Biallelic Nonsense Variants in NEFL May Cause a Non-Length-Dependent Neuropathy With Temporal Dispersion on Nerve...

Pathogenic variants in NEFL, the gene that encodes the light polypeptide subunit of neurofilaments, are an uncommon cause of autosomal recessive Charcot-Marie-Tooth (CMT) disease. In this study, we describe the clinical and electrophysiological features of two families with early-onset CMT carrying nonsense variants in the NEFL gene.

Clinical, genetic, and electrophysiological data were collected prospectively and systematically analyzed.

Five patients from two unrelated families were included. All patients had combined proximal and distal muscle weakness and facial weakness. In two individuals, marked proximal weakness of the upper limbs with preserved proximal strength in the lower limbs was observed, suggesting a non-length-dependent pattern of involvement. Pinprick sensation was preserved in all cases, whereas vibration sense was reduced, mainly distally. Nerve conduction studies demonstrated a demyelinating neuropathy with temporal dispersion in all patients. Whole-exome sequencing of the probands identified two distinct homozygous pathogenic nonsense variants in NEFL: c.54G>C; p.Tyr18* in proband I-1 and c.796G>T; p.Glu266* in proband II-1. Sanger sequencing confirmed segregation of the respective variants in affected siblings.

This study suggests that recessive nonsense variants in NEFL may cause a non-length-dependent sensory and motor neuropathy with facial involvement and temporal dispersion on nerve conduction studies, mimicking an acquired inflammatory demyelinating neuropathy.