2. Academic Validation
  3. FLAD1-associated multiple acyl-CoA dehydrogenase deficiency identified by newborn screening

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

  • Mol Genet Genomic Med. 2019 Sep;7(9):e915. doi: 10.1002/mgg3.915.
Kai Muru 1 2,  Karit Reinson 1 2,  Kadi Künnapas 1,  Hardo Lilleväli 1 3,  Zahra Nochi 4,  Signe Mosegaard 4,  Sander Pajusalu 1 2 5,  Rikke K J Olsen 4,  Katrin Õunap 1 2
Affiliations

Affiliations

  • 1 Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.
  • 2 Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
  • 3 Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
  • 4 Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
  • 5 Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
PMID: 31392824 DOI: 10.1002/mgg3.915
Abstract

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.

Keywords

FLAD1 gene; multiple acyl-CoA dehydrogenase deficiency; newborn screening; riboflavin.

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