FLAD1-associated multiple acyl-CoA dehydrogenase deficiency identified by newborn screening

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DOI

  • Kai Muru, University of Tartu
  • ,
  • Karit Reinson, University of Tartu
  • ,
  • Kadi Künnapas, University of Tartu
  • ,
  • Hardo Lilleväli, University of Tartu
  • ,
  • Zahra Nochi
  • Signe Mosegaard
  • Sander Pajusalu, University of Tartu, Yale School of Medicine
  • ,
  • Rikke K.J. Olsen
  • Katrin Õunap, University of Tartu

Background: Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric aciduria type II, is a mitochondrial fatty acid oxidation disorder caused by variants in ETFA, ETFB, and ETFDH. Recently, riboflavin transporter genes and the mitochondrial FAD transporter gene have also been associated with MADD-like phenotype. Methods: We present a case of MADD identified by newborn biochemical screening in a full-term infant suggestive of both medium-chain acyl-CoA dehydrogenase deficiency and MADD. Urine organic acid GC/MS analysis was also concerning for both disorders. However, panel sequencing of ETFA, ETFB, ETFDH, and ACADM was unrevealing. Ultimately, a variant in the FAD synthase gene, FLAD1 was found explaining the clinical presentation. Results: Exome sequencing identified compound heterozygous variants in FLAD1: NM_025207.4: c.[442C>T];[1588C>T], p.[Arg148*];[Arg530Cys]. The protein damaging effects were confirmed by Western blot. The patient remained asymptomatic and there was no clinical decompensation during the first year of life. Plasma acylcarnitine and urinary organic acid analyses normalized without any treatment. Riboflavin supplementation was started at 15 months. Conclusion: Newborn screening, designed to screen for specific treatable congenital metabolic diseases, may also lead to the diagnosis of additional, very rare metabolic disorders such as FLAD1 deficiency. The case further illustrates that even milder forms of FLAD1 deficiency are detectable in the asymptomatic state by newborn screening.

Original languageEnglish
Article numbere915
JournalMolecular Genetics and Genomic Medicine
Volume7
Issue9
Number of pages6
ISSN2324-9269
DOIs
Publication statusPublished - 2019

    Research areas

  • FLAD1 gene, multiple acyl-CoA dehydrogenase deficiency, newborn screening, riboflavin

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