Phenotypic spectrum of myelin protein zero-related neuropathies: a large cohort study from five mutation clusters across Italy.

Background: We aimed to investigate the clinical features of a large cohort of patients with myelin protein zero ()-related neuropathy, focusing on the five main mutation clusters across Italy.

Methods: We retrospectively gathered a minimal data set of clinical information in a series of patients with these frequent mutations recruited among Italian Charcot-Marie-Tooth (CMT) registry centres, including disease onset/severity (CMTES-CMT Examination Score), motor/sensory symptoms and use of orthotics/aids.

Results: We collected data from 186 patients: 60 had the p.

Serum Neurofilament Light Chain in Replication Factor Complex Subunit 1 CANVAS and Disease Spectrum.

Background: Biallelic intronic AAGGG repeat expansions in the replication factor complex subunit 1 (RFC1) gene were identified as the leading cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome. Patients exhibit significant clinical heterogeneity and variable disease course, but no potential biomarker has been identified to date.

Objectives: In this multicenter cross-sectional study, we aimed to evaluate neurofilament light (NfL) chain serum levels in a cohort of RFC1 disease patients and to correlate NfL serum concentrations with clinical phenotype and disease severity.

Daytime sleepiness and sleep quality in Charcot-Marie-Tooth disease.

Background: Sleep abnormalities have been reported in Charcot-Marie-Tooth disease (CMT), but data are scanty. We investigated their presence and correlation in a large CMT patients' series.

Methods: Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI) were administered to CMT patients of the Italian registry and controls.

Clinical spectrum and frequency of Charcot-Marie-Tooth disease in Italy: Data from the National CMT Registry.

Background And Purpose: Data are reported from the Italian CMT Registry.

Methods: The Italian CMT Registry is a dual registry where the patient registers and chooses a reference center where the attending clinician collects a minimal dataset of information and administers the Charcot-Marie-Tooth (CMT) Examination/Neuropathy Score. Entered data are encrypted.

Frequency, entity and determinants of fatigue in Charcot-Marie-Tooth disease.

Background And Purpose: Fatigue, a disabling symptom in many neuromuscular disorders, has been reported also in Charcot-Marie-Tooth disease (CMT). The presence of fatigue and its correlations in CMT was investigated.

Methods: The Modified Fatigue Impact Scale (MFIS) was administered to CMT patients from the Italian Registry and a control group.

Anxiety and depression in Charcot-Marie-Tooth disease: data from the Italian CMT national registry.

Background: There is little information about neuropsychiatric comorbidities in Charcot-Marie-Tooth disease (CMT). We assessed frequency of anxiety, depression, and general distress in CMT.

Methods: We administered online the Hospital Anxiety-Depression Scale (HADS) to CMT patients of the Italian registry and controls.

DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening.

Background And Purpose: Mutations in DNAJB2 are associated with autosomal recessive hereditary motor neuropathies/ Charcot-Marie-Tooth disease type 2 (CMT2). We describe an Italian family with CMT2 due to a homozygous DNAJB2 mutation and provide insight into the pathomechanisms.

Methods: Patients with DNAJB2 mutations were characterized clinically, electrophysiologically and by means of skin biopsy.

Autophagy and Lysosomal Functionality in CMT2B Fibroblasts Carrying the RAB7 Mutation.

Charcot-Marie-Tooth type 2B (CMT2B) disease is a dominant axonal peripheral neuropathy caused by five mutations in the gene. Autophagy and late endocytic trafficking were already characterized in CMT2B. Indeed, impairment of autophagy and an increase in lysosomal degradative activity were found in cells expressing the mutant proteins.

Challenges in Treating Charcot-Marie-Tooth Disease and Related Neuropathies: Current Management and Future Perspectives.

There is still no effective drug treatment available for Charcot-Marie-Tooth neuropathies (CMT). Current management relies on rehabilitation therapy, surgery for skeletal deformities, and symptomatic treatment of pain; fatigue and cramps are frequent complaints that are difficult to treat. The challenge is to find disease-modifying therapies.

Updated review of therapeutic strategies for Charcot-Marie-Tooth disease and related neuropathies.

: Charcot-Marie-Tooth disease (CMT) and related neuropathies represent the most prevalent inherited neuromuscular disorders. Nonetheless, there is still no pharmacological treatment available for any CMT type. However, the landscape is rapidly evolving and several novel approaches are providing encouraging results in preclinical studies and leading to clinical trials.

Charcot-Marie-Tooth disease type 2F associated with biallelic HSPB1 mutations.

Objective: This work aims to expand knowledge regarding the genetic spectrum of HSPB1-related diseases. HSPB1 is a gene encoding heat shock protein 27, and mutations in HSPB1 have been identified as the cause of axonal Charcot-Marie-Tooth (CMT) disease type 2F and distal hereditary motor neuropathy (dHMN).

