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

## TL;DR

This paper reports a new case of a genetic disorder caused by NDUFS6 mutations, showing a wider range of symptoms than previously known.

## Contribution

The study expands the known phenotypic spectrum of NDUFS6-related disease to include a novel truncating variant causing neuropathy-predominant symptoms.

## Key findings

- A novel homozygous NDUFS6 nonsense variant (c.130C>T, p.Gln44*) was identified in a patient with neuropathy-predominant symptoms.
- NDUFS6 mutations can cause a range of clinical presentations from neonatal encephalopathy to childhood-onset axonal neuropathy.
- The findings support including NDUFS6 in the list of genes associated with inherited peripheral neuropathy.

## Abstract

Biallelic variants in NDUFS6, encoding an accessory subunit of mitochondrial complex I, were initially associated with lethal neonatal mitochondrial encephalopathy and Leigh syndrome. Recent studies have demonstrated that NDUFS6 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 NDUFS6 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 NDUFS6 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 NDUFS6 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 NDUFS6 as a disease-causing gene for inherited peripheral neuropathy. These data support inclusion of NDUFS6 among established neuropathy and Charcot–Marie–Tooth genes.