title: Maternally inherited mitochondrial DNA disease in consanguineous families.
abstract: Mitochondrial respiratory chain disease represents one of the most common inborn errors of metabolism and is genetically heterogeneous, with biochemical defects arising from mutations in the mitochondrial genome (mtDNA) or the nuclear genome. As such, inheritance of mitochondrial respiratory chain disease can either follow dominant or recessive autosomal (Mendelian) inheritance patterns, the strictly matrilineal inheritance observed with mtDNA point mutations or X-linked inheritance. Parental consanguinity in respiratory chain disease is often assumed to infer an autosomal recessive inheritance pattern, and the analysis of mtDNA may be overlooked in the pursuit of a presumed nuclear genetic defect. We report the histochemical, biochemical and molecular genetic investigations of two patients with suspected mitochondrial disease who, despite being born to consanguineous first-cousin parents, were found to harbour well-characterised pathogenic mtDNA mutations, both of which were maternally transmitted. Our findings highlight that any diagnostic algorithm for the investigation of mitochondrial respiratory chain disease must include a full and complete analysis of the entire coding sequence of the mitochondrial genome in a clinically relevant tissue. An autosomal basis for respiratory chain disease should not be assumed in consanguineous families and that 'maternally inherited consanguineous' mitochondrial disease may thus be going undiagnosed.
authors.affiliation: Mitochondrial Research Group and NCG Mitochondrial Laboratory, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Alston
authors.forename: Langping
authors.initials: L
authors.lastname: He
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Morris
authors.forename: Imelda
authors.initials: I
authors.lastname: Hughes
authors.forename: Christian
authors.initials: C
authors.lastname: de Goede
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
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004272:DNA, Mitochondrial / Q000737:chemistry*; D004579:Electron Transport / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D028361:Mitochondrial Diseases / Q000175:diagnosis / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D017354:Point Mutation
chemical_list: D004272:DNA, Mitochondrial