Leigh syndrome in a patient with a novel C12orf65 pathogenic variant: case report and literature review

Abstract

Leigh syndrome is an early onset progressive disorder caused by defects in mitochondrial oxidative phosphorylation. Pathogenic variants in nuclear and mitochondrial genes are associated with the syndrome. Homozygous pathogenic variants in the C12orf65 gene impair the mitochondrial oxidative phosphorylation system. We describe a new case of Leigh syndrome caused by a novel pathogenic variant of the C12orf65 gene resulting in the lack of the Gly-Gly-Gln (GGQ) domain in the predicted protein, and review clinical and molecular data from previously reported patients. Our study supports that the phenotype caused by C12orf65 gene variants is heterogeneous and varies from spastic paraparesis to Leigh syndrome. Loss-of-function variants are more likely to cause the disease, and variants affecting the GGQ domain tend to be associated with more severe phenotypes, reinforcing a possible genotype-phenotype correlation.

The Leigh phenotype resulting from C12orf65 variants

“…We do not agree with the notion that LS is exclusively an early onset disease ( Perrone et al , 2020 ). Though presenting with an onset <2y of age in 80% of the cases ( Hong et al , 2020 ), the remaining portion of LS patients has an onset >2y of age ( Hong et al.…”

“…We also do not agree with the statement that “brain changes are almost identical in all patients” with LS ( Perrone et al , 2020 ). Though cerebral lesions are usually symmetric with regard to distribution, different structures may be affected.…”

“…With interest we read the article by Perrone et al. (2020) about a 2 years old female with Leigh syndrome (LS) due to the homozygous 14bp frameshift deletion in C12orf65 encoding COXPD7.…”

“…(2020) about a 2 years old female with Leigh syndrome (LS) due to the homozygous 14bp frameshift deletion in C12orf65 encoding COXPD7. It was concluded that the mutated protein domain GGQ is responsible for a conservative peptidyl-hydrolase function and that loss of function mutations in this domain play a pathogenetic role for the development of LS ( Perrone et al , 2020 ). We have the following comments and concerns.…”

“…Since LS may go along with epilepsy and since epileptiform discharges were recorded on electroencephalography (EEG) ( Perrone et al. , 2020 ), we should know if the patient ever developed seizures or not and if treatment with anti-epileptic drugs (AEDs) was ever necessary or not.…”