Next-generation sequencing of Tunisian Leigh syndrome patients reveals novel variations: impact for diagnosis and treatment

Abstract

Mitochondrial cytopathies, among which the Leigh syndrome (LS), are caused by variants either in the mitochondrial or the nuclear genome, affecting the oxidative phosphorylation process. The aim of this study consisted in defining the molecular diagnosis of a group of Tunisian patients with LS. Six children, belonging to five Tunisian families, with clinical and imaging presentations suggestive of LS were recruited. Whole mitochondrial DNA and targeted next generation sequencing of a panel of 281 nuclear genes involved in mitochondrial physiology were performed. Bioinformatic analyses were achieved in order to identify deleterious variations. A single m.10197G>A (p.Ala47Thr) variant was found in the mitochondrial MT-ND3 gene in one patient, while the others were related to autosomal homozygous variants: two c.1412delA (p.Gln471ArgfsTer42) and c.1264A>G (p.Thr422Ala) in SLC19A3, one c.454C>G (p.Pro152Ala) in SLC25A19 and one c.122G>A (p.Gly41Asp) in ETHE1. Our findings demonstrate the usefulness of genomic investigations to improve LS diagnosis in consanguineous populations, and further allow for treating the patients harboring variants in SLC19A3 and SLC25A19 that contribute to thiamine transport, by thiamine and biotin supplementation. Considering the Tunisian genetic background, the newly identified variants could be screened in patients with similar clinical presentation in related populations.

Expanding the genetic spectrum of mitochondrial diseases in Tunisia: novel variants revealed by whole-exome sequencing

“…Through this study, we emphasize the relevance and significance of early genetic testing in accurately confirming the clinical diagnosis of mitochondrial diseases. This approach ensures improved healthcare management for patients and allows for timely intervention, particularly in the cases where effective treatments are available (Hechmi et al, 2022).…”

Vitamin B1 deficiency leads to high oxidative stress and mtDNA depletion caused by SLC19A3 mutation in consanguineous family with Leigh syndrome

“…Today, the spectrum of SLC19A3 variants has expanded to neurologic mitochondrial syndromes, with the most common being LS (Gerards et al, 2013;Ortigoza-Escobar et al, 2014;Ortigoza-Escobar et al, 2016). The p.T422A variant is a recurrent pathogenic mutation in the Arab region, which was identi ed with a founder effect in the Saudi Arabian population for BTRBGD (Alfadhel et al, 2013) and was recently reported in a Tunisian LS patient (Hechmi et al, 2022). Supplementation of thiamine and biotin can be effective in treating patients harboring de ciency in thiamine transporter genes such as SLC19A3 and SLC25A19, since it can increase intracellular thiamine levels.…”