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 36 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.

NCAM1 and GDF15 are biomarkers of Charcot-Marie-Tooth disease in patients and mice

“…Additionally, there are many smaller studies of experimental treatments in various forms of CMT, which when taken together indicate that some therapies can be useful in specific genotypes based on the molecular mechanism. 12 , 13 Some genetic subtypes of inherited peripheral neuropathies are caused by enzyme defects leading to accumulation of toxic metabolites. An increase of serum deoxysphingolipids has been observed in patients with SPTLC1 mutations, 14 while high sorbitol levels were detected in SORD- related CMT2.…”

“…With many new therapies nearing clinical trials, the lack of molecular biomarkers remains a key limitation in assessing the efficacy of treatments in this slowly progressive disease. 12 To identify novel serum biomarkers common across CMT subtypes, we performed targeted mass spectrometry using serum of a cohort of 55 patients and four mouse models with different genetic forms of CMT. Combining the results in patients and mice led to the identification of NCAM1 and GDF15 as powerful biomarkers of CMT, and we found widespread dysregulation of the complement inflammatory system.…”

Emerging Therapies for Charcot-Marie-Tooth Inherited Neuropathies

“…High doses of ascorbic acid have inhibitory action on adenylate cyclase activity, the enzyme producing adenyl cyclic adenosine monophosphate (cAMP) [ 106 ] and resulted in reduced PMP22 expression and improved myelination profile, locomotion and survival in C22 mice [ 69 ]. However, despite multiple randomized clinical trials [ 107 ], ascorbic acid treatment failed to show any significant therapeutic benefit in CMT1A patients [ 70 , 71 , 72 , 73 ].…”

Targeted Therapies for Leigh Syndrome: Systematic Review and Steps Towards a ‘Treatabolome’

“…As part of the H2020 research project Solve-RD rare disease experts aim towards creating a database of treatable rare disease, the ‘Treatabolome’, at gene and variant levels [ 6 ]. Previous Treatabolomes have been created for congenital myasthenic syndromes [ 7 ], inherited neuropathies [ 8 ] and laminopathies [ 9 ]. As part of this international effort, we have systematically reviewed existing evidence of pharmacological treatments of LS.…”