A family with IVIg-responsive Charcot–Marie–Tooth disease

We report a family of intravenous immunoglobulin (IVIg)-responsive X-linked Charcot–Marie–Tooth disease Type 1 (CMT1X) with a novel gap junction protein 1 mutation. Two of three siblings in the family complained of subacute motor and sensory impairment, and their symptoms improved after the administration of IVIg. Additional IVIg treatment also resulted in similar improvement. The other also showed a mild improvement on IVIg. It has been suggested that an immune-mediated process is involved in the progression of neuropathy in CMT1X. The finding in our report provides evidence of susceptibility to immune-mediated demyelinating neuropathy in some form of CMT1X. Superimposed demyelinating neuropathy as well as a gradual deterioration of neuropathy over decades can be a clinical manifestation of CMT1X.     

Characterization of Charcot–Marie–Tooth optic neuropathy

Varying degrees of optic neuropathy can be seen in patients with Charcot–Marie–Tooth (CMT) disease. To define and characterize the extent of optic neuropathy in patients with CMT2A and CMT1A, two patients from both sub-classifications were evaluated. All patients underwent complete neuro-ophthalmic examinations, and optical coherence (OCT) measurements of the retinal nerve fiber layer (RNFL) and ganglion cell layer complex (GCC) were obtained, along with pattern visual evoked potential (VEP) and pattern electroretinogram (ERG) recordings. RNFL thickness measurements were decreased in both patients with CMT2A, and normal in both patients with CMT1A. GCC measurements were decreased in both patients with CMT2A, mildly decreased in one patient with CMT1A and normal in the second CMT1A patient. VEP latencies were delayed in one patient with CMT2A and one patient with CMT1A. VEP latencies were immeasurable in the other CMT2A patient and not obtained in the second CMT1A patient. Pattern ERG P50-N95 amplitudes were decreased in both patients with CMT2A and normal in one patient with CMT1A. The pattern ERG was immeasurable in the second patient with CMT1A. The pattern of RNFL and GCC thinning in CMT2A with optic neuropathy, a subset of HMSN VI, closely resembles that seen in other mitochondrial optic neuropathies.     

Inheritance of Charcot–Marie–Tooth disease 1A with rare nonrecurrent genomic rearrangement

Rare copy number variations by the nonrecurrent rearrangements involving PMP22 have been recently suggested to be associated with CMT1A peripheral neuropathy. As a mechanism of the nonrecurrent rearrangement, replication-based fork stalling template switching (FoSTeS) by microhomology-mediated break-induced replication (MMBIR) has been proposed. We found three Korean CMT1A families with putative nonrecurrent duplication. The duplications were identified by microsatellite typing and applying a CGH microarray. The breakpoint sequences in two families suggested an Alu–Alu-mediated rearrangement with the FoSTeS by the MMBIR, and a two-step rearrangement of the replication-based FoSTeS/MMBIR and meiosis-based recombination. The two-step mechanism has still not been reported. Segregation analysis of 17p12 microsatellite markers and breakpoint junction analysis suggested that the nonrecurrent rearrangements are stably inherited without alteration of junction sequence; however, they may allow some alteration of the genomic contents in duplication across generations by recombination event. It might be the first study on the pedigree analysis of the large CMT1A families with nonrecurrent rearrangements. It seems that the exact mechanism of the nonrecurrent rearrangements in the CMT1A may have a far more complex process than has been expected.     

Cranial nerve involvement in Charcot–Marie–Tooth Disease

BackgroundCharcot–Marie–Tooth Disease (CMT) is a rare disorder with less than 200,000 cases reported in the US every year, making diagnosis challenging. MR and CT imaging has become more common in the evaluation of CMT to identify areas of disease involvement.Case reportA 27-year-old female from Guatemala with a past history of polio initially presented to the emergency room for necrotizing pneumonia.MRI images demonstrated smoothly enlarged, mildly enhancing trigeminal nerves. CT showed bony widening of the skull base foramina. The patient was noted to have atrophy and weakness of her extremities with decreased sensation, distal more than proximal, and pes cavus. An electromyogram demonstrated absent response in the right median, ulnar, peroneal, and tibial motor studies and bilateral radial and right sural sensory studies. MRI of the spine demonstrated smooth, symmetric enlargement and mild enhancement of the distal spinal nerve roots and cauda equine.DiscussionCMT is a group of disorders with a wide range of clinical presentations and abnormalities. Cranial nerve involvement is infrequently described in CMT 1A. In our case and prior studies, there does not appear to be a correlation between cranial nerve involvement and symptoms. Trigeminal neuralgia has been described in patients in CMT, but is not common and was not seen in our patient despite abnormal trigeminal nerve findings on imaging. Our patient also demonstrated involvement of the facial nerve without facial muscle weakness. Clinical features are key in distinguishing CMT 1A from other forms of HMSN.     

