Mitochondrial Complex III and IV deficiencies in Leigh Syndrome: Genetic spectrum and Molecular Dynamics simulation study in a pediatric Indian cohort

Leigh syndrome (LS) or subacute necrotizing encephalopathy is a rare inherited mitochondrial disorder with a global prevalence of 1 in 40,000 and affecting majorly infants and neonates. Symptoms usually appear before 24 months of age and progression rates are higher compared to adult-onset. LS is characterized by regression of milestones, developmental delay, epileptic seizures, dystonia, ataxia and respiratory failures. In this study, we are reporting seven cases of early-onset LS. A wide spectrum of clinical phenotypes was observed with cases showing ophthalmoplegia, profound hearing loss, microcephaly and severe hypotonia. MRI findings have shown the involvement of subthalamic nuclei, caudate, putamen, basal ganglia and brainstem which are characteristic features of LS. Laboratory tests have shown elevated serum/CSF lactate levels. Mitochondrial complex (I-IV) enzyme activities have been estimated in buccal swabs of seven children suspected of Leigh Syndrome based on clinical and MRI findings. Genetic analysis has also been carried out followed by molecular dynamics simulation to determine the possible effect of genetic variants on protein structure. Respiratory chain enzyme analysis in our cohort using buccal swab samples demonstrated a predominance of complex III deficiency (4/7 patients), and complex IV deficiency (4/7 patients), with only one patient harboring complex II deficiency. This also revealed overall 4 patients having isolated complex deficiencies and multi-complex deficiencies in 2 patients. Genetic investigations have identified a novel variant in TTC19 gene (NM_017775.4:c.903T > A (p.Tyr301Ter). Missense variants were identified in MT-ND6, MT-ATP6, TPK1 and ECHS1 genes and nonsense variants in SURF1 gene. Further, molecular dynamic simulation studies have shown structural defects caused due to these variants. This study demonstrates the clinical, biochemical, genetic and neuroimaging heterogeneity of Leigh syndrome in an Indian cohort and highlights the value of integrating genotype, phenotype, and MRI findings for comprehensive disease characterization.