Charcot-Marie-Tooth disease type 2CC due to NEFH variants causes a progressive, non-length-dependent, motor-predominant phenotype - Inria - Institut national de recherche en sciences et technologies du numérique Accéder directement au contenu
Article Dans Une Revue Journal of Neurology, Neurosurgery and Psychiatry Année : 2021

Charcot-Marie-Tooth disease type 2CC due to NEFH variants causes a progressive, non-length-dependent, motor-predominant phenotype

Guilhem Sole
Mary M Reilly
  • Fonction : Auteur
  • PersonId : 1111109

Résumé

Objective Neurofilaments are the major scaffolding proteins for the neuronal cytoskeleton, and variants in NEFH have recently been described to cause axonal Charcot-Marie-Tooth disease type 2CC (CMT2CC). Methods In this large observational study, we present phenotype–genotype correlations on 30 affected and 3 asymptomatic mutation carriers from eight families. Results The majority of patients presented in adulthood with motor-predominant and lower limb-predominant symptoms and the average age of onset was 31.0±15.1 years. A prominent feature was the development of proximal weakness early in the course of the disease. The disease progressed rapidly, unlike other Charcot-Marie-Tooth disease (CMT) subtypes, and half of the patients (53%) needed to use a wheelchair on average 24.1 years after symptom onset. Furthermore, 40% of patients had evidence of early ankle plantarflexion weakness, a feature which is observed in only a handful of CMT subtypes. Neurophysiological studies and MRI of the lower limbs confirmed the presence of a non-length-dependent neuropathy in the majority of patients. All families harboured heterozygous frameshift variants in the last exon of NEFH, resulting in a reading frameshift to an alternate open reading frame and the translation of approximately 42 additional amino acids from the 3' untranslated region (3′-UTR). Conclusions This phenotype–genotype study highlights the unusual phenotype of CMT2CC, which is more akin to spinal muscular atrophy rather than classic CMT. Furthermore, the study will enable more informative discussions on the natural history of the disease and will aid in NEFH variant interpretation in the context of the disease’s unique molecular genetics.
Fichier principal
Vignette du fichier
jnnp-2021-327186.full.pdf (1.8 Mo) Télécharger le fichier
Origine : Publication financée par une institution

Dates et versions

hal-03353031 , version 1 (23-09-2021)

Identifiants

Citer

Menelaos Pipis, Andrea Cortese, James M Polke, Roy Poh, Jana Vandrovcova, et al.. Charcot-Marie-Tooth disease type 2CC due to NEFH variants causes a progressive, non-length-dependent, motor-predominant phenotype. Journal of Neurology, Neurosurgery and Psychiatry, 2021, jnnp-2021-327186. ⟨10.1136/jnnp-2021-327186⟩. ⟨hal-03353031⟩
42 Consultations
36 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More