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

INTRODUCTION

Rare diseases (RD) are individually rare but collectively common, affecting 6– 8% of the global population [1]. Their rarity poses unique problems to clinicians and their patients, resulting in significant delays in both diagnosis and treatment. One problem is that clinicians dealing with the relevant patients are largely unaware or unable to keep up with the increasing evidence base associated with these conditions. Considering that approximately 72% of rare disease cases are caused by Mendelian genetic variants [2], an ability to accurately and quickly inform clinicians of existing gene and variant-specific therapeutics would represent a quantum leap in clinical care. The ‘treatabolome’ project aims to systematically collate and evaluate evidence for the effectiveness of rare disease treatments to provide a database of ‘treatable’ variants. Currently, as part of the multi-national ‘Solve-RD’ project, several expert-led teams across the rare disease community are working towards building that database. This knowledgebase will be integrated into an interoperable rare disease genomics platform to facilitate clinicians’ access to the latest clinical data and enable timely treatment of rare disease patients. The first element of this project has been completed and published for congenital myasthenic syndromes [3], and a standardised protocol to be applied across the different arms of the treatabolome project has been submitted. We now aim to undertake an element of this project to define the treatabolome of hereditary peripheral neuropathies.

Hereditary peripheral neuropathies are a group of inherited disorders affecting the peripheral nervous system. These are divided into four major subgroups: hereditary sensory and motor neuropathies, distal hereditary motor neuropathies, hereditary sensory and autonomic neuropathies and more complex hereditary neuropathies. The most common form is the hereditary sensory and motor neuropathy, also known as Charcot-Marie-Tooth disease (CMT), with a prevalence of around 1/2500 [4, 5]. CMT can be further subdivided into demyelinating and axonal forms, depending on their pathophysiology. In demyelinating forms, myelin sheath degeneration precedes axon degeneration, whereas axon degeneration is the primary pathology in axonal forms.

As of January 2020, 93 genes have been identified to cause CMT [6]. These genes cover a wide range of molecular functions and intracellular processes, which can be broadly categorised as affecting intracellular transport in the axon, organelle dynamics and protein synthesis (axonal CMT), and cellular processes causing disruption of myelin production or organisation (demyelinating CMT). Inheritance patterns include all modes of Mendelian inheritance, maternal inheritance (mitochondrial DNA variants) and more complex patterns.

All CMT-related disorders are characterised by a length-dependent degeneration of the peripheral neurons and differ by the groups of neurons affected, with CMT affecting both sensory and motor neurons. Motor symptoms include weakness, atrophy or deformity, and sensory symptoms include numbness, paraesthesia or pain [7]. Some may involve the autonomic nervous system, resulting in features like impaired sweating, postural hypotension or insensitivity to pain [7]. Patients may also present with other neurological symptoms (e.g. spastic paraparesis, ataxia, cranial nerve abnormalities) and have non-neurological features (e.g. cataract, scoliosis, cardiac symptoms). It is important to note that the phenotype may be overlapping across the disease subgroups [5].

The disease typically follows a slowly progressive course. The prognosis of individuals depends on their genotype, but it is modified by other so far unknown genetic, epigenetic and environmental factors [8]. Curative pharmacological treatment is currently only available for some subtypes of hereditary peripheral neuropathies, but supportive management is useful in all cases. Supportive treatments involve physical therapy, occupational therapy, genetic counselling, orthotics (splints, braces, walking aids) and surgery [9].

METHODS

The systematic review was designed using Cochrane Collaboration methodology [10], as guided by the treatabolome project principles for generating FAIR-compliant datasets (soon to be published). Studies of randomised and non-randomised controlled trials, observational studies, case series and case reports of pharmacological treatment for patients with genetically confirmed hereditary peripheral neuropathies were considered for inclusion in the full systematic review. Reviews including systematic and expert reviews were screened for relevant primary data not included in our original search. All appropriate outcome measures clearly indicating a positive, neutral or negative (toxic) response to treatment were considered, including change in measures of muscle strength, functional ability and clinical examination results. Studies were assessed for quality using the Oxford Centre for Evidence-Based Medicine (OCEBM) 2011 Levels of Evidence [11] in conjunction with the Jadad scale [12]. All steps were carried out by two investigators (A.L. and M.J.) independently and reviewed by the expert team lead (R.H.), with regular meetings to establish consensus.

Inclusion criteria

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.

The condition studied was genetically confirmed hereditary peripheral neuropathy. We considered only studies involving patients with genetically confirmed mutations in known neuropathy genes. Hereditary peripheral neuropathies diagnosed by techniques other than formal genetic testing were excluded due to the phenotypic overlap between the different types of neuropathies, which could confound clinical or electrophysiological diagnoses. Participants with any level of severity, age of onset and level of penetrance of phenotypic features were included. Pharmacological therapies or genotype-related dietary changes specifically targeting the neuropathy were included in this study. Non-pharmacological interventions such as physiotherapy, surgery and genetic counselling were excluded.