Toxic medications in Charcot–Marie–Tooth patients: A systematic review

Background and Aims

Several widely used medications, with a relevant efficacy profile, are toxic to the peripheral nervous system and an even larger number of agents are suspected to be neurotoxic. There are concerns about the use of these drugs in patients with Charcot–Marie–Tooth disease (CMT), a hereditary motor and sensory neuropathy. This review provides evidence-based updated recommendations on this clinically relevant topic.

Methods

A systematic review of the available studies/reports written in English was performed from July to September 2022 including in the search string all reported putative neurotoxic drugs.

Results

The results of our systematic review provide evidence-based support for the statement that use of vincristine, and possibly paclitaxel, can occasionally induce an atypical, and more severe, course of drug-related peripheral neurotoxicity in CMT patients. It is therefore reasonable to recommend caution in the use of these compounds in CMT patients. However, no convincing evidence for a similar recommendation could be found for all other drugs.

Interpretation

It is important that patients with CMT are not denied effective treatments that may prolong life expectancy for cancer or improve their health status if affected by non-oncological diseases. Accurate monitoring of peripheral nerve function in CMT patients treated with any neurotoxic agent remains mandatory to detect the earliest signs of neuropathy worsening and atypical clinical courses. Neurologists monitoring CMT patients as part of their normal care package or for natural history studies should keep detailed records of exposures to neurotoxic medications and support reporting of accelerated neuropathy progression if observed.     

A novel homozygous nonsense mutation in NEFL causes autosomal recessive Charcot–Marie–Tooth disease

The neurofilament light polypeptide (NEFL) gene mutations cause mainly autosomal dominant Charcot–Marie–Tooth disease (CMT) and rarely the recessive forms of CMT. We describe a 13-year-old girl born of consanguineous parents. She presented an early onset of gait disturbance with weakness in lower extremities during the first decade. Nerve conduction velocity of median nerve was 24 m/s and amplitude of compound muscle action potential was 2.2 mV. Sensory nerve action potential was not recordable. Sural nerve biopsy showed severe loss of the large myelinated fibers. Electron microscopy revealed absence of neurofilaments in both myelinated and unmyelinated axons. Genetic analysis identified a novel homozygous nonsense mutation in NEFL c.487G>T (p.Glu163*) as the potential causative mutation in this patient. Our study expands the mutation spectrum of NEFL-related neuropathy.     

Charcot–Marie–Tooth disease: genetic subtypes in the Sardinian population

Charcot–Marie–Tooth disease (CMT) is characterised by great variability of genetic subtypes. This study aimed to assess the genetic subtypes of CMT disease in the Sardinian population. Genetic screening was performed for CMT cases (CMT1, CMT2, and hereditary neuropathy with susceptibility to pressure palsies [HNPP]). A total of 1,043 subjects (119 index cases) were evaluated. In CMT1 index cases (69/119; 58%), PMP22 duplication at 17p11.2 was the most frequent genetic diagnosis (60/69; 87%), followed by mutations in the GJB1 gene (5/69; 7.2%), in the SH3TC2 gene (3/69; 4.4%) and PMP22 Gly107Val point mutation (1/69; 1.4%). The CMT2 group (24/119; 20.1%) comprised 10/24 (41.6%) patients carrying MPZ gene Ser44Phe mutation, 6/24 (25%) with mutations in MFN2 and HSPB1, and 1/24 (4.2%) in GJB1 and LRSAM1. In the HNPP group (26/119; 21.9%), the majority of patients reported the PMP22 deletion (25/26; 96.2%). Further studies are needed to comprehend the overall picture of the disease in Mediterranean area.     

Influence of comorbidities on the phenotype of patients affected by Charcot–Marie–Tooth neuropathy type 1A

Charcot–Marie–Tooth type 1A (CMT1A) is the most common inherited neuropathy. The phenotype of patients affected by CMT1A is highly variable and may be influenced by several conditions. We evaluated how comorbidities such as diabetes, hypothyroidism, exposure to toxins and obesity can modify or exacerbate the clinical and neurophysiological phenotype of CMT1A patients. Disability was measured using the classic CMT neuropathy score. Compared to controls, all groups of CMT1A patients with comorbidities had higher CMT neuropathy score. In particular, patients with CMT1A and diabetes mellitus show motor subscores which are significantly higher than in control CMT1A. Amplitudes of ulnar CMAP are lower in patients with CMT1A and diabetes mellitus, but not at a significant level. As expected, motor nerve conduction velocity is not influenced by any of the comorbidities. The presence of concomitant diseases shows a tendency to worsen the clinical and neurophysiological CMT1A phenotype, especially in patients with CMT1A and diabetes mellitus, where higher values in the CMT neuropathy score and clinical motor subscore have been observed.     

New insights into the pathophysiology of pes cavus in Charcot–Marie–Tooth disease type 1A duplication

Forefoot pes cavus is a cardinal sign of Charcot–Marie–Tooth disease (CMT). This review is focused on the pathophysiology of pes cavus in CMT1A duplication, which is the most common subtype of the disease. Assessment of foot deformities in CMT1A, their prevalence and proposed mechanisms, and recent contributions of magnetic resonance imaging studies of lower-leg and foot musculature are revised. Special attention is given to papers on foot deformities at initial stages of the disease. We conclude that pes cavus is an early and age-dependent manifestation of CMT1A duplication. Selective denervation of intrinsic foot musculature, particularly of the lumbricals, and not imbalance of lower-leg muscles, seems to be the initial mechanism causing reduced ankle flexibility and forefoot cavus deformity.     

