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

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.

Navigating the Diagnostic Journey in Pediatric Gastroenterology: Decoding Recurrent Vomiting and Epigastric Pain in a Child with Glutaric Aciduria Type II

“…The ETFDH mutation identified in this case is likely responsible for a partial enzyme deficiency, leading to a comparatively milder clinical presentation. In stark contrast, a complete deficiency of ETFDH is often linked to a severe neonatal onset, marked by profound hypotonia, hypoglycemia, and significantly increased mortality risk [ 2 , 13 ].…”

“…Glutaric aciduria type II (GA II), also known as multiple acyl-CoA dehydrogenase deficiency (MADD), is an autosomal recessive disorder affecting fatty acid, amino acid, and choline metabolism, occurring in only about 1 in 250,000 newborns [ 1 ]. This condition results from mutations in the ETFDH, ETFA, and ETFB genes, leading to deficiencies in the electron transport chain, particularly in electron transfer flavoprotein (ETF) or electron flavoprotein dehydrogenase (ETFDH) [ 2 ]. These deficiencies cause lipid accumulation in cells like cardiomyocytes, hepatocytes, and renal tubular cells [ 3 ].…”

“…These forms are often fatal. In contrast, the late-onset variant (type c) is generally milder and often presents with diverse manifestations and a variable age of onset [ 2 , 3 ].…”

Genetic background and clinical characteristics of infantile hyperammonemia

“…The known genetic causes of infantile HA mainly include urea cycle disorder (UCD), organic acidemia (OA), and fatty acid oxidation disorder (FAOD) (6)(7)(8)22,23). A wide range of genes have been identified and reported in the human phenotype ontology associated with infantile HA (24)(25)(26). However, in clinical practice, the status of several other genes, such as ABCC8 (27) and GALT (28,29), in HA remains unknown.…”

Genetic background and clinical characteristics of infantile hyperammonaemia

“…The known genetic causes of infantile HA mainly include urea cycle disorder (UCD), organic acidemia (OA), and fatty acid oxidation disorder (FAOD) [6-8, 22, 23]. A wide range of genes have been identi ed and reported in the human phenotype ontology associated with infantile hyperammonaemia [24][25][26]. However, in clinical practice, the status of several other genes, such as ABCC8 [27] and GALT [28,29], in hyperammonaemia remains unknown.…”