Journal of Neuromuscular Diseases - Volume 8, issue 3

Authors: Bonne, Gisèle

Article Type: Editorial

DOI: 10.3233/JND-219003

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 3, pp. 337-339, 2021

Authors: Over, Laura | Brüggemann, Norbert | Lohmann, Katja

Article Type: Systematic Review

Abstract: Parkinson’s disease (PD) is a disabling neurological condition characterized by the loss of dopaminergic neurons. Currently, the treatment for PD is symptomatic and compensates for the endogenous loss of dopamine production. In cases where the pharmacological therapy is only partly beneficial or results in major wearing-off complications, surgical interventions such as deep brain stimulation may be an alternative treatment. The disease cause often remains unknown, but in some patients, a monogenic cause can be identified. Mutations in at least six genes, LRRK2, SNCA , and VPS35 (dominant forms) or Parkin/PRKN, PINK1 , and DJ1/PARK7 (recessive forms) have been …unequivocally linked to PD pathogenesis. We here systematically screened 8,576 publications on these monogenic PD forms. We identified 2,226 mutation carriers from 456 papers. Levodopa was the most widely applied treatment; only 34 patients were indicated to be untreated at the time of reporting. Notably, detailed treatment data was rarely mentioned including response quantification (good, moderate, minimal) in 951 and/or dose in 293 patients only. Based on available data, levodopa showed an overall good outcome, especially in LRRK2, VPS35, Parkin , and PINK1 mutation carriers (“good” response in 94.6–100%). Side effects of levodopa therapy were reported in ∼15–40%of levodopa-treated patients across genes with dyskinesias as the most frequent one. Non-levodopa medication was indicated to be administered to <200 patients with mainly good outcome. Only a few reports were available on outcomes of brain surgery. Here, most mutation carriers showed a good response. Importantly, none of the available treatments is harmful to one genetic form but effective in another one. In the light of different medication schemes, the progressive nature of PD, and side effects, an improvement of therapeutic options for PD is warranted including a treatabolome database to guide clinicians in treatment decisions. Further, novel disease-cause-modifying drugs are needed. Show more

Keywords: Treatabolome, genetic Parkinson’s disease, levodopa, deep brain stimulation, treatment, systematic literature review, MDSGene

DOI: 10.3233/JND-200598

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 3, pp. 341-356, 2021

Authors: Desaphy, Jean-François | Altamura, Concetta | Vicart, Savine | Fontaine, Bertrand

Article Type: Systematic Review

Abstract: Background: Skeletal muscle ion channelopathies include non-dystrophic myotonias (NDM), periodic paralyses (PP), congenital myasthenic syndrome, and recently identified congenital myopathies. The treatment of these diseases is mainly symptomatic, aimed at reducing muscle excitability in NDM or modifying triggers of attacks in PP. Objective: This systematic review collected the evidences regarding effects of pharmacological treatment on muscle ion channelopathies, focusing on the possible link between treatments and genetic background. Methods: We searched databases for randomized clinical trials (RCT) and other human studies reporting pharmacological treatments. Preclinical studies were considered to gain further information regarding mutation-dependent drug effects. …All steps were performed by two independent investigators, while two others critically reviewed the entire process. Results: For NMD, RCT showed therapeutic benefits of mexiletine and lamotrigine, while other human studies suggest some efficacy of various sodium channel blockers and of the carbonic anhydrase inhibitor (CAI) acetazolamide. Preclinical studies suggest that mutations may alter sensitivity of the channel to sodium channel blockers in vitro , which has been translated to humans in some cases. For hyperkalemic and hypokalemic PP, RCT showed efficacy of the CAI dichlorphenamide in preventing paralysis. However, hypokalemic PP patients carrying sodium channel mutations may have fewer benefits from CAI compared to those carrying calcium channel mutations. Few data are available for treatment of congenital myopathies. Conclusions: These studies provided limited information about the response to treatments of individual mutations or groups of mutations. A major effort is needed to perform human studies for designing a mutation-driven precision medicine in muscle ion channelopathies. Show more

Keywords: Non-dystrophic myotonia, periodic paralysis, congenital myopathy, congenital myasthenic syndrome, sodium channel, calcium channel, chloride channel, targeted therapy, precision medicine

DOI: 10.3233/JND-200582

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 3, pp. 357-381, 2021

Authors: Jennings, Matthew J. | Lochmüller, Angela | Atalaia, Antonio | Horvath, Rita

Article Type: Systematic Review

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. Show more

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

DOI: 10.3233/JND-200546

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 3, pp. 383-400, 2021

Authors: Manta, A. | Spendiff, S. | Lochmüller, H. | Thompson, R.