Literature and trial database search

Several electronic databases were searched in order to cover all available evidence regarding pharmacological treatment for hereditary peripheral neuropathies. Firstly, to discover studies of the highest OCEBM evidence levels, we searched for randomised controlled trials and systematic reviews of genetic neuropathies using the Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Neuromuscular Disease Group Specialized Register, ClinicalTrials.gov, European Clinical Trials Database (EudraCT), WHO International Clinical Trials Registry (ICTRP) and the Centre for Reviews and Dissemination (CRD) database. Secondly, we carried out a wider search using the PubMed database, intending to capture a greater range of relevant literature. Full details of search terms and filters used for each database can be seen in the Supplementary Table 1. Database specific filters were applied to ensure only interventional studies with results available were included, and that major “miss-hit” diseases (e.g. Guillain-Barré syndrome) were excluded. Additionally, a filter for publication date after 01/01/1991 was applied where necessary, as causative genes for inherited peripheral neuropathies were discovered after this date [13, 14].

RESULTS

Our search identified 2043 potentially relevant entries across all databases (Fig. 1). Following duplicate analysis with manual confirmation and elimination of duplicates, 1892 individual studies remained. The titles and abstracts of these studies were then screened for inclusion using the stated inclusion criteria in progressive steps (see Data Selection). 119 studies met all the criteria on initial screening, whereas 1776 studies failed to satisfy at least one aspect of the criteria (Fig. 1). Next, studies which passed this stage were read in full by two assessors to confirm their suitability according to the criteria, excluding a further 88 studies. The characteristics and findings of these studies were recorded in full in Supplementary Table 2. At this stage, systematic reviews and expert reviews included in our search were examined for any additional primary data that was missed. Then, the expert team lead (R.H.) reviewed the process and the 34 studies remained for detailed analysis. Additionally, 1 study which was not included in the original dataset was flagged for inclusion [15], giving a total of 36 included studies. The final studies are presented as grouped by the causative genes involved (Tables 1– 3). For studies involving more than two different gene mutations, all described mutations are listed in Supplementary Table 3.

Of all included studies (n = 34) the largest two genetic groups were amyloid neuropathy caused by mutations in the TTR gene (n = 15) and CMT1A, due to the duplication of PMP22 (n = 8) and point mutation (n = 1) respectively. Numbers of studies were much fewer for other genotypes. Four studies looked at HSAN due to mutations in ELP1 (n = 2), SPTLC1 (n = 1) and SPTLC2 (n = 1). Two studies examined Brown-Vialetto-Van Laere Syndrome caused by mutation in SLC52A2 (n = 1) or SLC52A3 (n = 1). The genes MT-ATP6 (n = 1) and SCN9A (n = 1) each had 1 study. The remaining studies looked at neuropathies due to metabolic causes associated with mutations in PHYH (Refsum disease, n = 2).

DISCUSSION

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.

We performed a systematic review to evaluate the evidence for pharmacological and gene-based treatments in inherited peripheral neuropathies. Our original search identified 1892 independent publications, of which 34 were included in our final analysis. The evidence for the efficacy of the studied treatments was weighted based on the quality of the clinical trials or case studies. We identified 15 treatments, which should be initiated in patients with some genetic forms of inherited neuropathies.

However, our study has some limitations. Firstly, we may have missed some papers reporting positive effect of a treatment as part of a larger study on novel disease genes or describing large cohorts of diverse patients. However, search terms including these would have produced many times more results, thereby precluding careful consideration of studies. The future inclusion of machine-readable variant-level genotype information in clinical trial registration and reporting would improve data collation in the rare disease field. Indeed, we had to add one paper based on our expertise in inherited neuropathies on riboflavin-responsive neuropathy (BVVL) [28, 31]. Secondly, although there are supporting data on the rationale and efficacy of some of these treatments, the degree of evidence is not satisfactory in many studies. The reasons include insufficient study design, inappropriate outcome measures, low number of participants and short study duration. Our review highlights these limitations and demonstrates that we must improve our standards in planning clinical trials. Careful consideration of study size and duration, number of participants, appropriate outcome measures and international collaboration (multi-centre studies) are essential to improve the development of treatments in inherited neuropathies. Thirdly, many studies did not give gene and variant data of study participants in sufficient detail, which meant they were of limited use to our study. Lastly, this database needs regular updating in the future, as the number of clinical trials and relevant case studies are steadily increasing in inherited peripheral neuropathies. This is a time intensive process and requires a dedicated expert team.

Most evidence has been gathered in CMT1A. Ascorbic acid has been extensively researched and proven to be ineffective in this disease subtype. More recently, a combination of baclofen, naltrexone and sorbitol (PXT3003) has shown significant improvement in CMT scores (CMTNS and ONLS) and may be a strong candidate for pharmacotherapy in the future. However, these results must first be confirmed in the phase III trial currently ongoing [1]. Therefore, based on the evidence presented in this review, no definitive recommendations can be made for first-line treatment at present.

