2020 Vision J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2020-324327 on 14 July 2020. Downloaded from A MODERN 2020 CENTENARY PERSPECTIVE ON TRAIL BLAZING PAPERS FROM THE JNNP ARCHIVE A 2020 centenary perspective on neuromuscular disorders Stephen A Goutman , Brian Christopher Callaghan , Eva Feldman
last 100 years is remarkable. When JNNP able to create the groupings of patients first began publishing articles the struc- needed to begin deciphering the under- ture of DNA was unknown, and today we lying genetic causes of disease. These have effective gene-targeted therapies that groupings were in place as technology alter the course of multiple neuromuscular moved from linkage analysis to Sanger diseases. One year ago, we were chal- sequencing to next generation sequencing, lenged to consider the ‘most important or creating the clinical framework to detect transformative development in neurology’ the underlying defects in the genetic code. in the past 100 years and how JNNP contributed to this achievement given its Gene-based therapeutic targets 3 broad scope. To our surprise, no nomi- At this writing, the GeneTable of nation for neuromuscular disorders made Neuromuscular Disorders (http://www. 4 the final list. Therefore, we wish to put musclegenetable.fr/ index.html) lists 587 forth a nomination for neuromuscular genes associated with 1042 disorders. disorders. All articles cited for this nomi- These include 97 entries for heredi- nation are published in JNNP. We contend Genetic diagnoses and gene-based tary motor sensory neuropathies, 50 for the subspeciality of neuromuscular disor- therapies have transformed our muscular dystrophies, 35 for congenital ders leads the neurologic community in muscular dystrophies, 44 for congenital approach to neuromuscular disorders the most important achievements in the myopathies, 30 for other myopathies, and created new therapies to treat last 100 years: discovering the genetic 19 for distal myopathies, 6 for myotonic previously incurable diseases aetiology of previously untreatable neuro- syndromes, 8 for ion channel muscle muscular disorders and turning these
disorders, 29 for metabolic myopathies, copyright. discoveries into therapies. Genetic diagnoses and 71 for motor neuron disorders and 32 for congenital myasthenic syndromes. These gene-based therapies have Describe, decipher, detect all represent potential targets for gene- transformed our approach to So how did we get here? Quite literally by based treatments.8 neuromuscular disorders and standing on the shoulders of giants. We Knowledge of these genes and func- created new therapies to treat have relied on the dedication of pioneers tion enabled the development and recent previously incurable diseases that have come before us to describe and approval of drugs for SMA, specifically In August 1921, the Journal of Neurology, detail the diseases under this umbrella. the antisense oligonucleotide nusinersen9 Neurosurgery and Psychiatry (JNNP) Their detailed descriptions, such as those and the gene therapy onasemnogene,8 published a case of recurrent hypertro- by Anita Harding and Peter (PK) Thomas both of which led to not only the achieve-
1 http://jnnp.bmj.com/ phic neuritis, which detailed the clinical describing Kennedy’s disease and inher- ment of motor milestones in children with course of a patient with a likely inherited ited neuropathies,5 6 have helped shape SMA, but also a reduction in mortality neuropathy. Although unknown in 1921, our understanding of variability within the for this previously universally fatal condi- this article foreshadowed the critical role same diseases. It is only by understanding tion. These critical clinical achievements that genetics would play in altering the phenotypes, whether they be based on have led to mandatory SMA gene testing course of neuromuscular diseases in the history, examination or pathology, that in over half of the USA and has turned a next 100 years. In fact, 98 years later patients with the same disease can be lethal neuromuscular disorder in infants JNNP published a review on periph- grouped into common entities. These into a treatable possibly curable condi- on September 28, 2021 by guest. Protected eral neuropathy in complex inherited 2 broad groupings then become important tion. Similarly, transthyretin (TTR) diseases. As a group of disorders, neuro- as they provide clues to additional features amyloidosis began with identification of muscular diseases include entities that that alter disease. For example, consider the underlying genetic cause and patho- affect muscle, the neuromuscular junc- spinal muscular atrophy (SMA). Children physiology and evolved into a disease tion, peripheral nerves, nerve roots and with SMA type 1 have the same genetic with multiple gene-based therapies. We motor neurons. At each location, genetic mutation in survival motor neuron protein have antisense oligonucleotide (ASO) alterations can result in severe disease, (SMN) as children with SMA type 2, but and RNA interference medications that resulting in mild-to-severe disability for the expression of the SMN2 gene deter- can halt or even reverse the neuropathy those carrying mutations. The progress mines disease phenotype. The wide range experienced by these patients.10 SMA and made in our understanding of the genetic of phenotypes from early to later onset TTR amyloidosis are only two examples aetiology of neuromuscular diseases in the serve as the cornerstone for therapeutic of neuromuscular therapeutics. There development.7 These early pioneers that are currently a large number of gene Neurology, University of Michigan, Ann Arbor, Michigan, USA steadfastly catalogued the range of signs therapy studies listed on ClinicalT rials.gov and symptoms, and did so in a time prior ranging from those for X-Linked Myotu- Correspondence to Dr Eva Feldman, Ann Arbor, Michigan, USA; efeldman@ umich.edu to computerised disease registries, were bular Myopathy (NCT03199469), Limb
