Experimental Therapeutics in Hereditary Neuropathies: The Past, the Present, and the Future

Abstract

Summary:Hereditary neuropathies represent approximately 40% of undiagnosed neuropathies in a tertiary clinic setting. The Charcot-Marie-Tooth neuropathies (CMT) are the most common. Mutations in more than 40 genes have been identified to date in CMT. Approximately 50% of CMT cases are accounted for by CMT type 1A, due to a duplication within the peripheral myelin protein 22 gene (PMP22). Mutations in the gap junction beta 1 gene (GJB1), the myelin protein zero gene (MPZ), and the mitofusin 2 gene (MFN2) account for a substantial proportion of other genetically definable CMT. Some 15% of demyelinating CMT and 70% of axonal CMT await genetic clarification. Other hereditary neuropathies include the hereditary sensory and autonomic neuropathies, the familial amyloid polyneuropathies, and multisystem disorders (e.g., lipid storage diseases and inherited ataxias) that have peripheral neuropathy as a major or minor component. This review surveys the challenges of developing effective therapies for hereditary neuropathies in terms of past, present, and future experimental therapeutics in CMT.

Novel outcome measures for Charcot−Marie−Tooth disease: validation and reliability of the 6‐min walk test and StepWatch™ Activity Monitor and identification of the walking features related to higher quality of life

“…Although some clinical and pharmacological trials have been performed, the results have not been encouraging [3][4][5][6][7][8][9][10]. The relatively small number of studies in CMT patients parallels the difficulties with study design and execution [4]. It is challenging to recruit large, homogeneous cohorts of similarly treated patients and then find agreement on the outcome measures (OMs) to be used.…”

Inherited Neuropathies

“…Characterization of point mutations in subtypes of CMT (Table 1) will be important to target common molecular mechanisms such as protein misfolding and endoplasmic reticulum retention, altered Schwann cell-axonal interactions, and mitochondrial dysfunction [3•]. Physical therapy and exercise, orthotics, orthopedic surgery, dietary supplements, and pain management have been used to treat CMT patients, although evidence of efficacy is still lacking [9]. Recently, an unaffected pregnancy was successfully carried out after preimplantation genetic diagnosis [10, Class IV].…”

Animal models and therapeutic prospects for Charcot–Marie–Tooth disease

“…68 So far, experimental studies have focused on the pathomechanisms and therapeutic strategies for single genes. 68 So far, experimental studies have focused on the pathomechanisms and therapeutic strategies for single genes.…”

“…Although the range of therapeutic strategies for CMT is expanding, the pharmaceutical industry has shown a rather limited interest in the development of treatments. 68 So far, experimental studies have focused on the pathomechanisms and therapeutic strategies for single genes. Given the genetic heterogeneity of the diseases, this might be an obstacle to investment by the pharmaceutical industry.…”