Characterization of etfdh and phgdh mutations in a patient with mild glutaric aciduria type ii and serine deficiency

Amanat Ali, Nahid Al Dhahouri, Fatmah Saeed Ali Almesmari, Waseem Mahmoud Fathalla, Fatma Al Jasmi

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


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 dehydro-genase (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.

Original languageEnglish
Article number703
Issue number5
Publication statusPublished - May 2021


  • 3-phosphoglycerate dehydrogenase
  • Electron transfer flavoprotein dehydrogenase
  • GA-II
  • Serine deficiency
  • Syria
  • Whole exome sequencing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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