PT - JOURNAL ARTICLE AU - Menelaos Pipis AU - Andrea Cortese AU - James M Polke AU - Roy Poh AU - Jana Vandrovcova AU - Matilde Laura AU - Mariola Skorupinska AU - Arnaud Jacquier AU - Raul Juntas-Morales AU - Philippe Latour AU - Philippe Petiot AU - Guilhem Sole AU - Yves Fromes AU - Sachit Shah AU - Julian Blake AU - Byung-Ok Choi AU - Ki Wha Chung AU - Tanya Stojkovic AU - Alexander M Rossor AU - Mary M Reilly TI - Charcot-Marie-Tooth disease type 2CC due to <em>NEFH</em> variants causes a progressive, non-length-dependent, motor-predominant phenotype AID - 10.1136/jnnp-2021-327186 DP - 2022 Jan 01 TA - Journal of Neurology, Neurosurgery &amp; Psychiatry PG - 48--56 VI - 93 IP - 1 4099 - http://jnnp.bmj.com/content/93/1/48.short 4100 - http://jnnp.bmj.com/content/93/1/48.full SO - J Neurol Neurosurg Psychiatry2022 Jan 01; 93 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. The data that support the findings of this study are available from the corresponding author, upon reasonable request. The data are not publicly available since they contain information that could compromise the privacy of research participants.