Article Type: Systematic Review

Abstract: Background: Metabolic myopathies are a heterogenous group of muscle diseases typically characterized by exercise intolerance, myalgia and progressive muscle weakness. Effective treatments for some of these diseases are available, but while our understanding of the pathogenesis of metabolic myopathies related to glycogen storage, lipid metabolism and β -oxidation is well established, evidence linking treatments with the precise causative genetic defect is lacking. Objective: The objective of this study was to collate all published evidence on pharmacological therapies for the aforementioned metabolic myopathies and link this to the genetic mutation in a format amenable to databasing for further computational …use in line with the principles of the “treatabolome” project. Methods: A systematic literature review was conducted to retrieve all levels of evidence examining the therapeutic efficacy of pharmacological treatments on metabolic myopathies related to glycogen storage and lipid metabolism. A key inclusion criterion was the availability of the genetic variant of the treated patients in order to link treatment outcome with the genetic defect. Results: Of the 1,085 articles initially identified, 268 full-text articles were assessed for eligibility, of which 87 were carried over into the final data extraction. The most studied metabolic myopathies were Pompe disease (45 articles), multiple acyl-CoA dehydrogenase deficiency related to mutations in the ETFDH gene (15 articles) and systemic primary carnitine deficiency (8 articles). The most studied therapeutic management strategies for these diseases were enzyme replacement therapy, riboflavin, and carnitine supplementation, respectively. Conclusions: This systematic review provides evidence for treatments of metabolic myopathies linked with the genetic defect in a computationally accessible format suitable for databasing in the treatabolome system, which will enable clinicians to acquire evidence on appropriate therapeutic options for their patient at the time of diagnosis. Show more

Keywords: Treatabolome, drug therapies, metabolic myopathies, genotype-treatment correlation, systematic review, Pompe disease, multiple acyl-CoA dehydrogenase deficiency, systemic primary carnitine deficiency

DOI: 10.3233/JND-200621

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 3, pp. 401-417, 2021

Authors: Atalaia, Antonio | Ben Yaou, Rabah | Wahbi, Karim | De Sandre-Giovannoli, Annachiara | Vigouroux, Corinne | Bonne, Gisèle

Article Type: Systematic Review

Abstract: Background: Variants in the LMNA gene, encoding lamins A/C, are responsible for a growing number of diseases, all of which complying with the definition of rare diseases. LMNA -related disorders have a varied phenotypic expression with more than 15 syndromes described, belonging to five phenotypic groups: Muscular Dystrophies, Neuropathies, Cardiomyopathies, Lipodystrophies and Progeroid Syndromes. Overlapping phenotypes are also reported. Linking gene and variants with phenotypic expression, disease mechanisms, and corresponding treatments is particularly challenging in laminopathies. Treatment recommendations are limited, and very few are variant-based. Objective: The Treatabolome initiative aims to provide a shareable dataset of existing …variant-specific treatment for rare diseases within the Solve-RD EU project. As part of this project, we gathered evidence of specific treatments for laminopathies via a systematic literature review adopting the FAIR (Findable, Accessible, Interoperable, and Reusable) guidelines for scientific data production. Methods: Treatments for LMNA -related conditions were systematically collected from MEDLINE and Embase bibliographic databases and clinical trial registries (Cochrane Central Registry of Controlled Trials, clinicaltrial.gov and EudraCT). Two investigators extracted and analyzed the literature data independently. The included papers were assessed using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence. Results: From the 4783 selected articles by a systematic approach, we identified 78 papers for our final analysis that corresponded to the profile of data defined in the inclusion and exclusion criteria. These papers include 2 guidelines/consensus papers, 4 meta-analyses, 14 single-arm trials, 15 case series, 13 cohort studies, 21 case reports, 8 expert reviews and 1 expert opinion. The treatments were summarized electronically according to significant phenome-genome associations. The specificity of treatments according to the different laminopathic phenotypical presentations is variable. Conclusions: We have extracted Treatabolome-worthy treatment recommendations for patients with different forms of laminopathies based on significant phenome-genome parings. This dataset will be available on the Treatabolome website and, through interoperability, on genetic diagnosis and treatment support tools like the RD-Connect’s Genome Phenome Analysis Platform. Show more

Keywords: Lamin A/C, LMNA gene, laminopathies, Treatabolome, muscular dystrophy, lipodystrophies, sudden cardiac death, cardiomyopathy, progeria

DOI: 10.3233/JND-200596

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 3, pp. 419-439, 2021

Authors: Wang, Leo H. | Tawil, Rabi

Article Type: Review Article

Abstract: Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies. Over the last decade, a consensus was reached regarding the underlying cause of FSHD allowing—for the first time—a targeted approach to treatment. FSHD is the result of a toxic gain-of-function from de-repression of the DUX4 gene, a gene not normally expressed in skeletal muscle. With a clear therapeutic target, there is increasing interest in drug development for FSHD, an interest buoyed by the recent therapeutic successes in other neuromuscular diseases. Herein, we review the underlying disease mechanism, potential therapeutic approaches as well as the state of trial …readiness in the planning and execution of future clinical trials in FSHD. Show more

Keywords: All neuromuscular disease, muscle disease, facioscapulohumeral dystrophy (FSHD), outcome measures

DOI: 10.3233/JND-200554

Citation: Journal of Neuromuscular Diseases, vol. 8, no. 3, pp. 441-451, 2021