Leigh Syndrome: Spectrum of Molecular Defects and Clinical Features in Russia

Abstract

Leigh syndrome (LS), also known as infantile subacute necrotizing encephalopathy, is the most frequent mitochondrial disorder in children. Recently, more than 80 genes have been associated with LS, which greatly complicates the diagnosis. In this article, we present clinical and molecular findings of 219 patients with LS and give the detailed description of three cases with rare findings in nuclear genes MORC2, NARS2 and VPS13D, demonstrating wide genetic heterogeneity of this mitochondrial disease. The most common cause of LS in Russian patients are pathogenic variants in the SURF1 gene (44.3% of patients). The most frequent pathogenic variant is c.845_846delCT (66.0% of mutant alleles; 128/192), which is also widespread in Eastern Europe. Five main LS genes, SURF1, SCO2, MT-ATP6, MT-ND5 and PDHA1, account for 70% of all LS cases in the Russian Federation. Using next generation sequencing (NGS) technique, we were able to detect pathogenic variants in other nuclear genes: NDUFV1, NDUFS2, NDUFS8, NDUFAF5, NDUFAF6, NDUFA10, SUCLG1, GFM2, COX10, PMPCB, NARS2, PDHB and SLC19A3, including two genes previously associated with Leigh-like phenotypes—MORC2 and VPS13D. We found 49 previously undescribed nucleotide variants, including two deep intronic variants which affect splicing.

New Case of Spinocerebellar Ataxia, Autosomal Recessive 4, Due to VPS13D Variants

“…In addition, the ClinVar database (25 April 2024) contains 52 pathogenic or likely pathogenic variants, with 21 being nonsense and 16 being frameshift variants (Figure 4). [2,8,9], totaling five cases. In our previous study, we described a 6-year-old boy, exhibited developmental [2,8,9], totaling five cases.…”

“…[2,8,9], totaling five cases. In our previous study, we described a 6-year-old boy, exhibited developmental [2,8,9], totaling five cases. In our previous study, we described a 6-year-old boy, exhibited developmental delay, ataxia, epileptic seizures, and neuroimaging findings indicative of basal ganglia involvement.…”

“…However, the literature also presents patients with more variable clinical symptoms, including spastic paraplegia, spastic ataxia, chorea, dystonia, tremor, and seizures. In two publications, patients with pathogenic variants in the VPS13D gene were assigned to Leigh syndrome (LS; OMIM #256000), a frequent mitochondrial pathology of childhood [8,9].…”

“…The most severe phenotype of VPS13D-associated disorders is Leigh-like syndrome, which manifests in childhood. Cases with a Leigh-like phenotype were previously described by Gauthier et al (2018), Lee et al (2020), and Kistol et al (2023)[2,8,9], totaling five cases. In our previous study, we described a 6-year-old boy, exhibited developmental…”

Caso de curso letal de mutación homocigota del gen nuclear mitocondrial hidroxiisobutiril-CoA hidrolasa HIBCH

“…El SL tiene habitualmente un curso rápidamente progresivo y la mayoría de los niños mueren antes de cumplir los 3 años (2,4,7). Aunque también se ha reportado SL de inicio en adultos como una presentación muy rara, observada en las variantes patogénicas en el gen MTHFR-metilentetrahidrofolato reductasa, uno de los genes nucleares más frecuentes como causa de SL que puede tener un inicio tardío, hasta los 17 años, curso más leve y con supervivencias en edades adultas (8).…”