A Patient with Complex I Deficiency Caused by a Novel ACAD9 Mutation Not Responding to Riboflavin Treatment

Case Report
Part of the JIMD Reports book series (JIMD, volume 12)


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.


ACAD9 Mutations Riboflavin Treatment Homozygous Regions Patient Fibroblasts Hypertrophic Cardiomyopathy 
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© SSIEM and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Nijmegen Centre for Mitochondrial Disorders at the Department of PediatricsRadboud University Medical CentreNijmegenThe Netherlands
  2. 2.Department of Clinical GeneticsCopenhagen University Hospital, RigshospitaletCopenhagenDenmark
  3. 3.Centre for Molecular and Biomolecular InformaticsRadboud University Nijmegen Medical CentreNijmegenThe Netherlands
  4. 4.Department of PediatricsRoskilde University HospitalRoskildeDenmark
  5. 5.Department of NeonatologyCopenhagen University Hospital, RigshospitaletCopenhagenDenmark
  6. 6.Nijmegen Centre for Mitochondrial Disorders at the Department of PediatricsRadboud University Nijmegen Medical CentreNijmegenThe Netherlands

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