Adolescent-Onset Leigh Syndrome Associated with Homozygous NDUFV1 c.640G>A (p.E214K) in Low-German Mennonites of Southwestern Ontario

Objective: Leigh syndrome, formerly known as infantile subacute necrotizing encephalomyelopathy, is a progressive neurometabolic disorder characterized by midbrain and brainstem lesions leading to rapid neurodegeneration. Pathological variants in over 80 nuclear encoded genes, predominantly affecting respiratory chain and energy metabolism proteins, have been implicated in Leigh syndrome. This paper aims to provide an overview of current understanding of Leigh syndrome, emphasizing clinical, pathological, and molecular genetic aspects, with a specific focus on a novel finding of adolescent onset Leigh syndrome associated with variant c.640G>A identified among Low German-speaking Mennonite families in Southwestern Ontario. Methods: We present a case series detailing the clinical manifestations of five patients homozygous for the c.640G>A (p.E214K) variant in the nuclear DNA encoded NDUFV1 gene, which affects mitochondrial respiratory chain complex 1. Additionally, in silico tools are used to evaluate the structural and functional role of this variant on complex 1 activity. Results: The five patients exhibited diverse clinical presentations associated with Leigh syndrome. Biochemical evaluation demonstrated mildly elevated cerebrospinal-fluid lactate in two patients and isolated complex I deficiency in skin fibroblasts. Brain MRI, when available, consistently showed symmetric T2-hyperintensities of the putamina and dorsal brainstem, characteristic of Leigh syndrome, with all patients developing rapid onset in adolescence. This variant represents a novel finding of adolescent onset Leigh syndrome in the Low German-speaking Mennonite population, contributing to our understanding of Leigh syndrome's genetic heterogeneity. Conclusion: This study underscores the clinical and genetic diversity of Leigh syndrome and highlights the importance of identifying novel mutations within specific populations for accurate diagnosis and targeted treatment strategies. Though no cure exists, thiamine therapy has been shown to provide clinical improvement.