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

Abstract

Background: 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. 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 presentation: We 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. Conclusions: 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 also enlarge ETFDH genotype-phenotype correlations spectrum.

Clinical Presentations and Genetic Characteristics of Late-Onset MADD Due to ETFDH Mutations in Five Patients: A Case Series

“…In our study, patient 4 with compound heterozygous variants, a frameshift mutation c.582_583insTA (p.P196T fs * 17) and a missense variant c.295C>T (p.R99C) had a relatively average age of onset and typical clinical picture of LOMADD. Nevertheless, previous reports reveal that patients with heterozygous frameshift and missense mutations appear to have an earlier age of onset than those with heterozygous missense mutations (32,(34)(35)(36)(37). Additionally, they frequently exhibit episodes of vomiting, drowsiness, appetite loss, asthenia, and acetonemic breath (32,(34)(35)(36)(37), none of which are prevalent in LOMADD.…”

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

“…MADD is a rare, potentially treatable β-oxidation disorder with three main subtypes: types I/II represent early onset in the neonatal period or infancy and type III represents the late onset of the disease [3,22].…”

Clinical, Biochemical, and Genetic Heterogeneity in Glutaric Aciduria Type II Patients

“…Multiple studies have demonstrated that patients with MADD generally have mutations in ETFA, ETFB or ETFDH genes [ 11 , 12 , 13 ]. According to the Human Gene Mutation Database (HGMD), over 190 different variants of ETFDH have been reported so far and most of them are associated with the late-onset form of GA-II [ 14 , 15 , 16 ]. The majority of patients presented with the late-onset form are responsive to riboflavin therapy, but the molecular mechanism remains elusive.…”