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.
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Communicated by: Piero Rinaldo, MD, PhD
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Biochemical investigations in patient (DOCX 21 kb)
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Key Message
Analysis of FLAD1 is recommended in cases of MADD, if no pathological variants are identified in ETFA, ETFB, or ETFDH, and a trial of riboflavin is recommended in all patients with FLAD1 variants.
Author Contributions
Ryder B: primary drafting of the manuscript and clinical care of patient.
Tolomeo M: scientist performing quantification of cellular flavin content and measurement of FAD synthesis rate.
Nochi Z: scientist performing Western blot analysis of FADS and flavoenzymes.
Colella M: senior scientist supervising cell culturing and management.
Barile M: senior scientist supervising quantification of cellular flavin content and measurement of FAD synthesis rate.
Olsen R: senior scientist supervising Western blot analysis of FADS and flavoenzymes.
Inbar-Feigenberg M: primary metabolic physician directing patient care, senior clinician supervising drafting of manuscript.
Corresponding Author
Dr. Bryony Ryder
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No conflicts of interest reported.
Acknowledgments and Funding
The study was supported by the Danish Council of Independent Medical Research grant (4004-00548) to Olsen RK.
M. Tolomeo was supported by a postgraduate research fellowship financed by “Fondazione Cassa di Risparmio di Puglia,” Bari, Italy.
The technical assistance in HPLC measurements of Dr. M.L. Defrancesco (University of Bari) and in immunoblotting to Margrethe Kjeldsen is gratefully acknowledged.
Thanks to Stacy Hewson and Michelle Mecija for their clinical care.
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Ethics approval was not required for this paper.
Parental consent was obtained for the publication of the article.
This article does not contain any studies with human or animal subjects performed by the any of the authors.
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© 2018 Society for the Study of Inborn Errors of Metabolism (SSIEM)
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Ryder, B. et al. (2018). A Novel Truncating FLAD1 Variant, Causing Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) in an 8-Year-Old Boy. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 45. JIMD Reports, vol 45. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2018_139
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DOI: https://doi.org/10.1007/8904_2018_139
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