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

  • B. Ryder
  • M. Tolomeo
  • Z. Nochi
  • M. Colella
  • M. Barile
  • R. K. Olsen
  • M. Inbar-Feigenberg
Research Report
Part of the JIMD Reports book series

Abstract

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.

Keywords

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

Supplementary material

8904_2018_139_MOESM1_ESM.docx (22 kb)
Supplementary Material Biochemical investigations in patient (DOCX 21 kb)

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Copyright information

© Society for the Study of Inborn Errors of Metabolism (SSIEM) 2018

Authors and Affiliations

  • B. Ryder
    • 1
    • 2
  • M. Tolomeo
    • 3
  • Z. Nochi
    • 4
  • M. Colella
    • 3
  • M. Barile
    • 3
  • R. K. Olsen
    • 4
  • M. Inbar-Feigenberg
    • 1
  1. 1.Division of Clinical and Metabolic Genetics, The Hospital for Sick ChildrenUniversity of TorontoTorontoCanada
  2. 2.National Metabolic Service, Starship Children’s HospitalAucklandNew Zealand
  3. 3.Department of Bioscience, Biotechnology and BiopharmaceuticsUniversity of BariBariItaly
  4. 4.Research Unit for Molecular Medicine, Department for Clinical MedicineAarhus University and Aarhus University HospitalAarhusDenmark

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