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

Maria Eleftheriadou, Evita Medici- van den Herik, Kyra Stuurman, Yolande van Bever, Debby M.E.I. Hellebrekers, Marjon van Slegtenhorst, George Ruijter, Tahsin Stefan Barakat*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)
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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
JournalMolecular Genetics and Genomic Medicine
Issue number2
Publication statusPublished - 11 Jan 2021

Bibliographical note

We are indebted to the patient and their parents for their kind cooperation. ME was supported by an Erasmus+ Traineeship Programme and Noréus travel scholarship from V. and G. Noréus Scholarship Foundation. TSB’s lab is supported by the Netherlands Organisation for Scientific Research (ZonMW Veni, grant 91617021), a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation, an Erasmus MC Fellowship 2017 and Erasmus MC Human Disease Model Award 2018.

Publisher Copyright: © 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.


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