Isobutyryl-CoA dehydrogenase deficiency associated with autism in a girl without an alternative genetic diagnosis by trio whole exome sequencing: A case report

M. Eleftheriadou, E. Medici-van den Herik, K. Stuurman, Y. van Bever, D.M.E.I. Hellebrekers, M. van Slegtenhorst, G. Ruijter, T.S. Barakat*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Background: Isobutyryl-CoA dehydrogenase (IBD) is a mitochondrial enzyme catalysing the third step in the degradation of the essential branched-chain amino acid valine and is encoded by ACAD8. ACAD8 mutations lead to isobutyryl-CoA dehydrogenase deficiency (IBDD), which is identified by increased C4-acylcarnitine levels. Affected individuals are either asymptomatic or display a variety of symptoms during infancy, including speech delay, cognitive impairment, failure to thrive, hypotonia, and emesis.Methods: Here, we review all previously published IBDD patients and describe a girl diagnosed with IBDD who was presenting with autism as the main disease feature.Results: To assess whether a phenotype-genotype correlation exists that could explain the development or absence of clinical symptoms in IBDD, we compared CADD scores, in silico mutation predictions, LoF tolerance scores and C4-acylcarnitine levels between symptomatic and asymptomatic individuals. Statistical analysis of these parameters did not establish significant differences amongst both groups.Conclusion: As in our proband, trio whole exome sequencing did not establish an alternative secondary genetic diagnosis for autism, and reported long-term follow-up of IBDD patients is limited, it is possible that autism spectrum disorders could be one of the disease-associated features. Further long-term follow-up is suggested in order to delineate the full clinical spectrum associated with IBDD.
Original languageEnglish
Article numbere1595
Number of pages10
JournalMolecular genetics & genomic medicine
Issue number2
Early online date11 Jan 2021
Publication statusPublished - Feb 2021


  • acad8
  • autism
  • carnitine
  • children
  • disorders
  • encephalopathy
  • follow-up
  • genotype-phenotype correlation
  • identification
  • inborn-errors
  • isobutyryl-coa dehydrogenase deficiency
  • mutations
  • tandem mass-spectrometry
  • whole exome sequencing
  • ACAD8
  • isobutyryl-CoA dehydrogenase deficiency

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