Multiple Acyl-CoA Dehydrogenase Deficiency with Variable Presentation Due to a Homozygous Mutation in a Bedouin Tribe.

Orna Staretz-Chacham,Shirly Amar,Ohad Wormser,Shlomo Almashanu,Ben Pode-Shakked,Eli Hershkovitz,Ann Saada

doi:10.3390/genes12081140

Abstract

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a fatty acid and amino acid oxidation defect caused by a deficiency of the electron-transfer flavoprotein (ETF) or the electron-transfer flavoprotein dehydrogenase (ETFDH). There are three phenotypes of the disease, two neonatal forms and one late-onset. Previous studies have suggested that there is a phenotype–genotype correlation. We report on six patients from a single Bedouin tribe, five of whom were sequenced and found to be homozygous to the same variant in the ETFDH gene, with variable severity and age of presentation. The variant, NM_004453.3 (ETFDH): c.524G>A, p.(R175H), was previously recognized as pathogenic, although it has not been reported in the literature in a homozygous state before. R175H is located near the FAD binding site, likely affecting the affinity of FAD for EFT:QO. The single homozygous ETFDH pathogenic variant was found to be causing MADD in this cohort with an unexpectedly variable severity of presentation. The difference in severity could partly be explained by early diagnosis via newborn screening and early treatment with the FAD precursor riboflavin, highlighting the importance of early detection by newborn screening.

Highlights

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a fatty acid and amino acid oxidation defect known as glutaric aciduria type II
The disease is caused by a deficiency of either electron-transfer flavoprotein (ETF) or electron-transfer flavoprotein dehydrogenase (ETFDH)
The most common etiology of MADD is mutations in the ETFDH gene, which encodes the electron transfer flavoprotein dehydrogenase (ETFDH) [23,24], relative to which most cases are associated with late onset or RR-MADD as is the case for the patients reported in this study

Summary

Introduction

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a fatty acid and amino acid oxidation defect known as glutaric aciduria type II. 750,000–2,000,000 newborns [1] with a much higher prevalence in China [2]. MADD affects mitochondrial fatty acid oxidation as well as the catabolism of branched amino acids, lysine and tryptophan [3]. The disease is caused by a deficiency of either electron-transfer flavoprotein (ETF) or electron-transfer flavoprotein dehydrogenase (ETFDH). ETF is composed of α and β subunits, encoded by the ETFA and ETFB genes, respectively, as well as electron-transfer flavoprotein-ubiquinone oxidoreductase (ETFQO) [4,5], encoded by ETFDH [4,6]. MADD is inherited in an autosomal recessive manner

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Conclusion