Goutman SA, et al. J Neurol Neurosurg Psychiatry August 2020 Vol 91 No 8 791 2020 Vision J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2020-324327 on 14 July 2020. Downloaded from Girdle Muscular Dystrophy (LGMD) Have your say To cite Goutman SA, Callaghan BC, Feldman E. J Type 2C (NCT01344798), LGMD2D JNNP is asking readers to choose the Neurol Neurosurg Psychiatry 2020;91:791–792. (NCT01976091) and Becker Muscular most important or transformative devel- Received 19 June 2020 Dystrophy and Sporadic Inclusion Body opment in neurology, neurosurgery or Accepted 22 June 2020 Myositis (NCT01519349), to name a few. psychiatry in the past 100 years. To cast J Neurol Neurosurg Psychiatry 2020;91:791–792. These gene therapies are complimented your vote visit our website at https://jnnp. doi:10.1136/jnnp-2020-324327 by ASO studies for Duchenne Muscular bmj.com/pages/jnnp-100-a-centenary-of- ORCID iDs Dystrophy (NCT00159250), Myotonic publishing-neuroscience-achievement/. Stephen A Goutman http://orcid. org/0000- 0001-8780- Dystrophy Type 1 (NCT02312011), Voting closes on 15 August 2020. 6637 SOD1 Amyotrophic Lateral Sclerosis Brian Christopher Callaghan http://orcid. org/0000- (NCT02623699) and C9ORF72 ALS 0002-8885- 6748 Contributors SAG, BCC and EF were involved in all Eva Feldman http://orcid. org/0000- 0002-9162- 2694 (NCT04288856). Neuromuscular disor- aspects of the Editorial. ders leads the neurological community in Funding Support was provided by NIH NIEHS References using our new understanding of genetic K23ES027221 (SAG) and the NeuroNetwork for 1 Nattrass FJ. Recurrent hypertrophic neuritis. J Neurol inheritance to develop and implement Emerging Therapies at University of Michigan (BCC Psychopathol 1921;2:159–65. effective therapies. and ELF). 2 Rossor AM, Carr AS, Devine H, et al. Peripheral Competing interests SAG consults with Biogen neuropathy in complex inherited diseases: an approach to diagnosis. J Neurol Neurosurg Psychiatry The next 100 years and ITF Pharma. He also serves on an ALS DSMB via Watermark Research Partners. BCC consults for a 2017;88:846–63. What do the next 100 years hold? We PCORI grant, DynaMed, the Immune Tolerance Network 3 Kiernan MC. Milestones. J Neurol Neurosurg Psychiatry will leverage the knowledge gained by and performs medical legal consultations including 2019;90:1189. treating multiple patients with the same consultations for the Vaccine Injury Compensation 4 Kiernan MC. The Journal of Neurology, Neurosurgery mutation with the same drug to treat one Program. and Psychiatry centenary milestone award 2020. J Neurol Neurosurg Psychiatry 2020;91:677. patient with one genetic defect for a true Patient consent for publication Not required. 5 Harding AE, Thomas PK, Baraitser M, et al. X-Linked personalised approach to neuromuscular Provenance and peer review Commissioned; recessive bulbospinal neuronopathy: a report of ten diseases. Further, given the complexity internally peer reviewed. cases. J Neurol Neurosurg Psychiatry 1982;45:1012–9. of some neuromuscular diseases, we will 6 Harding AE, Thomas PK. Autosomal recessive forms harness the availability of new technology of hereditary motor and sensory neuropathy. J Neurol Neurosurg Psychiatry 1980;43:669–78. and large cohorts to find the polygenic 7 Wadman RI, Stam M, Gijzen M, et al. Association of causes of diseases where previously mono- motor milestones, SMN2 copy and outcome in spinal muscular atrophy types 0–4. J Neurol Neurosurg genetic causes were elusive. Next, we copyright. Psychiatry 2017;88:365–7. will better understand the interactions of Open access This is an open access article distributed 8 Kariyawasam D, Alexander IE, Kurian M, et al. in accordance with the Creative Commons Attribution our genes with the world around us—the Great expectations: virus-mediated gene therapy in 11 Non Commercial (CC BY-NC 4.0) license, which permits exposome. This deeper understanding neurological disorders. J Neurol Neurosurg Psychiatry others to distribute, remix, adapt, build upon this work will in turn allow better drug targeting for 2020;91:849–60. non-commercially, and license their derivative works on 9 Farrar MA, Teoh HL, Carey KA, et al. Nusinersen multiple genes as well as any genes that different terms, provided the original work is properly are impacted by environmental exposures, for SMA: expanded access programme. J Neurol cited, appropriate credit is given, any changes made Neurosurg Psychiatry 2018;89:937–42. a particularly relevant topic as our world indicated, and the use is non-commercial . See: http:// 10 Sekijima Y, Transthyretin SY. Transthyretin (ATTR) experiences the COVID-19 pandemic. creativecommons.org/ licenses/by- nc/4. 0/. amyloidosis: clinical spectrum, molecular pathogenesis These therapies bring hope and allow us © Author(s) (or their employer(s)) 2020. Re-use and disease-modifying treatments. J Neurol Neurosurg to envision a future where neurologists permitted under CC BY-NC. No commercial re-use. See Psychiatry 2015;86:1036–43. rights and permissions. Published by BMJ. 11 Goutman SA, Boss J, Patterson A, et al. High plasma http://jnnp.bmj.com/ both diagnose and provide life-altering concentrations of organic pollutants negatively impact therapies for neuromuscular patients of survival in amyotrophic lateral sclerosis. J Neurol all ages. Neurosurg Psychiatry 2019;90:907–12. on September 28, 2021 by guest. Protected
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