Expanding the Phenotypic Spectrum of NDUFS6-Related Disease: From Neonatal Mitochondrial Encephalopathy to Childhood-Onset Axonal Neuropathy

Biallelic variants in <i>NDUFS6</i>, encoding an accessory subunit of mitochondrial complex I, were initially associated with lethal neonatal mitochondrial encephalopathy and Leigh syndrome. Recent studies have demonstrated that <i>NDUFS6</i> variants can also cause childhood- or adolescent-onset axonal neuropathy and Charcot-Marie-Tooth (CMT)-like phenotypes, indicating marked clinical heterogeneity. Here, we report a patient with a novel homozygous truncating <i>NDUFS6</i> variant presenting with a neuropathy-predominant phenotype accompanied by epilepsy, in the absence of neonatal metabolic decompensation. The patient presented with childhood-onset progressive gait abnormality, pes cavus deformity, distal weakness requiring Achilles tendon-release surgery, pyramidal signs, urinary incontinence, and focal epileptiform EEG findings. Brain MRI showed bilateral lenticular nucleus abnormalities. Whole-exome sequencing identified a novel homozygous <i>NDUFS6</i> nonsense variant (c.130C>T, p.Gln44*). While neuropathy has previously been reported primarily in association with the recurrent splice-site variant c.309+5G>A, our findings demonstrate that truncating <i>NDUFS6</i> mutations can also underlie a neuropathy-predominant phenotype. Together with previously published cases, our findings support a phenotypic heterogeneity ranging from lethal encephalopathy to neuropathy and reinforce the role of <i>NDUFS6</i> as a disease-causing gene for inherited peripheral neuropathy. These data support inclusion of <i>NDUFS6</i> among established neuropathy and Charcot-Marie-Tooth genes.