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Diagnostics and treatment of neuromusuclar disorders – a role model for rare diseases?

Schoser, Benedikt

doi: 10.1097/WCO.0000000000000588
NEUROMUSCULAR DISEASE: Edited by Benedikt Schoser

Friedrich-Baur-Institute, Neurology, Ziemssenstr. Munich, Germany

Correspondence to Benedikt Schoser, MD, Friedrich-Baur-Institute, Department of Neurology, Interdisciplinary Center of Neuromuscular Disorders Klinikum München, Ludwig-Maximilians-University Munich, Ziemssenstr. 1a, D-80336 Munich, Germany. Tel: +49 89 4400 57400; e-mail: benedikt.schoser@med.uni-muenchen.de

Neuromuscular diseases encompass a group of over 800 rare diseases and several of them are now responsive to treatment. This new situation is increasing awareness and interest in neuromuscular disorders, and stimulating research and pharmaceutical industry activities. Improvements in diagnosis are reflected in the decline of unsolved or undiagnosed patients around the world. However, the outcome of recent next-generation sequencing or even transcriptome studies in highly preselected patient cohorts of neuromuscular disorders, is that the pick-up rate for genetic diagnosis has plateaued at around 40% (Fig. 1). What are the reasons for this low diagnostic outcome? There are still numerous gaps to be filled; we need to develop new tools to analyse variants of unknown significance; we have to be able to identify medium to long repeat tracts and repeat variants, and be able to identify small and large deletions, and intronic changes; and finally we have to find out how to tackle splice site gene mutations better. Nevertheless new techniques and methods are evolving, so within the next years, we will be able to narrow down these obvious obstacles.

FIGURE 1

FIGURE 1

The development of possible treatments for a disorder is well reflected in the increase of scientific literature on a disease and is complemented by the gain of knowledge on disease phenotypes and their natural disease courses. This helps to understand better the burden of disease and the unmet medical needs of patients (Fig. 2). Twelve years ago, alglucosidase alfa was one of the first internationally licensed drugs in the neuromuscular field. Subsequently several other drugs became licenced, and even genetic motor neuron disorders, such as the spinal muscular atrophy have had their first licenced drug in 2017, nusinersen (Fig. 2). This enormous success was only possible by a well-organized and networking neuromuscular clinical and scientific community. All members have taken up work packages as a prerequisite to a disease becomes treatable, for example, they applied for scientific grants, established animal models, and adopted preclinical models and tools. Moreover, they harmonized international patient registries, developed specific disease outcome measures and patient reported outcomes. All these are fundamental requirements for a successful large scale roll-out of a specific treatment for the patients and for the industrial production of specific medications. In 2018 we will open additional therapeutic avenues by approved gene replacement therapy in the first neuromuscular disorder. Several innovative therapeutics are currently under preclinical and clinical investigation, and will soon become reality for our patients. Although having worked for such a scenario for our patients, we now have to discuss nationally and internationally the affordable pricing of new drugs. Fresh thinking is needed among all stakeholders to provide access for all nations around the world, for example, flat-rate pricing independent of patients’ body weight, and payment by instalments based on therapeutic success over several years, etc. Accordingly, plenty of novel aspects come into focus now for the neuromuscular world. So, as a role model for all rare diseases, patients, clinicians, scientists, and the pharmaceutical industry must take the lead in the development of affordable next-generation translational therapy.

FIGURE 2

FIGURE 2

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Acknowledgements

I thank multiple colleagues around the world for ongoing discussions on how to support best our patients in diagnostics and therapy.

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Financial support and sponsorship

None.

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Conflicts of interest

B.S. has received within the last 3 years research grants from the European Union, Federal Ministry of Education and Research Germany; scientific advisory board fees, consulting fees, and speaker fees from Amicus Therapeutics, Alexion Pharmaceuticals, Audentes Therapeutics, Lupin Pharmaceuticals, Recordati Pharma, Sanofi Genzyme, and Vertex Pharmaceuticals.

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