Leigh Syndrome: A Comprehensive Review of the Disease and Present and Future Treatments

Abstract

Leigh syndrome (LS) is a severe neurodegenerative condition with an early onset, typically during early childhood or infancy. The disorder exhibits substantial clinical and genetic diversity. From a clinical standpoint, Leigh syndrome showcases a broad range of irregularities, ranging from severe neurological issues to minimal or no discernible abnormalities. The central nervous system is most affected, resulting in psychomotor retardation, seizures, nystagmus, ophthalmoparesis, optic atrophy, ataxia, dystonia, or respiratory failure. Some patients also experience involvement of the peripheral nervous system, such as polyneuropathy or myopathy, as well as non-neurological anomalies, such as diabetes, short stature, hypertrichosis, cardiomyopathy, anemia, renal failure, vomiting, or diarrhea (Leigh-like syndrome). Mutations associated with Leigh syndrome impact genes in both the mitochondrial and nuclear genomes. Presently, LS remains without a cure and shows limited response to various treatments, although certain case reports suggest potential improvement with supplements. Ongoing preclinical studies are actively exploring new treatment approaches. This review comprehensively outlines the genetic underpinnings of LS, its current treatment methods, and preclinical investigations, with a particular focus on treatment.

Keywords: Leigh syndrome; genetics; neurology; preclinical research; therapy.

Figure 1

Clinical characteristics of Leigh syndrome. Predominantly impacting the brain, muscles, and eyes, the most common clinical features are highlighted. Additionally, abnormalities extend to the cardiovascular, gastrointestinal, renal, and hematological systems. The origin of Leigh syndrome lies in pathogenic mutations found in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA), leading to disruptions in the oxidative phosphorylation (OXPHOS) capabilities of the mitochondria. Mitochondria are represented at the center of the image, surrounded by clinical manifestations, despite nuclear gene mutations being more frequently responsible. This is due to Leigh syndrome being classified as a mitochondrial disease because it impairs mitochondrial oxidative phosphorylation, leading to reduced ATP production and a consequent increase in glycolysis.