A Novel Truncating FLAD1 Variant, Causing Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) in an 8-Year-Old Boy

Research output: Contribution to book/anthology/report/proceedingBook chapterResearchpeer-review

DOI

  • B Ryder, National Metabolic Service, Starship Children's Hospital, Auckland, New Zealand. bryonykryder@gmail.com.
  • ,
  • M Tolomeo, Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy.
  • ,
  • M Colella, Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy.
  • ,
  • M Barile, Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy.
  • ,
  • R K Olsen
  • M Inbar-Feigenberg, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
  • ,
  • Zahra Nochi

Multiple acyl-CoA dehydrogenase deficiency (MADD) or glutaric aciduria type II (GAII) is a clinically heterogeneous disorder affecting fatty acid and amino acid metabolism. Presentations range from a severe neonatal form with hypoglycemia, metabolic acidosis, and hepatomegaly with or without congenital anomalies to later-onset lipid storage myopathy. Genetic testing for MADD traditionally comprises analysis of ETFA, ETFB, and ETFDH. Patients may respond to pharmacological doses of riboflavin, particularly those with late-onset MADD due to variants in ETFDH. Increasingly other genes involved in riboflavin transport and flavoprotein biosynthesis are recognized as causing a MADD phenotype. Flavin adenine dinucleotide synthase (FADS) deficiency caused by biallelic variants in FLAD1 has been identified in nine previous cases of MADD. FLAD1 missense mutations have been associated with a riboflavin-responsive phenotype; however the effect of riboflavin with biallelic loss of function FLAD1 mutations required further investigation. Herein we describe a novel, truncating variant in FLAD1 causing MADD in an 8-year-old boy. Fibroblast studies showed a dramatic reduction in FADS protein with corresponding reduction in the FAD synthesis rate and FAD cellular content, beyond that previously documented in FLAD1-related MADD. There was apparent biochemical and clinical response to riboflavin treatment, beyond that previously reported in cases of biallelic loss of function variants in FLAD1. Early riboflavin treatment may have attenuated an otherwise severe phenotype.

Original languageEnglish
Title of host publicationJIMD Reports
EditorsEva Morava, Matthias Baumgartner, Marc Patterson, Shamima Rahman, Johannes Zschocke, Verena Peters
Number of pages8
PublisherSpringer
Publication year2019
Pages37-44
ISBN (print)978-3-662-58646-4
ISBN (Electronic)978-3-662-58647-1
DOIs
Publication statusPublished - 2019
SeriesJIMD Reports
Volume45
ISSN2192-8304

    Research areas

  • FAD synthase, FLAD1, Multiple acyl-CoA dehydrogenase deficiency (MADD), Myopathy, Riboflavin

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