This page has only limited features, please log in for full access.
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.
Amanat Ali; Fatmah Saeed Ali Almesmari; Nahid Al Dhahouri; Arwa Mohammad Saleh Ali; Mohammed Ahmed Ali Mohamed Ahmed Aldhanhani; Ranjit Vijayan; Amal Al Tenaiji; Aisha Al Shamsi; Jozef Hertecant; Fatma Al Jasmi. Clinical, Biochemical, and Genetic Heterogeneity in Glutaric Aciduria Type II Patients. Genes 2021, 12, 1334 .
AMA StyleAmanat Ali, Fatmah Saeed Ali Almesmari, Nahid Al Dhahouri, Arwa Mohammad Saleh Ali, Mohammed Ahmed Ali Mohamed Ahmed Aldhanhani, Ranjit Vijayan, Amal Al Tenaiji, Aisha Al Shamsi, Jozef Hertecant, Fatma Al Jasmi. Clinical, Biochemical, and Genetic Heterogeneity in Glutaric Aciduria Type II Patients. Genes. 2021; 12 (9):1334.
Chicago/Turabian StyleAmanat Ali; Fatmah Saeed Ali Almesmari; Nahid Al Dhahouri; Arwa Mohammad Saleh Ali; Mohammed Ahmed Ali Mohamed Ahmed Aldhanhani; Ranjit Vijayan; Amal Al Tenaiji; Aisha Al Shamsi; Jozef Hertecant; Fatma Al Jasmi. 2021. "Clinical, Biochemical, and Genetic Heterogeneity in Glutaric Aciduria Type II Patients." Genes 12, no. 9: 1334.
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.
Amanat Ali; Nahid Dhahouri; Fatmah Almesmari; Waseem Fathalla; Fatma Jasmi. Characterization of ETFDH and PHGDH Mutations in a Patient with Mild Glutaric Aciduria Type II and Serine Deficiency. Genes 2021, 12, 703 .
AMA StyleAmanat Ali, Nahid Dhahouri, Fatmah Almesmari, Waseem Fathalla, Fatma Jasmi. Characterization of ETFDH and PHGDH Mutations in a Patient with Mild Glutaric Aciduria Type II and Serine Deficiency. Genes. 2021; 12 (5):703.
Chicago/Turabian StyleAmanat Ali; Nahid Dhahouri; Fatmah Almesmari; Waseem Fathalla; Fatma Jasmi. 2021. "Characterization of ETFDH and PHGDH Mutations in a Patient with Mild Glutaric Aciduria Type II and Serine Deficiency." Genes 12, no. 5: 703.