Abstract
Charcot–Marie–Tooth (CMT) disease is the most commonly inherited neurological disorder. This study includes patients affected by CMT during regular follow-ups at the CMT clinic in Genova, a neuromuscular university center in the northwest of Italy, with the aim of describing the genetic distribution of CMT subtypes in our cohort and reporting a peculiar phenotype. Since 2004, 585 patients (447 index cases) have been evaluated at our center, 64.9% of whom have a demyelinating neuropathy and 35.1% of whom have an axonal neuropathy. A genetic diagnosis was achieved in 66% of all patients, with the following distribution: CMT1A (48%), HNPP (14%), CMT1X (13%), CMT2A (5%), and P0-related neuropathies (7%), accounting all together for 87% of all the molecularly defined neuropathies. Interestingly, we observe a peculiar phenotype with initial exclusive lower limb involvement as well as lower limb involvement that is maintained over time, which we have defined as a “strictly length-dependent” phenotype. Most patients with this clinical presentation shared variants in either HSPB1 or MPZ genes. The identification of distinctive phenotypes such as this one may help to address genetic diagnosis. In conclusion, we describe our diagnostic experiences as a multidisciplinary outpatient clinic, combining a gene-by-gene approach or targeted gene panels based on clinical presentation.
Highlights
Charcot–Marie–Tooth disease (CMT) is the most commonly inherited neuromuscular disorder, with a prevalence ranging from 9.7/100,000 in Serbia to 82.3/100,000 in Norway [1].CMT comprises a group of inherited motor and sensory neuropathies that are phenotypically and genetically heterogeneous, with more than 100 different disease-associated genes identified [2].Electrophysiological and neuropathological findings differentiate CMT forms into the demyelinating type, with motor nerve conduction velocities of 38 m/s [3]
Genetic testing for CMT involves the sequencing of individual genes addressed by the mode of inheritance, clinical and electrophysiological phenotypes, and data about the prevalence of different genetic subtypes, as well as peculiar genotype–phenotype associations
The next-generation sequencing (NGS) approach more realistically allows us to reach a genetic diagnosis in 30% of genetically undetermined patients when PMP22 duplication has been previously ruled out [32]
Summary
Charcot–Marie–Tooth disease (CMT) is the most commonly inherited neuromuscular disorder, with a prevalence ranging from 9.7/100,000 in Serbia to 82.3/100,000 in Norway [1].CMT comprises a group of inherited motor and sensory neuropathies that are phenotypically and genetically heterogeneous, with more than 100 different disease-associated genes identified [2].Electrophysiological and neuropathological findings differentiate CMT forms into the demyelinating type, with motor nerve conduction velocities (mNCV) of 38 m/s [3]. Charcot–Marie–Tooth disease (CMT) is the most commonly inherited neuromuscular disorder, with a prevalence ranging from 9.7/100,000 in Serbia to 82.3/100,000 in Norway [1]. CMT comprises a group of inherited motor and sensory neuropathies that are phenotypically and genetically heterogeneous, with more than 100 different disease-associated genes identified [2]. Electrophysiological and neuropathological findings differentiate CMT forms into the demyelinating type, with motor nerve conduction velocities (mNCV) of 38 m/s [3]. This classification, somehow “didactic”, still helps to address genetic investigations or the interpretation of molecular results. Since the frequencies of gene pathogenic variants may vary considerably between different populations, data on patient cohorts from different countries are useful for improving the diagnostic molecular algorithms [5]
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