A novel electron transfer flavoprotein dehydrogenase (ETFDH) gene mutation identified in a newborn with glutaric acidemia type II: a case report of a Chinese family

Mingcai Ou,Lin Zhu,Qi Hu,Xingyue Su,Lijuan Yang,Xuelian Chen,Wenjun Wang,Yong Zhang,Jingyao Zhou,Yu Zhang,Yaguo Zhang,Ting Li

doi:10.1186/s12881-020-00995-2

Abstract

BackgroundGlutaric acidemia type II (GA II) or multiple acyl-CoA dehydrogenase deficiency (MADD, OMIM 231680) is an inherited autosomal recessive disease affecting fatty acid, amino acid and choline metabolism, due to mutations in one of three genes namely, electron transfer flavoprotein alpha-subunit, ETFA, electron transfer flavoprotein β-subunit, ETFB and electron transfer flavoprotein dehydrogenase, ETFDH. Currently, few studies have reported genetic profiling of neonatal-onset GA II. This study aimed to identify the genetic mutations in a Chinese family with GA II.Case presentationWe reported a case of GA II with purulent meningitis and septicemia and identified a novel ETFDH gene mutation in a female infant. The patient developed an episode of hypoglycemia and hypotonicity on the postnatal first day. Laboratory investigations revealed elevations of multiple acylcarnitines indicating glutaric acidemia type II in newborn screening analysis. Urinary organic acids were evaluated for the confirmation and revealed a high glutaric acid excretion. Genetic analysis revealed two mutations in the ETFDH gene (c.623_626 del / c. 1399G > C), which were considered to be the etiology for the disease. The novel mutation c.623_626 del was identified in the proband infant and her father, her mother was carriers of the mutation c.1399G > C.ConclusionsA novel variant (c.623_626 del) and a previously reported missense (c.1399G > C) in the ETFDH gene have been identified in the family. The two variants of ETFDH gene identified probably underlie the pathogenesis of Glutaric acidemia type II in this family, and also enlarge ETFDH genotype-phenotype correlations spectrum.

Highlights

Glutaric acidemia type II (GA II) or multiple acyl-CoA dehydrogenase deficiency (MADD, OMIM 231680) is an inherited autosomal recessive disease affecting fatty acid, amino acid and choline metabolism, due to mutations in one of three genes namely, electron transfer flavoprotein alpha-subunit, ETFA, electron transfer flavoprotein β-subunit, ETFB and electron transfer flavoprotein dehydrogenase, ETF dehydrogenase (ETFDH)
A novel variant (c.623_626 del) and a previously reported missense (c.1399G > C) in the ETFDH gene have been identified in the family
The two variants of ETFDH gene identified probably underlie the pathogenesis of Glutaric acidemia type II in this family, and enlarge ETFDH genotype-phenotype correlations spectrum

Summary

Introduction

Glutaric acidemia type II (GA II) or multiple acyl-CoA dehydrogenase deficiency (MADD, OMIM 231680) is an inherited autosomal recessive disease affecting fatty acid, amino acid and choline metabolism, due to mutations in one of three genes namely, electron transfer flavoprotein alpha-subunit, ETFA, electron transfer flavoprotein β-subunit, ETFB and electron transfer flavoprotein dehydrogenase, ETFDH. Glutaric acidemia type II (GA II), known as multiple acyl-CoA dehydrogenase deficiency, is an autosomal recessive inborn error of amino acid and fatty acid metabolism [1]. The ETF/ETFDH deficiencies are responsible for multiple defects of the dehydrogenation system because they block fatty acid oxidation, and the oxidation of branched-chain amino acids and glutaryl-CoA on the catabolic pathway of lysine, hydroxylysine, and tryptophan [5]. Since one of the three genes is affected in GA II, it is essential to accumulate information on genetic mutations to determine any genotype/phenotype correlation and to identify defective enzymes for an accurate diagnosis/prenatal diagnosis of GA II

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