Homozygous R627W mutations in POLG cause mitochondrial DNA depletion leading to encephalopathy, seizures and stroke-like episodes

Mutations in the mitochondrial DNA maintenance gene POLG (DNA Polymerase Gamma, Catalytic Subunit), encoding mitochondrial DNA polymerase gamma (pol γ), are associated with an extremely broad phenotypic spectrum. We identified homozygous POLG c.1879C>T; p.R627W mutations in two siblings from a consanguineous South Asian family following targeted resequencing of 75 nuclear-encoded mitochondrial genes. Both patients presented with encephalopathy, seizures and stroke-like episodes, and mitochondrial DNA depletion was confirmed in the proband's muscle tissue. Subsequent Sanger sequencing of POLG in a further 275 unrelated probands with genetically unconfirmed mitochondrial disease revealed a third unrelated proband with a similar phenotype harboring homozygous c.1879C>T; p.R627W mutations and a fourth patient, with a milder clinical disorder, harboring compound heterozygous POLG c.1879C>T; p.R627W and c.2341G>A; p.A781T mutations. Given endogamous practices in the Indian subcontinent, homozygous POLG c.1879C>T; p.R627W mutations should be excluded in South Asian patients presenting with encephalopathy, seizures and stroke-like episodes

Novel Biallelic NSUN3 Variants Cause Early-Onset Mitochondrial Encephalomyopathy and Seizures

Epitranscriptomic systems enable post-transcriptional modifications of cellular RNA that are essential for regulating gene expression. Of the ~ 170 known RNA chemical modifications, methylation is among the most common. Loss of function mutations in NSUN3, encoding the 5-methylcytosine (m5C) methyltransferase NSun3, have been linked to multisystem mitochondrial disease associated with combined oxidative phosphorylation deficiency. Here, we report a patient with early-onset mitochondrial encephalomyopathy and seizures in whom the novel biallelic NSUN3 missense variants c.421G>C (p.A141P) and c.454T>A (p.C152S) were detected. Segregation studies and in silico functional analysis confirmed the likely pathogenic effects of both variants. These findings expand the molecular and phenotypic spectrum of NSUN3-related mitochondrial disease

by multi-angle

Automated classification and recognition of bacterial particles in flo