A founder mutation in the ETHE1 gene and ethylmalonic encephalopathy in the Omani population

Background: Ethylmalonic encephalopathy (EE) is a devastating early-onset inborn error of metabolism, and heterogenous disorders manifest as chronic diarrhea, petechial rash, and neurological manifestations. The mutation in the ETHE1 gene leads to hydrogen sulfide accumulation and eventually results in mucosal cell damage in the large intestines and vascular endothelial cells system. Case presentation: Here, we describe four patients from three different tribes in Oman, and the clinical data revealed that the four patients shared an early-onset phenotype and the neurological manifestations were variable. The biochemical markers, specifically the urine organic acid and hyperlactimic acidosis, supported and tailored the diagnosis. Molecular diagnosis was confirmed by full gene sequencing of the ETHE1 gene in the index case and followed by target variant testing for others. Interestingly, all four patients identified to harbor the same homozygous missense pathogenic variant (c.487c > t) in the ETHE1 gene, and their parents were all heterozygous. These findings indicate that we probably have a founder variant associated with EE in our area. Conclusion: These findings are of great importance for diagnosis and surveillance for Omani families with EE. Given the relatively high number and frequency of genetic diseases in the region and the limited resources, screening for these founder mutations should provide a rapid and cost-effective tool for molecular diagnosis. Additionally, these findings should help in designing appropriate measures for carrier screening measures at the regional level. [JBCGenetics 2021; 4(1.000): 51-55

Phenotypes and genotypes of mitochondrial aminoacyl-tRNA synthetase deficiencies from a single neurometabolic clinic

Mitochondrial aminoacyl-tRNA synthetases play a major role in protein translation, synthesis, and oxidative phosphorylation. We reviewed all patients diagnosed with mitochondrial aminoacyl-tRNA synthetase deficiencies diagnosed in a single neurometabolic clinic. We report five patients with mitochondrial aminoacyl-tRNA synthetase deficiencies including DARS2, EARS2, PARS2, and RARS2 deficiencies. Siblings with DARS2 deficiency presented with global developmental delay within the first year of life. DARS2, EARS2, PARS2, and RARS2 deficiencies were identified by whole exome sequencing. We report coagulation factor abnormalities in PARS2 deficiency for the first time. We also report symmetric increased signal intensity in globus pallidi in FLAIR images in brain MRI in EARS2 deficiency for the first time. One patient with RARS2 deficiency had compound heterozygous variants in RARS2. One of those variants was an intronic variant. We confirmed the pathogenicity by mRNA studies. Mitochondrial aminoacyl-tRNA synthetase deficiencies are diagnosed by molecular genetic investigations. Clinically available non-invasive biochemical investigations are non-specific for the diagnosis of mitochondrial aminoacyl-tRNA synthetase deficiencies. A combination of brain MRI features and molecular genetic investigations should be undertaken to confirm the diagnosis of mitochondrial aminoacyl-tRNA synthetase deficiencies

Phenotypes and genotypes of mitochondrial aminoacyl-tRNA synthetase deficiencies from a single neurometabolic clinic

Mitochondrial aminoacyl-tRNA synthetases play a major role in protein translation, synthesis, and oxidative phosphorylation. We reviewed all patients diagnosed with mitochondrial aminoacyl-tRNA synthetase deficiencies diagnosed in a single neurometabolic clinic. We report five patients with mitochondrial aminoacyl-tRNA synthetase deficiencies including DARS2, EARS2, PARS2, and RARS2 deficiencies. Siblings with DARS2 deficiency presented with global developmental delay within the first year of life. DARS2, EARS2, PARS2, and RARS2 deficiencies were identified by whole exome sequencing. We report coagulation factor abnormalities in PARS2 deficiency for the first time. We also report symmetric increased signal intensity in globus pallidi in FLAIR images in brain MRI in EARS2 deficiency for the first time. One patient with RARS2 deficiency had compound heterozygous variants in RARS2. One of those variants was an intronic variant. We confirmed the pathogenicity by mRNA studies. Mitochondrial aminoacyl-tRNA synthetase deficiencies are diagnosed by molecular genetic investigations. Clinically available non-invasive biochemical investigations are non-specific for the diagnosis of mitochondrial aminoacyl-tRNA synthetase deficiencies. A combination of brain MRI features and molecular genetic investigations should be undertaken to confirm the diagnosis of mitochondrial aminoacyl-tRNA synthetase deficiencies