Characterization of ETFDH and PHGDH Mutations in a Patient with Mild Glutaric Aciduria Type II and Serine Deficiency

Abstract

Glutaric aciduria type II (GA-II) is a rare autosomal recessive disease caused by defects in electron transfer flavoprotein (ETF), ultimately causing insufficiencies in multiple acyl-CoA dehydrogenase (MAD). 3-phosphoglycerate dehydrogenase (3-PHGDH) deficiency, is another rare autosomal disorder that appears due to a defect in the synthesis of L-serine amino acid. Several mutations of ETFDH and PHGDH genes have been associated with different forms of GA-II and serine deficiency, respectively. In this study, we report a unique case of GA-II with serine deficiency using biochemical, genetic, and in silico approaches. The proband of Syrian descent had positive newborn screening (NBS) for GA-II. At two years of age, the patient presented with developmental regression, ataxia, and intractable seizures. Results of amino acid profiling demonstrated extremely low levels of serine. Confirmatory tests for GA-II and whole exome sequencing (WES) were performed to determine the etiology of intractable seizure. Sequencing results indicated a previously reported homozygous missense mutation, c.679 C>A (p.Pro227Thr) in the ETFDH gene and a novel missense homozygous mutation c.1219 T>C (p.Ser407Pro) in the PHGDH gene. In silico tools predicted these mutations as deleterious. Here, the clinical and biochemical investigations indicate that ETFDH:p.Pro227Thr and PHGDH:p.Ser407Pro variants likely underlie the pathogenesis of GA-II and serine deficiency, respectively. This study indicates that two rare autosomal recessive disorders should be considered in consanguineous families, more specifically in those with atypical presentation.

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

“…Previous studies not only support our findings but also highlight the effectiveness of personalized treatments, such as riboflavin supplementation for specific genetic mutations. These studies underscore the significance of tailored management strategies in addressing the identified phenotype–genotype correlations [ 16 , 19 , 20 , 21 ].…”

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

“…Several studies have identified hotspots in ETFDH gene and their association with GA-II [ 16 , 72 , 73 , 74 ]. Interestingly, the majority of GA-II patients have been reported from Asian countries.…”