The Path to Precision Medicine in Leigh Syndrome Spectrum: A Four-Decade Chronicle of Genetic Discovery and Targeted Treatment.

Abstract

Leigh syndrome (LS), first reported in 1951, is the most common primary mitochondrial disease. The overarching term, Leigh Syndrome Spectrum (LSS) was proposed by a ClinGen Expert Panel to encompass the wide continuum of neurodegenerative and non-neurologic manifestations which were associated with classic LS and Leigh-Like Syndrome (LLS). Notably, LSS typically presents developmental regression or delay by two years of age, with about 20% of cases presenting as late-/adult-onset forms after 2 years. Historically defined by clinical, biochemical, and neuropathological findings, the genetic basis of LSS has been elucidated through the use of Sanger and next-generation sequencing (NGS), resulting in the discovery of over 120 causative genes. Moreover, LSS can be caused by mutations in both nuclear-encoded genes and mitochondrial DNA (mtDNA), with overlapping clinical characteristics that occur at similar frequencies. This review aims to summarize the clinical and onset characteristics of LSS, genetic testing-aided diagnosis criteria, and the development of treatments. Furthermore, this review organizes the years since the first reports of gene and mutation discoveries into four consecutive eras: Clinical-Biochemical Era (1990-1999), Early Genomics Era (2000-2009), NGS Revolution Era (2010-2019), and Modern Era (2020-Present). Thus, using this framework, this review chronicles the evolution of LSS molecular genetics and treatment development, highlighting the shift from supportive care to targeted therapies driven by modern technologies. Cornerstone experimental models, such as the Ndufs4 ^-/-knockout mouse and patient-derived induced pluripotent stem cells (iPSCs), have facilitated mechanistic studies and drug repurposing screens, including the identification of sildenafil as a potential therapeutic agent, which has led to medical improvements in patients. Current advances in gene editing, including mitochondrial single-base editors such as eTd-mtABE and mitoBEs, are enabling gene therapy with precise introduction and correction of LS-causing variants in rat and mouse models. On the preventative front, Mitochondrial Replacement Therapy (MRT), guided by precise maternal mtDNA genotyping, has been successfully applied in clinical practice, allowing mothers carrying LSS-causing mtDNA variants to have healthy babies free of the LS manifestation. Collectively, these advances in gene discovery, genetic diagnosis, sophisticated disease modeling, rapid screening of small molecule drugs, precise gene editing for gene therapy, and innovative treatment strategies, such as MRT, are ushering in an era of precision medicine for LSS.