In TTR-related amyloid neuropathy, four treatments (tafamidis, patisiran, inotersen and diflunisal) showed significant benefit in high quality RCTs and should be initiated in patients with pathogenic variants in TTR. These drugs have been approved in many different countries for treatment of TTR-related neuropathy. There are still uncertainties about what the long-term clinical benefits are, when to initiate treatment and how to incorporate these treatments into the current algorithms. The choice of treatment and time of commencement needs careful consideration in specialised centres [17], and is influenced by national regulatory and licensing guidelines [33]. Early diagnosis of this condition is essential for timely access to treatment. The availability of gene silencing treatments raises issues regarding genetic screening and management of asymptomatic individuals.

In other forms of CMT and metabolic neuropathies, treatment recommendations are based on a slightly weaker evidence base of case studies and smaller trials. A positive effect of L-serine supplementation in patients with HSAN due to mutations in SPTLC1 (and potentially SPTLC2) is emerging, and we highlighted the efficacy of targeted dietary supplementation and restriction in a few other rare genetic neuropathies (BVVL, Refsum and methylenetetrahydrofolate reductase deficiency). Therefore, if pathogenic mutations are identified in these genes, targeted treatments should be considered in clinical practice.

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.

We detected an increase in the number of publications in recent years (Fig. 2B), although this increase was still driven mainly by case studies and case series. Well-designed RCTs were performed mostly in CMT1A and in amyloid neuropathy caused by TTR mutations (Fig. 2B). When plotting study size against clinical outcome (Fig. 3B), we observed that RCTs with the largest patient enrolments (n > 100) were more likely to demonstrate efficacy in TTR amyloid neuropathy or conclude lack of benefit in CMT1A. This reflects the greater statistical power of larger studies as compared to smaller studies. Case studies and small case series are more likely to report a clinical improvement, but this may be based on unsatisfactory evidence. For example, there is often reporting bias as unusual patient presentations are more likely to be reported. However, some case studies targeting the molecular defect in rare metabolic conditions should be applied to treat specific genetic neuropathies even without performing RCTs.

Although the number of effective treatments in inherited peripheral neuropathies is still very limited, the availability of large international patient cohorts, better outcome measures and more accurate natural history data will facilitate the development of further effective therapies. The recent identification of new genetic forms of CMT has launched research into developing novel therapies, which may in the future be added to the treatabolome database. Since the completion of our search, the discovery of mutations in SORD has unveiled how existing aldose reductase inhibitors have great potential to treat this common type of CMT [34]. Based on in vitro studies in patient-derived fibroblasts and in Drosophila, aldose reductase inhibitors normalized intracellular sorbitol levels and also ameliorated motor and eye phenotypes. These findings will form the basis for future clinical trials in patients with this form of CMT. Further progress is being made due to the technological advancements in molecular genetics, allowing scientists to generate diverse animal models that closely resemble the CMT phenotype. Additionally, it is now possible to culture patient-derived neurons in a dish using cellular reprogramming and differentiation techniques [35].

There is an ever-increasing need for data sharing in rare genetic diseases. This need is beginning to be met by the establishment and implementation of several large databases, which integrate next generation sequencing data with clinical phenotyping data (e.g. RD-CONNECT, DECIPHER, GENESIS, etc). These databases contain information on several thousands of patients and their family members, as well as being easily accessible to clinicians analysing their patients’ samples. On average, each human genome has approximately 30,000 variants compared to the standard assembly, which may be benign or pathogenic. For this reason, appropriate filtering for rare, causative variants and linking the available phenotypic information (HPO terms in RD-CONNECT) results in a higher diagnostic rate. Furthermore, to enable rapid translation from diagnosis to treatment, variants in the genes highlighted as part of the treatabolome project will be flagged in RD-CONNECT. This data will be immediately reported back to the clinician, together with the genetic diagnosis as determined by exome sequencing. Our work will allow this streamlined solution to be made available to clinicians dealing with inherited peripheral neuropathy patients. This approach facilitates clinicians’ access to the latest clinical data relevant to the genotype of their patients and enables timely treatment, ultimately leading to improved prognosis and a better quality of life of rare disease patients. The treatabolome project therefore offers a powerful tool, with significant advantages for both clinicians and patients with inherited peripheral neuropathies.

Funding

The authors of this study are supported by the Newton Fund UK/Turkey (MR/N027302/1 to RH), the Medical Research Council (UK) (MR/N025431/1 to RH), the Wellcome Investigator fund (109915/Z/15/Z to RH), the Lily Foundation UK (to RH), the European Research Council (309548 to RH) and the Evelyn Trust (19/14 to RH); and the Wellcome Trust Pathfinder Scheme (201064/Z/16/Z to RH). The study was further supported by the Horizon 2020 research and innovation program via grant 779257 “Solve-RD”, the RD-Connect Genome-Phenome Analysis platform developed under FP7/2007-2013 funded project (grant agreement nº 305444).). Authors of this publication are members of the European Reference Network for Rare Neuromuscular Diseases EURO-NMD (AA, RH).