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

Genes (Basel). 2021 May 8;12(5):703. doi: 10.3390/genes12050703.

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.

Keywords: 3-phosphoglycerate dehydrogenase; GA-II; Syria; electron transfer flavoprotein dehydrogenase; serine deficiency; whole exome sequencing.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbohydrate Metabolism, Inborn Errors / blood
  • Carbohydrate Metabolism, Inborn Errors / genetics*
  • Carbohydrate Metabolism, Inborn Errors / pathology
  • Child, Preschool
  • Electron-Transferring Flavoproteins / genetics*
  • Female
  • Humans
  • Iron-Sulfur Proteins / genetics*
  • Microcephaly / blood
  • Microcephaly / genetics*
  • Microcephaly / pathology
  • Multiple Acyl Coenzyme A Dehydrogenase Deficiency / genetics*
  • Multiple Acyl Coenzyme A Dehydrogenase Deficiency / pathology
  • Mutation, Missense
  • Oxidoreductases Acting on CH-NH Group Donors / genetics*
  • Phosphoglycerate Dehydrogenase / blood
  • Phosphoglycerate Dehydrogenase / deficiency*
  • Phosphoglycerate Dehydrogenase / genetics*
  • Psychomotor Disorders / blood
  • Psychomotor Disorders / genetics*
  • Psychomotor Disorders / pathology
  • Seizures / blood
  • Seizures / genetics*
  • Seizures / pathology
  • Serine / blood
  • Serine / deficiency*

Substances

  • Electron-Transferring Flavoproteins
  • Iron-Sulfur Proteins
  • Serine
  • Phosphoglycerate Dehydrogenase
  • Oxidoreductases Acting on CH-NH Group Donors
  • electron-transferring-flavoprotein dehydrogenase

Supplementary concepts

  • Phosphoglycerate Dehydrogenase Deficiency