Mutations targeting distinct domains of the neuron-specific kinesin KIF5A associate with different neurodegenerative/neurodevelopmental disorders, but the molecular bases of this clinical heterogeneity are unknown. We characterised five key mutants covering the whole spectrum of KIF5A-related phenotypes: spastic paraplegia (SPG, R17Q and R280C), Charcot-Marie-Tooth disease (CMT, R864*), amyotrophic lateral sclerosis (ALS, N999Vfs*40), and neonatal intractable myoclonus (NEIMY, C975Vfs*73) KIF5A mutants. CMT-R864*-KIF5A and ALS-N999Vfs*40-KIF5A showed impaired autoinhibition and peripheral localisation accompanied by altered mitochondrial distribution, suggesting transport competence disruption.
View Article and Find Full Text PDFDominant missense mutations of the calcium-permeable cation channel TRPV4 cause Charcot-Marie-Tooth disease (CMT) type 2C and two forms of distal spinal muscular atrophy. These conditions are collectively referred to as TRPV4-related neuromuscular disease and share features of motor greater than sensory dysfunction and frequent vocal fold weakness. Pathogenic variants lead to gain of ion channel function that can be rescued by TRPV4 antagonists in cellular and animal models.
View Article and Find Full Text PDFBackground: 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.
Sleep-disordered breathing has been reported in Charcot-Marie-Tooth disease (CMT) type 1A in association with diaphragmatic weakness and sleep apnea syndrome, mainly of the obstructive type (OSA). Improvement has been observed not only in sleep quality but also in neuropathy symptoms in CMT1A patients with OSA following the initiation of continuous positive airway pressure. We report the cases of two siblings affected by CMT1A associated with hemidiaphragm relaxatio necessitating nocturnal non-invasive ventilation (NIV).
View Article and Find Full Text PDFBackground: 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.
The hereditary neuropathies, collectively referred as Charcot-Marie-Tooth disease (CMT) and related disorders, are heterogeneous genetic peripheral nerve disorders that collectively comprise the commonest inherited neurological disease with an estimated prevalence of 1:2500 individuals. The field of hereditary neuropathies has made significant progress in recent years with respect to both gene discovery and treatment as a result of next-generation sequencing (NGS) approach. These investigations which have identified over 100 causative genes and new mutations have made the classification of CMT even more challenging.
View Article and Find Full Text PDFBackground: 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.
Neuromuscul Disord
August 2023
There is still no effective drug treatment available for Charcot-Marie-Tooth disease (CMT). Current management relies on rehabilitation therapy, surgery for skeletal deformities, and symptomatic treatment. The challenge is to find disease-modifying therapies.
View Article and Find Full Text PDFBackground 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.
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.
Background And Purpose: Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of disorders caused by mutations in at least 100 genes. However, approximately 60% of cases with axonal neuropathies (CMT2) still remain without a genetic diagnosis. We aimed at identifying novel disease genes responsible for CMT2.
View Article and Find Full Text PDFObjective: The paucity of longitudinal natural history studies in MPZ neuropathy remains a barrier to clinical trials. We have completed a longitudinal natural history study in patients with MPZ neuropathies across 13 sites of the Inherited Neuropathies Consortium.
Methods: Change in Charcot-Marie-Tooth Examination Score (CMTES) and Rasch modified CMTES (CMTES-R) were evaluated using longitudinal regression over a 5-year period in subjects with MPZ neuropathy.
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.
Introduction: Biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 (RFC1) gene was recently identified in two/third of patients with cerebellar ataxia, sensory neuropathy, and bilateral vestibular areflexia syndrome (CANVAS). The phenotypic spectrum has expanded since (i.e.
View Article and Find Full Text PDFBackground 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.
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.
View Article and Find Full Text PDFThere 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.
View Article and Find Full Text PDFJ Neurol Neurosurg Psychiatry
January 2022
: 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.
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