename: Elena J
authors.initials: EJ
authors.lastname: Tucker
authors.forename: Bi-Xia
authors.initials: BX
authors.lastname: Ke
authors.forename: Phillipa J
authors.initials: PJ
authors.lastname: Lamont
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
authors.forename: Robert
authors.initials: R
authors.lastname: McFarland
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002467:Cell Nucleus / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics*; D004789:Enzyme Activation / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D040582:Inheritance Patterns / Q000235:genetics; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000401:mortality; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; D042967:Electron Transport Complex I