Exacerbation of Charcot–Marie–Tooth type 2E neuropathy following traumatic nerve injury

Abstract

Charcot-Marie-Tooth disease (CMT) is the most commonly inherited peripheral neuropathy. CMT disease signs include distal limb neuropathy, abnormal gait, sensory defects, and deafness. We generated a novel line of CMT2E mice expressing hNF-LE397K, which displayed muscle atrophy of the lower limbs without denervation, proximal reduction in large caliber axons, and decreased nerve conduction velocity. In this study, we challenged wild type, hNF-L, and hNF-LE397K mice with crush injury to the sciatic nerve. We analyzed functional recovery by measuring toe spread and analyzed gaitusing the Catwalk system. hNF-LE397K mice demonstrated reduced recovery from nerve injury consistent with increased susceptibility to neuropathy observed in CMT patients. In addition, hNF-LE397K developed a permanent reduction in their ability to weight bear, increased mechanical allodynia, and premature gait shift in the injured limb, which led to increasingly disrupted interlimb coordination in hNF-LE397K. Exacerbation of neuropathy after injury and identification of gait alterations in combination with previously described pathology suggests that hNF-LE397K mice recapitulate many of clinical signs associated with CMT2. Therefore, hNF-LE397K mice provide a model for determining the efficacy of novel therapies.

Painful Charcot–Marie–Tooth neuropathy type 2E/1F due to a novel NEFL mutation

“…We did not identify any other cause of painful peripheral neuropathy and therefore assume that the clinical picture is caused by the NEFL gene mutation. Increased mechanical allodynia after nerve injury has recently been described in a mouse model of CMT2E with mutated human neurofilament light chain …”

“…Increased mechanical allodynia after nerve injury has recently been described in a mouse model of CMT2E with mutated human neurofilament light chain. 8 Painful neuropathy is related to dysfunction and loss of small unmyelinated nerve fibers. Indeed, skin biopsy showed a reduction of small unmyelinated nerve fibers in our patient, and he had impairment of thermal sensation on clinical examination, indicating small fiber damage.…”

“…Motor deficits are predominant, but sensory symptoms and signs are detectable in all affected individuals . Giant axons have been reported in nerve biopsies of patients with CMT2E and are considered a characteristic histological feature of the disease . Electron microscopy has shown accumulation of disorganized neurofilaments in giant axons and in axons of normal size …”

“…7 Giant axons have been reported in nerve biopsies of patients with CMT2E and are considered a characteristic histological feature of the disease. 8 Electron microscopy has shown accumulation of disorganized neurofilaments in giant axons and in axons of normal size. 5,7 We report a patient with a typical electrophysiological and morphological phenotype of CMT2E and a novel mutation in the NEFL gene, who presented with neuropathic pain as a predominant symptom.…”

Muscle spindle alterations precede onset of sensorimotor deficits in Charcot–Marie–Tooth type 2E

“…In the original description of this mutation (Züchner et al ), and in previous publications (Butinar et al ; Dale et al ; Shen et al ; Villalon et al ), this mutation was referred to as E397K. However, mouse (GenBank: AAH16436.1) and human NF‐L (GenBank: CAA29097.1) protein sequence show that the mutated amino acid is E396 and not E397.…”