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

Amanat Ali,Arwa Mohammad Saleh Ali,Ranjit Vijayan,Fatma Al Jasmi,Aisha Al Shamsi,Nahid Al Dhahouri,Jozef Hertecant,Amal Al Tenaiji,Fatmah Saeed Ali Almesmari,Mohammed Ahmed Ali Mohamed Ahmed Aldhanhani

doi:10.3390/genes12091334

Amanat Ali, Arwa Mohammad Saleh Ali + Show 8 more

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https://doi.org/10.3390/genes12091334

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Abstract

The variants of electron transfer flavoprotein (ETFA, ETFB) and ETF dehydrogenase (ETFDH) are the leading cause of glutaric aciduria type II (GA-II). In this study, we identified 13 patients harboring six variants of two genes associated with GA-II. Out of the six variants, four were missense, and two were frameshift mutations. A missense variant (ETFDH:p.Gln269His) was observed in a homozygous state in nine patients. Among nine patients, three had experienced metabolic crises with recurrent vomiting, abdominal pain, and nausea. In one patient with persistent metabolic acidosis, hypoglycemia, and a high anion gap, the ETFDH:p.Gly472Arg, and ETFB:p.Pro94Thrfs*8 variants were identified in a homozygous, and heterozygous state, respectively. A missense variant ETFDH:p.Ser442Leu was detected in a homozygous state in one patient with metabolic acidosis, hypoglycemia, hyperammonemia and liver dysfunction. The ETFDH:p.Arg41Leu, and ETFB:p.Ile346Phefs*19 variants were observed in a homozygous state in one patient each. Both these variants have not been reported so far. In silico approaches were used to evaluate the pathogenicity and structural changes linked with these six variants. Overall, the results indicate the importance of a newborn screening program and genetic investigations for patients with GA-II. Moreover, careful interpretation and correlation of variants of uncertain significance with clinical and biochemical findings are needed to confirm the pathogenicity of such variants.

Highlights

Inborn errors of metabolism (IEM) constitute a rare heterogeneous set of genetic diseases with a wide range of overlapping or non-specific clinical phenotypes [1]
Patients who had a positive newborn screening (NBS) for Glutaric aciduria type II (GA-II) and/or clinical features suggestive of GA-II along with a diagnostic mutational analysis report were included in this retrospective study
The results of plasma acylcarnitine obtained during NBS confirmatory work-up were suggestive of GA-II (Table 2)

Summary

Introduction

Inborn errors of metabolism (IEM) constitute a rare heterogeneous set of genetic diseases with a wide range of overlapping or non-specific clinical phenotypes [1]. The complexity of metabolic pathways is increased by several proteins that play regulatory and enzymatic functions. IEM generally appears due to genetic mutations that disrupt the normal functioning of important proteins involved in cellular metabolism [2]. Glutaric aciduria type II (GA-II), known as multiple acyl-CoA dehydrogenase deficiency (MADD) is an inborn error of fatty acid, choline, and amino acid metabolism that primarily affects fat and protein metabolism [3]. It is inherited in an autosomal recessive manner. GA-II is caused by a defect in the electron transfer flavoprotein subunits (ETFA and ETFB), and the electron transfer flavoprotein dehydrogenase (ETFDH) [4]

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