Charcot-Marie-Tooth disease type 2CC due toNEFHvariants causes a progressive, non-length-dependent, motor-predominant phenotype
Open Access
- 13 September 2021
- journal article
- research article
- Published by BMJ in Journal of Neurology, Neurosurgery & Psychiatry
- Vol. 93 (1), 48-56
- https://doi.org/10.1136/jnnp-2021-327186
Abstract
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.Funding Information
- British Medical Association (Vera Down (2018); no grant number)
- UCLH Biomedical Research Centre ((no specific award/grant number))
- Muscular Dystrophy Association (MDA510281)
- National Institute of Neurological Disorders and Stroke (U54NS065712)
- Medical Research Council (MR/S005021/1, MR/T001712/1)
- Fondazione Regionale per la Ricerca Biomedica ((no specific award/grant number))
- Charcot-Marie-Tooth Association ((no specific award/grant number))
- National Center for Advancing Translational Sciences (RDCRN INC U54NS065712)
- National Research Foundation (2021R1A4A2001389)
- Fondazione Cariplo (2019-1836)
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