An Atypical Neurosensory-Predominant Presentation Associated with a Homozygous NDUFS3 Variant: A Diagnostic Challenge...

Mitochondrial complex I deficiency represents a major cause of pediatric mitochondrial disease and is associated with a broad phenotypic spectrum, classically including Leigh syndrome and severe neurodegenerative presentations. Variants in NDUFS3, encoding a core structural subunit of complex I, are rare and most often linked to severe multisystem involvement. However, emerging reports suggest that NDUFS3 variants may be associated with more heterogeneous and atypical clinical manifestations. Here, we describe a child with a neurosensory-predominant phenotype presenting a diagnostic challenge involving retinal and auditory findings in the context of a homozygous NDUFS3 variant.

A girl born to consanguineous parents presented with global developmental delay, bilateral digital contractures, impaired visual responses, and progressive hearing difficulties. Ophthalmologic evaluation revealed Stargardt-like maculopathy, while audiologic assessment confirmed bilateral sensorineural hearing loss. Neurological examination showed mild motor delay without neuroregression. Brain magnetic resonance imaging and spectroscopy were unremarkable, and no cardiomyopathy or metabolic crises were observed. Whole-exome sequencing identified a homozygous NDUFS3 c.721G>A (p.Ala241Thr; rs776795187) variant, classified as a variant of uncertain significance and predicted to be deleterious by multiple in silico tools (SIFT, PolyPhen-2, MutationTaster, and CADD). Heterozygous variants were also detected in ABCA4 and HMCN1. Parental segregation analysis was not available at the time of evaluation. Supportive mitochondrial therapy was initiated, and the patient remained clinically stable during long-term follow-up, with nonprogressive neurosensory findings.

This case highlights the diagnostic complexity of interpreting atypical neurosensory-predominant phenotypes in mitochondrial disease. While the homozygous NDUFS3 variant may contribute to systemic mitochondrial vulnerability, the coexistence of heterozygous retinal gene variants suggests a possible modifying or oligogenic effect. Rather than defining a distinct monogenic entity, this report underscores the importance of cautious genotype-phenotype correlation and comprehensive genetic evaluation in children presenting with combined retinal and auditory involvement.