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

Abstract

Objectives To analyse and describe the clinical and genetic spectrum of Charcot-Marie-Tooth disease (CMT) caused by mutations in the neurofilament light polypeptide gene (NEFL). Methods Combined analysis of new patients with NEFL-related CMT, identified from those attending clinics at the participating institutions, and all previously reported cases from the literature. Results Five new unrelated patients with CMT carrying heterozygous NEFL mutations (N98S, P8R and L311P) were identified. Combined data from these cases and 62 kindreds from the literature revealed four common mutations (P8R, P22S, N98S and E396K) and three mutational hotspots accounting for 55% and 75% of kindreds, respectively. De novo mutations were identified in eight patients. Loss of large-myelinated fibres was a uniform feature in 21 sural nerve biopsies, and ‘onion bulb’ formations and/or thin myelin sheaths were observed in 67%. The neurophysiological phenotype was broad but most patients carrying the mutations E90K and N98S had all reported upper limb motor conduction velocities <38 m/s. Age of symptoms onset was ≤ 3 years in 25 cases. Pyramidal tract signs were described in 13 patients and seven patients were initially diagnosed with or tested for inherited ataxia. Patients with E90K and N98S frequently presented before age 3 years and developed hearing loss or other neurological features including ataxia or cerebellar atrophy on brain MRI. Conclusions NEFL-related CMT is clinically and genetically heterogeneous. Based on this study, however, we propose mutational hotspots and relevant clinical-genetic associations that may be helpful in the evaluation of NEFL sequence variants and the differential diagnosis with other forms of CMT.

A novel pathogenic variant of NEFL responsible for deafness associated with peripheral neuropathy discovered through next‐generation sequencing and review of the literature

“…Only six pathogenic variants responsible for CMT associated with deafness, (p.(Glu90Lys), p.(Asn98Ser), p.(Asn98Thr), p.(Leu268Pro), p.(Cys322_Asn326del), p.(Glu396Lys)) have been reported to date in 17 patients from seven families and four different countries, mainly in Europe (Table ). Familial and sporadic cases were equivalent.…”

“…They contain three major domains: a globular N‐terminal head (amino acids 2‐92), an alpha‐helical central rod (amino acids 93‐396) and a C‐terminal tail (amino acids 397‐543). The rod domain is required for co‐assembly of the subunits, whereas the head and tail domains are involved in the regulation of assembly, axonal transport, and radial growth (Figure ) . Neurofilaments comprise the axoskeleton and functionally maintain neuronal calibre.…”

“…Patients carrying the p.(Asn98Ser), p.(Cys322_Asn326del), or p.(Glu396Lys) pathogenic variants were initially diagnosed with or genetically tested for spinocerebellar ataxia or Friedreich's ataxia, some with dysarthria and/or nystagmus. Cerebellar atrophy by brain MRI was observed for four patients with the p.(Asn98Ser) and p.(Glu396Lys) pathogenic variants …”

“…Abe et al reported that patients with pathogenic variants of NEFL often show hearing impairment . Deafness has been reported in 64% of patients who presented with the p.(Glu90Lys) or p.(Asn98Ser) variants . Likar et al reported a female patient with the p.(Asn98Ser) variant who showed mild sensorineural hearing loss between 0.125 and 4 KHz, moderate hearing loss between 4 and 8 KHz, delayed motoric milestones, difficulty walking, progressive distal weakness of the lower and upper limbs, cerebellar dysfunction, and peripheral motor and sensory neuropathy .…”

“…The association of pathogenic variants of NEFL with various phenotypes, including a dominant or recessive demyelinating form of CMT1 (CMT1F), a dominant axonal form of CMT2 (CMT2E), and a dominant intermediate form of CMT (CMTDIG) has been confirmed . Pathogenic variants in the NEFL gene have been observed in less than 1% of CMT cases, resulting in the reporting of 35 in 173 CMT patients to date. However, only six variants have been reported in 17 patients with impaired hearing .…”