Longitudinal characterization of a Leigh-like presentation associated with the MT-ND4 m.11470A>C variant

Leigh syndrome comprises genetically heterogeneous mitochondrial disorders, but interpretation of rare mitochondrial DNA variants is often limited by sparse longitudinal data. We report a male patient followed from childhood to age 16 with the MT-ND4 m.11470A>C (p. (Lys237Asn)) variant. Right-eye strabismus and optic atrophy appeared at age 3, followed by progressive limb weakness, gait instability, and dysarthria. At age 16, magnetic resonance imaging showed bilateral lesions involving the basal ganglia, thalami, midbrain, pons, and medulla oblongata. The patient subsequently developed respiratory failure requiring intubation and mechanical ventilation. The variant was detected in saliva at a pipeline-reported heteroplasmy level of 51.8% and was not detected by Sanger sequencing in saliva from the mother or dizygotic twin brother. APOGEE 2 predicted a potential deleterious effect, the affected residue was conserved, and static structural visualization suggested altered local contacts. A targeted review identified previous associations of m.11470A>C with MELAS and a Leigh syndrome record in a pediatric cohort. This detailed longitudinal case adds clinical and neuroimaging resolution to the reported m.11470A>C spectrum and supports integrating disease trajectory, tissue source, heteroplasmy, and family data when interpreting rare mitochondrial DNA variants.