Demyelinating Charcot-Marie-Tooth Neuropathy Associated Withfbln5mutations

Background and purpose Charcot-Marie-Tooth disease type 1 (CMT1) is a group of autosomal dominantly inherited demyelinating sensorimotor neuropathies. Symptoms usually start in the first to second decade and include distal muscle weakness and wasting, sensory disturbances and foot deformities. The most frequent cause is a duplication ofPMP22whilst point mutations inPMP22and other genes are rare causes. Recently,FBLN5mutations have been reported in CMT1 families. Methods Individuals withFBLN5-associated CMT1 were compiled from clinical and research genetic testing laboratories. Clinical data were extracted from medical records or obtained during patients' visits at our centres or primary care sites. Results Nineteen CMT1 families containing 38 carriers of three differentFBLN5missense variants were identified and a mutational hotspot at c.1117C>T (p.Arg373Cys) was confirmed. Compared to patients with the commonPMP22duplication, individuals withFBLN5variants had a later age of diagnosis (third to fifth decade) and less severely reduced motor median nerve conduction velocities (around 31 m/s). The most frequent clinical presentations were prominent sensory disturbances and painful sensations, often as initial symptom and pronounced in the upper limbs, contrasting with rather mild to moderate motor deficits. Conclusions Our study confirms the relevance ofFBLN5mutations in CMT1. It is proposed to includeFBLN5in the genetic work-up of individuals suspected with CMT1, particularly when diagnosis is established beyond the first and second decade and comparably moderate motor deficits contrast with early and marked sensory involvement.FBLN5-associated CMT1 has a recognizable clinical phenotype and should be referred to as CMT1H according to the current classification scheme.