Nefl-Related Charcot-Marie tooth disease due to P440L mutation in two italian families: expanding the phenotype and defining modulating factors

Mutations in the neurofilament polypetide light chain (NEFL) gene account for <1 % of all forms of Charcot-Marie-Tooth (CMT) diseases, and present with different phenotypes, including demyelinating, axonal and intermediate neuropathies and with diverse pattern of transmission, with dominant and recessive inheritance being described. Here we present clinical and molecular data in two new unrelated Italian families, affected with CMT. We studied fifteen subjects (11 women, 4 men), age range 23-62 year. Onset of symptoms was mainly in childhood, with running/walking difficulties; some patients were pauci-asymptomatic; almost all shared variably distributed features of absent/reduced deep tendon reflexes, impaired gait, reduced sensation and distal weakness in the legs. Skeletal deformities were seldom documented and were of mild degree. Additional features included sensorineural hearing loss in three patients, underactive bladder in two patients and cardiac conduction abnormalities, requiring pacemaker implantation, in one child. Central nervous system impairment was not documented in any subject. Neurophysiological investigation disclosed feature suggestive of demyelinating sensory-motor polyneuropathy in one family and resembling an intermediate form in the other. Multigene panel analysis of all known CMT genes revealed two heterozygous variants in NEFL: p.E488K and p.P440L. Whilst, the latter change segregated with the phenotype, the p.E488K variant appeared to act as a modifier factor being associated to axonal nerve damage. Our study expands the array of clinical features associated with NEFL- related CMT.