RT Journal Article SR Electronic T1 Charcot-Marie-Tooth disease type 2CC due to NEFH variants causes a progressive, non-length-dependent, motor-predominant phenotype JF Journal of Neurology, Neurosurgery & Psychiatry JO J Neurol Neurosurg Psychiatry FD BMJ Publishing Group Ltd SP jnnp-2021-327186 DO 10.1136/jnnp-2021-327186 A1 Menelaos Pipis A1 Andrea Cortese A1 James M Polke A1 Roy Poh A1 Jana Vandrovcova A1 Matilde Laura A1 Mariola Skorupinska A1 Arnaud Jacquier A1 Raul Juntas-Morales A1 Philippe Latour A1 Philippe Petiot A1 Guilhem Sole A1 Yves Fromes A1 Sachit Shah A1 Julian Blake A1 Byung-Ok Choi A1 Ki Wha Chung A1 Tanya Stojkovic A1 Alexander M Rossor A1 Mary M Reilly YR 2021 UL http://jnnp.bmj.com/content/early/2021/09/13/jnnp-2021-327186.abstract AB 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.Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplemental information.