title: Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency.
abstract: BACKGROUND
  Isolated complex II deficiency is a rare form of mitochondrial disease, accounting for approximately 2% of all respiratory chain deficiency diagnoses. The succinate dehydrogenase (SDH) genes (SDHA, SDHB, SDHC and SDHD) are autosomally-encoded and transcribe the conjugated heterotetramers of complex II via the action of two known assembly factors (SDHAF1 and SDHAF2). Only a handful of reports describe inherited SDH gene defects as a cause of paediatric mitochondrial disease, involving either SDHA (Leigh syndrome, cardiomyopathy) or SDHAF1 (infantile leukoencephalopathy). However, all four SDH genes, together with SDHAF2, have known tumour suppressor functions, with numerous germline and somatic mutations reported in association with hereditary cancer syndromes, including paraganglioma and pheochromocytoma.
  
  
  RESULTS
  Here, we report the clinical and molecular investigations of two patients with histochemical and biochemical evidence of a severe, isolated complex II deficiency due to novel SDH gene mutations; the first patient presented with cardiomyopathy and leukodystrophy due to compound heterozygous p.Thr508Ile and p.Ser509Leu SDHA mutations, while the second patient presented with hypotonia and leukodystrophy with elevated brain succinate demonstrated by MR spectroscopy due to a novel, homozygous p.Asp48Val SDHB mutation. Western blotting and BN-PAGE studies confirmed decreased steady-state levels of the relevant SDH subunits and impairment of complex II assembly. Evidence from yeast complementation studies provided additional support for pathogenicity of the SDHB mutation.
  
  
  CONCLUSIONS
  Our report represents the first example of SDHB mutation as a cause of inherited mitochondrial respiratory chain disease and extends the SDHA mutation spectrum in patients with isolated complex II deficiency.
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Alston
authors.forename: James E
authors.initials: JE
authors.lastname: Davison
authors.forename: Francesca
authors.initials: F
authors.lastname: Meloni
authors.forename: Francois H
authors.initials: FH
authors.lastname: van der Westhuizen
authors.forename: Langping
authors.initials: L
authors.lastname: He
authors.forename: Hue-Tran
authors.initials: HT
authors.lastname: Hornig-Do
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Peet
authors.forename: Paul
authors.initials: P
authors.lastname: Gissen
authors.forename: Paola
authors.initials: P
authors.lastname: Goffrini
authors.forename: Ileana
authors.initials: I
authors.lastname: Ferrero
authors.forename: Evangeline
authors.initials: E
authors.lastname: Wassmer
authors.forename: Robert
authors.initials: R
authors.lastname: McFarland
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D002675:Child, Preschool; D004579:Electron Transport; D042963:Electron Transport Complex II / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D005816:Genetic Complementation Test; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D056784:Leukoencephalopathies / Q000150:complications / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008661:Metabolism, Inborn Errors / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000737:chemistry / Q000235:genetics*
chemical_list: D042963:Electron Transport Complex II; C511268:SDHA protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase