Leigh Syndrome Spectrum: A Portuguese Population Cohort in an Evolutionary Genetic Era

Mitochondrial diseases are the most common inherited inborn error of metabolism resulting in deficient ATP generation, due to failure in homeostasis and proper bioenergetics. The most frequent mitochondrial disease manifestation in children is Leigh syndrome (LS), encompassing clinical, neuroradiological, biochemical, and molecular features. It typically affects infants but occurs anytime in life. Considering recent updates, LS clinical presentation has been stretched, and is now named LS spectrum (LSS), including classical LS and Leigh-like presentations. Apart from clinical diagnosis challenges, the molecular characterization also progressed from Sanger techniques to NGS (next-generation sequencing), encompassing analysis of nuclear (nDNA) and mitochondrial DNA (mtDNA). This upgrade resumed steps and favored diagnosis. Hereby, our paper presents molecular and clinical data on a Portuguese cohort of 40 positive cases of LSS. A total of 28 patients presented mutation in mtDNA and 12 in nDNA, with novel mutations identified in a heterogeneous group of genes. The present results contribute to the better knowledge of the molecular basis of LS and expand the clinical spectrum associated with this syndrome.

Automated summary

Mitochondrial diseases, characterized by deficient ATP generation, are the most common inherited metabolic disorders. Leigh syndrome (LS) is the most frequent manifestation in children, which has been recently expanded to include Leigh-like presentations. The molecular characterization of LS has advanced from Sanger techniques to next-generation sequencing, allowing for the identification of novel mutations. A Portuguese cohort study on LS patients revealed both mitochondrial DNA and nuclear DNA mutations, contributing to a better understanding of the molecular basis and clinical spectrum of LS.