Recent advances in the genetic neuropathies

Abstract

Purpose of review Charcot-Marie-Tooth disease (CMT) is one of the commonest inherited neuromuscular diseases with a population prevalence of 1 in 2500. This review will cover recent advances in the genetics and pathomechanisms of CMT and how these are leading to the development of rational therapies. Recent findings Pathomechanistic and therapeutic target advances in CMT include the identification of the ErbB receptor signalling pathway as a therapeutic target in CMT1A and pharmacological modification of the unfolded protein response in CMT1B. In CMT2D, due to mutations in GARS, VEGF-mediated stimulation of the Nrp1 receptor has been identified as a therapeutic target. Preclinical advances have been accompanied by the publication of large natural history cohorts and the identification of a sensitive biomarker of disease (muscle MRI) that is able to detect disease progression in CMT1A over one year. Summary Advances in next generation sequencing technology, cell biology and animal models of CMT are paving the way for rational treatments. The combination of robust natural history data and the identification of sensitive biomarkers mean that we are now entering an exciting therapeutic era in the field of the genetic neuropathies.

Clinical and genetic investigation in Chinese patients with demyelinating Charcot‐Marie‐Tooth disease

“…Forty‐four patients from 25 families, consisting of 38 familial patients (36 patients from 18 families were autosomal‐dominant, 2 patients from 1 family were autosomal‐recessive) and 6 sporadic patients were recruited from the First Affiliated Hospital of Fujian Medical University from December 2001 to April 2017. Neurologic examinations including clinical presentations, physical examinations, laboratory tests, electromyography (EMG), and Charcot‐Marie‐Tooth neuropathy score (CMTNS) were conducted . All patients were corresponded with the demyelinating CMT diagnostic standard (MNCV <25 m/s) .…”

“…Diagnosis of demyelinating CMT depends on electrophysiological studies, which typically demonstrate remarkable decreased nerve conduction velocity (CV). At least 20 disease genes for demyelinating CMT have been reported, complicating the molecular diagnosis in patients . The most common subtype of CMT is CMT1A, associated with a 17p11.2 duplication encompassing the coding sequence of the myelin protein PMP22 , which accounts for more than 70% of demyelinating CMT cases .…”

“…Mutations in MPZ (CMT1B) and PMP22 (CMT1E) gene, which are considered second and third most common type of CMT, only account for 4% and 2% of demyelinating CMT patients . For demyelinating CMT patients, it is the first step to test for 17p11.2 heterozygous duplication with multiplex ligation‐dependent probe amplification (MLPA) methods, then next step to test for CMT disease causing genes by next‐generation sequencing (NGS) technology …”

Peripheral neuropathy in complex inherited diseases: an approach to diagnosis

“…For each condition identified in the search, the presence of a neuropathy was confirmed by reviewing the original clinical description and neurophysiology. Multiple reviews exist, including our recent review, for the ‘pure’ neuropathies,1 that is, CMT and related disorders so these will not be covered except for selected cases that we feel are more appropriately classified as a complex inherited neuropathy syndrome.…”

Nerve size correlates with clinical severity in Charcot–Marie–Tooth disease 1A

“…Charcot–Marie–Tooth disease (CMT) is the most common group of inherited peripheral nervous system disorders and encompasses genetically and pathologically heterogeneous motor‐sensory peripheral polyneuropathies . Autosomal dominant CMT1A associated with the PMP22 gene duplication represents the most common CMT (>60% of cases) and is demyelinating, according to nerve conduction studies (NCS) and pathological findings .…”