Clinical spectrum and gender differences in a large cohort of Charcot–Marie–Tooth type 1A patients

IntroductionHeterogeneous clinical presentation and gender differences were reported in Charcot–Marie–Tooth disease type 1A (CMT1A).MethodsThis report examined demographic and clinical data collected during a randomised controlled trial, to describe the clinical spectrum of a large and well-defined cohort of CMT1A patients.ResultsAmong the 189 symptomatic patients screened, three patients (1.6%) reported first symptoms in the upper limbs, which may be misleading when establishing the clinical diagnosis. The quality of life (QoL) of patients was significantly deteriorated compared to the standard population, and slightly better compared to multiple sclerosis patients. According to the literature, patients reported several disorders which may be associated with CMT1A, including auditory dysfunction (7.9%), Carpal Tunnel Syndrome (CTS) (7.9%) or sleep apnoea (4.2%). Compared to available data, we reported more patients with CTS and fewer patients with sleep apnoea. Women were more affected by CTS than men (11% and 2.8%, respectively). Women also reported an earlier onset of symptoms than men (8.6 ± 9.5 years and 13.1 ± 14 years, respectively), higher deterioration of their QoL and higher disability of their upper limb, assessed by Overall Neuropathy Limitation Scale (p = 0.023).ConclusionsThis information will be useful for better understanding of this disease and for designing future clinical studies.     

A novel AIFM1 mutation in a Chinese family with X-linked Charcot–Marie–Tooth disease type 4

X-linked Charcot–Marie–Tooth disease type 4 (CMTX4), caused by AIFM1 (Apoptosis-Inducing Factor, Mitochondrion associated 1) mutations and associated with deafness and cognitive impairment, is a rare subtype of Charcot–Marie–Tooth disease. Here, we report a novel missense variant of AIFM1 in a X-linked recessive Chinese family with childhood-onset, slowly progressive, isolated axonal motor and sensory neuropathy. Calf magnetic resonance imaging revealed fatty infiltration and atrophy severely involving the muscles of peroneal compartment. Pathologies exhibited abnormal mitochondrial morphology and accumulation in axoplasm of nerve fiber and subsarcolemmal area of muscle. A hemizygous variant (c.513G>A, p.Met171Ile) in the family was identified and was classified as likely pathogenic according to the standards and guidelines of the American College of Medical Genetics and Genomics. Our report expands the genetic spectrum of diseases related to AIFM1 mutations and indicates that fatty infiltration and atrophy of muscles in the peroneal compartment may be a feature of CMTX4 in early stage.     

Charcot–Marie–Tooth causing HSPB1 mutations increase Cdk5-mediated phosphorylation of neurofilaments

Mutations in the small heat shock protein HSPB1 (HSP27) are a cause of axonal Charcot–Marie–Tooth neuropathy (CMT2F) and distal hereditary motor neuropathy. To better understand the effect of mutations in HSPB1 on the neuronal cytoskeleton, we stably transduced neuronal cells with wild-type and mutant HSPB1 and investigated axonal transport of neurofilaments (NFs). We observed that mutant HSPB1 affected the binding of NFs to the anterograde motor protein kinesin, reducing anterograde transport of NFs. These deficits were associated with an increased phosphorylation of NFs and cyclin-dependent kinase Cdk5. As Cdk5 mediates NF phosphorylation, inhibition of Cdk5/p35 restored NF phosphorylation level, as well as NF binding to kinesin in mutant HSPB1 neuronal cells. Altogether, we demonstrate that HSPB1 mutations induce hyperphosphorylation of NFs through Cdk5 and reduce anterograde transport of NFs.     

Novel GJB1 mutation causing adult-onset Charcot–Marie–Tooth disease in a female patient

Charcot–Marie–Tooth disease (CMT), which is the eponym for hereditary motor and sensory neuropathy (HMSN), affects ～1 in 2500 individuals. The most common subtype of X-linked CMT, CMTX1, is caused by mutations in GJB1, the gene encoding connexin 32, a gap junction protein in myelinated Schwann cells. We report a woman, who presented at the age of 56 years with gait unsteadiness and tingling in her feet. Clinical investigation revealed impaired sensation to pinprick, light touch and vibration in her distal lower limbs. Ankle reflexes were bilaterally absent. Sequencing revealed a novel heterozygous c.712C>T (p.R238C) mutation in the GJB1 gene. This mutation is predicted to result in the loss of disulfide bonds and thus in abnormal protein structure. In this woman, the reported novel GJB1 mutation resulted in sensory abnormalities, slowly progressive loss of distal lower limb strength, and notable loss of balance, with onset of symptoms late in adult age.