Targeted Therapies for Hereditary Peripheral Neuropathies: Systematic Review and Steps Towards a 'treatabolome'

Abstract

Background: Hereditary peripheral neuropathies are inherited disorders affecting the peripheral nervous system, including Charcot-Marie-Tooth disease, familial amyloid polyneuropathy and hereditary sensory and motor neuropathies. While the molecular basis of hereditary peripheral neuropathies has been extensively researched, interventional trials of pharmacological therapies are lacking.

Objective: We collated evidence for the effectiveness of pharmacological and gene-based treatments for hereditary peripheral neuropathies.

Methods: We searched several databases for randomised controlled trials (RCT), observational studies and case reports of therapies in hereditary peripheral neuropathies. Two investigators extracted and analysed the data independently, assessing study quality using the Oxford Centre for Evidence Based Medicine 2011 Levels of Evidence in conjunction with the Jadad scale.

Results: Of the 2046 studies initially identified, 119 trials met our inclusion criteria, of which only 34 were carried over into our final analysis. Ascorbic acid was shown to have no therapeutic benefit in CMT1A, while a combination of baclofen, naltrexone and sorbitol (PXT3003) demonstrated some efficacy, but phase III data are incomplete. In TTR-related amyloid polyneuropathy tafamidis, patisiran, inotersen and revusiran showed significant benefit in high quality RCTs. Smaller studies showed the efficacy of L-serine for SPTLC1-related hereditary sensory neuropathy, riboflavin for Brown-Vialetto-Van Laere syndrome (SLC52A2/3) and phytanic acid-poor diet in Refsum disease (PHYH).

Conclusions: The 'treatable' variants highlighted in this project will be flagged in the treatabolome database to alert clinicians at the time of the diagnosis and enable timely treatment of patients with hereditary peripheral neuropathies.

Keywords: Charcot-Marie-Tooth disease; clinical trials; gene based treatments; inherited peripheral neuropathies; pharmacological.

Fig.1

Systematic Review methodology. (A) PRISMA flowchart of studies identified under the search strategy, showing filtering steps to produce study database for codification of data (B) Sankey diagram showing numbers of studies from each source and progressive exclusion of studies according to inclusion criteria.

Fig.2

Characteristics of included studies. (A) Treemap showing number of studies by mutated gene. (B) Percentages of study type for studies overall, and then broken down by disease type (amyloid TTR neuropathy, ATTR; Charcot-Marie-Tooth type 1A, CMT1A; all other studies). (C) Distribution of publications by year, colours indicating study types.

Fig.3

Meta-analysis of studies. (A) Comparison of OCEBM levels with Jadad scoring, the size of each point indicating the number of studies at that point, colour indicating the quality defined as the product of these two scores (lower OCEBM with higher Jadad being the highest quality studies). (B) Distribution of study outcomes, stratified by patient number and labelled by study type.