Methods: Two patients with axonal sensorimotor neuropathy underwent detailed clinical examinations, neurophysiological studies, and next-generation sequencing with subsequent bioinformatic prioritization of genetic variants and in silico analysis of the likely causal mutation.

Pregnancy in Charcot-Marie-Tooth disease: Data from the Italian CMT national registry.

Objective: To collect information on frequency of pregnancy and delivery complications in Charcot-Marie-Tooth (CMT) disease and on CMT course during pregnancy.

Methods: Through an ad hoc online questionnaire, we investigated pregnancy and neuropathy course in women with CMT adhering to the Italian CMT Registry. Data were compared to those of controls (recruited among friends and unaffected relatives) and the Italian (or other reference) population.

Validation of the Italian version of the Charcot-Marie-Tooth Health Index.

The Charcot-Marie-Tooth Health Index (CMT-HI) is a disease-specific patient-reported outcome measure measuring overall disease burden in Charcot-Marie-Tooth (CMT) patients, designed for natural history studies and clinical trials in English-speaking affected individuals. We developed and validated its Italian Charcot-Marie-Tooth Health Index (I-CMT-HI) version. The questionnaire was translated and culturally adapted from source into Italian by two neurologists experienced in CMT and neuromuscular disorders (NMDs).

Author Correction: Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Charcot-Marie-Tooth Type 2B: A New Phenotype Associated with a Novel Mutation and Inhibited EGFR Degradation.

The rare autosomal dominant Charcot-Marie-Tooth type 2B (CMT2B) is associated with mutations in the gene, involved in the late endocytic pathway. CMT2B is characterized by predominant sensory loss, ulceromutilating features, with lesser-to-absent motor deficits. We characterized clinically and genetically a family harboring a novel pathogenic variant and performed structural and functional analysis of the mutant protein.

Late-onset and fast progressive neuropathy and cardiomyopathy in Val32Ala transthyretin gene mutation.

More than 100 mutations of the transthyretin gene have been reported in autosomal dominant familial amyloid polyneuropathy. This rare disease causes severe motor and sensory disability, dysautonomia, and in some patients also cardiomyopathy. The diagnosis can be challenging mainly in sporadic adult patients showing clinical, laboratory, and neurophysiological findings overlapping other forms of chronic neuropathy.

A nonsense mutation in myelin protein zero causes congenital hypomyelination neuropathy through altered P0 membrane targeting and gain of abnormal function.

Protein zero (P0) is the major structural protein in peripheral myelin, and mutations in the Myelin Protein Zero (Mpz) gene produce wide-ranging hereditary neuropathy phenotypes. To gain insight in the mechanisms underlying a particularly severe form, congenital hypomyelination (CH), we targeted mouse Mpz to encode P0Q215X, a nonsense mutation associated with the disease, that we show escapes nonsense mediated decay and is expressed in CH patient nerves. The knock-in mice express low levels of the resulting truncated protein, producing a milder phenotype when compared to patients, allowing to dissect the subtle pathogenic mechanisms occurring in otherwise very compromised peripheral myelin.

PFN2 and GAMT as common molecular determinants of axonal Charcot-Marie-Tooth disease.

Background: Charcot-Marie-Tooth type 2 (CMT2) neuropathy is characterised by a vast clinical and genetic heterogeneity complicating its diagnosis and therapeutic intervention. Identification of molecular signatures that are common to multiple CMT2 subtypes can aid in developing therapeutic strategies and measuring disease outcomes.

Methods: A proteomics-based approach was performed on lymphoblasts from CMT2 patients genetically diagnosed with different gene mutations to identify differentially regulated proteins.

New developments in Charcot-Marie-Tooth neuropathy and related diseases.

Purpose Of Review: Charcot-Marie-Tooth disease (CMT) and related neuropathies represent a heterogeneous group of hereditary disorders. The present review will discuss the most recent advances in the field.

Recent Findings: Knowledge of CMT epidemiology and frequency of the main associated genes is increasing, with an overall prevalence estimated at 10-28/100 000.

A novel NDRG1 mutation in a non-Romani patient with CMT4D/HMSN-Lom.

Charcot-Marie-Tooth disease type 4D (CMT4D), also known as hereditary motor and sensory neuropathy Lom type (HMSNL), is an autosomal recessive, early onset, severe demyelinating neuropathy with hearing loss, caused by N-Myc downstream-regulated gene 1 (NDRG1) mutations. CMT4D is rare with only three known mutations, one of which (p.Arg148Ter) is found in patients of Romani ancestry and accounts for the vast majority of cases.