title: A Patient with Complex I Deficiency Caused by a Novel ACAD9 Mutation Not Responding to Riboflavin Treatment.
abstract: Here we report a patient with a new pathogenic mutation in ACAD9. Shortly after birth she presented with respiratory insufficiency and a high lactate level. At age 7 weeks, she was diagnosed with severe hypertrophic cardiomyopathy and she suffered from muscle weakness and hypotonia. Her condition deteriorated during intercurrent illnesses and she died at 6 months of age in cardiogenic shock. Analysis of respiratory chain activities in muscle and fibroblasts revealed an isolated complex I deficiency. A genome-wide screen for homozygosity revealed several homozygous regions. Four candidate genes were found and sequencing revealed a homozygous missense mutation in ACAD9. The mutation results in an Ala220Val amino acid substitution located near the catalytic core of ACAD9. SDS and BN-PAGE analysis showed severely decreased ACAD9 and complex I protein levels, and lentiviral complementation of patient fibroblasts partially rescued the complex I deficiency. Riboflavin supplementation did not ameliorate the complex I deficiency in patient fibroblasts. More than a dozen ACAD9 patients with complex I deficiency have been identified in the last 3 years, indicating that ACAD9 is important for complex I assembly, and that ACAD9 mutations are a relatively frequent cause of complex I deficiency.
authors.affiliation: Nijmegen Centre for Mitochondrial Disorders at the Department of Pediatrics, Radboud University Medical Centre, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Jessica
authors.initials: J
authors.lastname: Nouws
authors.forename: Flemming
authors.initials: F
authors.lastname: Wibrand
authors.forename: Mariël
authors.initials: M
authors.lastname: van den Brand
authors.forename: Hanka
authors.initials: H
authors.lastname: Venselaar
authors.forename: Morten
authors.initials: M
authors.lastname: Duno
authors.forename: Allan M
authors.initials: AM
authors.lastname: Lund
authors.forename: Simon
authors.initials: S
authors.lastname: Trautner
authors.forename: Leo
authors.initials: L
authors.lastname: Nijtmans
authors.forename: Elsebet
authors.initials: E
authors.lastname: Ostergard