Compound heterozygous mutations in electron transfer flavoprotein dehydrogenase identified in a young Chinese woman with late-onset glutaric aciduria type II

Ying Xue,Yuhui Wang,Abudurexiti Kayoumu,Yun Zhou,Keqin Zhang,Zhiqiang Lu,Liye Chen,Ling Li

doi:10.1186/s12944-017-0576-5

Abstract

BackgroundGlutaric aciduria type II (GA II) is an autosomal recessive disorder affecting fatty acid and amino acid metabolism. The late-onset form of GA II disorder is almost exclusively associated with mutations in the electron transfer flavoprotein dehydrogenase (ETFDH) gene. Till now, the clinical features of late-onset GA II vary widely and pose a great challenge for diagnosis. The aim of the current study is to characterize the clinical phenotypes and genetic basis of a late-onset GAII patient.MethodsIn this study, we described the clinical and biochemical manifestations of a 23-year-old female Chinese patient with late-onset GA II, and performed genomic DNA-based PCR amplifications and sequence analysis of ETFDH gene of the whole pedigree. We also used in-silicon tools to analyze the mutation and evaluated the pathogenicity of the mutation according to the criteria proposed by American College of Medical Genetics and Genomics (ACMG).ResultsThe muscle biopsy of this patient revealed lipid storage myopathy. Blood biochemical test and urine organic acid analyses were consistent with GA II. Direct sequence analysis of the ETFDH gene (NM_004453) revealed compound heterozygous mutations: c.250G > A (p.A84T) on exon 3 and c.920C > G (p.S307C) on exon 8. Both mutations were classified as “pathogenic” according to ACMG criteria.ConclusionsIn conclusion, our study described the phenotype and genotype of a late-onset GA II patient, reiterating the importance of ETFDH gene screening in these patients.

Highlights

Glutaric aciduria type II (GA II) is an autosomal recessive disorder affecting fatty acid and amino acid metabolism
Glutaric aciduria type II (GA II), known as multiple Acyl-CoA dehydrogenase deficiency (MADD), is a rare autosomal recessive disorder of fatty acid, amino acid and choline metabolism caused by a defect in the alpha or beta subunit of the mitochondrial electron transfer flavoprotein (ETFA, ETFB) protein or the electron transfer flavoprotein dehydrogenase (ETFDH) protein [1]
We identified heterozygous mutations in ETFDH gene, including a p.A84T, located at the flavin adenine dinucleotide (FAD)-binding domain and a p.S307C mutation, located within the ubiquinone (UQ)binding domain of electron transfer flavoprotein: ubiqionone oxidoreductase (ETF) dehydrogenase

Summary

Introduction

Glutaric aciduria type II (GA II) is an autosomal recessive disorder affecting fatty acid and amino acid metabolism. In the mild form, the age of onset and the symptoms are variable with intermittent episodes, challenging the clinical diagnosis [2]. These patients often present with fluctuating proximal muscle weakness or episodes of rhabdomyolysis. In late-onset patients, the elevation of acylcarnitine levels may be mild and atypical, or detectable only during an acute episode. Under these circumstances, genetic screening is the key to establish a definitive diagnosis

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