NEFL N98S mutation: another cause of dominant intermediate Charcot–Marie–Tooth disease with heterogeneous early-onset phenotype

Abstract

The purpose of this study was to describe a pedigree with NEFL N98S mutation associated with a dominant intermediate Charcot-Marie-Tooth disease (DI-CMT) and heterogeneous early-onset phenotype. The pedigree comprised two patients, the proband and her son, aged 38 and 5 years. The proband, evaluated at age 31, showed delayed motor milestones that, as of the second decade, evolved into severe phenotype consisting of sensorimotor neuropathy, pes cavus, clawing hands, gait and kinetic cerebellar ataxia, nystagmus and dysarthria, she being wheelchair bound. By then, a working diagnosis of sporadic early onset cerebellar ataxia with peripheral neuropathy was established. Screening of mutations associated with SCA and autosomal recessive cerebellar ataxias was negative. Her son showed a mild phenotype characterized by delayed motor milestones, and lower-limb hypotonia and areflexia. Electrophysiology in both patients showed nerve conduction slowing in the intermediate range, both in proximal and distal nerve segments, but where compound muscle action potentials exhibited severe attenuation there was conduction slowing down to the demyelinating range. In the proband, cranial magnetic resonance imaging (MRI) showed cerebellar atrophy, electromyography disclosed active denervation in tibialis anterior, and MRI of lower-limb musculature demonstrated widespread and distally accentuated muscle fatty atrophy; furthermore, on water sensitive MRI sequences there was edema of calf muscles. We conclude that the NEFL N98S mutation is associated with a DI-CMT phenotype characterized by early-onset sensorimotor neuropathy delaying motor milestones, which may evolve into a severe and complex clinical picture including cerebellar ataxia.

N98S mutation in NEFL gene is dominantly inherited with a phenotype of polyneuropathy and cerebellar atrophy

“…A 6-year-old boy inherited a heterozygous N98S mutation from his affected mother [2]. However, in contrast to our study, the boy reported by Berciano et al was mildly affected and the atrophy in the proband only affected cerebellum but not spinal cord.…”

Genetic and clinical characteristics ofNEFL-related Charcot-Marie-Tooth disease

“…Although only 5 out of 14 patients conformed to the full syndrome, its recognition may aid in the differential diagnosis with other autosomal recessive cerebellar ataxias. 18 Of note, NFL E90K or N98S mutants share a particular phenotype in vitro, different from that observed with substitutions of amino acid P8, 50 and Nefl N98S/+ mice display an earlyonset phenotype with tremor and pathological changes in the CNS including neurofilament aggregates in the spinal cord and cerebellum. 56 Beyond the above genotype-phenotype associations, identification of uncommon clinical features such as hearing loss, pyramidal tract signs or ataxia may be useful in the differential diagnosis of NEFL-related CMT with other forms of CMT (see online supplementary table 5).…”

“…Twenty-four mutations were clustered in six regions of the NFL polypeptide (figure 4): the initial segment of the head domain (amino acid positions [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22], the junction between the head and the rod domains (90-98), coil 2A (265-268), the mid portion of coil 2B (311-336), the end portion of coil 2B (384-396) and the tail subdomain A (421-440). Mutations in the head domain and the two ends of the rod domain accounted for 75% of kindreds and four common mutations within these regions (P8R, P22S, N98S and E396K) were observed in 55% of kindreds.…”

“…[4][5][6][7] Mutations in the NEFL gene encoding NFL were first identified as a cause of autosomal dominant CMT in 2000, 8 and subsequent reports have confirmed the association of NEFL mutations with different phenotypes including CMT1 (designated CMT1F), CMT2 (designated CMT2E), dominant intermediate CMT and autosomal recessive CMT. [9][10][11][12][13][14][15][16][17][18] Despite the growing number of reports about NEFL-related CMT published in the past 15 years, it remains a rare form of inherited neuropathy, accounting for <1% of all CMT cases in large cohorts, 19 20 and obvious genotype-phenotype correlations have not been established so far. 21 Here we report five new patients with NEFL-related CMT and review all previously published cases to describe the clinical and genetic spectrum of the disease.…”

“…-18 23 24 27-38 44-46 The majority developed a classical CMT phenotype but some of them had additional features including hearing loss, tremor, cerebellar features and pyramidal tract signs (tables 3 and 4).…”