title: Mitochondrial encephalomyopathy due to a novel mutation in ACAD9.
abstract: OBJECTIVE
  Mendelian forms of complex I deficiency are usually associated with fatal infantile encephalomyopathy. Application of "MitoExome" sequencing (deep sequencing of the entire mitochondrial genome and the coding exons of >1000 nuclear genes encoding the mitochondrial proteome) allowed us to reveal an unusual clinical variant of complex I deficiency due to a novel homozygous mutation in ACAD9. The patient had an infantile-onset but slowly progressive encephalomyopathy and responded favorably to riboflavin therapy.
  
  
  METHODS
  A 13-year-old boy had exercise intolerance, weakness, and mild psychomotor delay. Muscle histochemistry showed mitochondrial proliferation, and biochemical analysis revealed severe complex I deficiency (15% of normal). The level of complex I holoprotein was reduced as determined by use of Western blot both in muscle (54%) and in fibroblasts (57%).
  
  
  CONCLUSIONS
  The clinical presentation of complex I deficiency due ACAD9 mutations spans from fatal infantile encephalocardiomyopathy to mild encephalomyopathy. Our data support the notion that ACAD9 functions as a complex I assembly protein. ACAD9 is a flavin adenine dinucleotide-containing flavoprotein, and treatment with riboflavin is advisable.
authors.affiliation: Department of Neurology, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York2Human Genetics, Joint PhD Program, Universities of Turin and Bologna, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Garone
authors.forename: Maria Alice
authors.initials: MA
authors.lastname: Donati
authors.forename: Michele
authors.initials: M
authors.lastname: Sacchini
authors.forename: Beatriz
authors.initials: B
authors.lastname: Garcia-Diaz
authors.forename: Claudio
authors.initials: C
authors.lastname: Bruno
authors.forename: Sarah
authors.initials: S
authors.lastname: Calvo
authors.forename: Vamsi K
authors.initials: VK
authors.lastname: Mootha
authors.forename: Salvatore
authors.initials: S
authors.lastname: Dimauro
mesh_terms: D000293:Adolescent; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D017237:Mitochondrial Encephalomyopathies / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D012256:Riboflavin / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D004272:DNA, Mitochondrial; D012256:Riboflavin