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Twenty-Five Years of Spinal Muscular Atrophy Research: From Phenotype to Genotype to Therapy, and What Comes Next Brunhilde Wirth, Mert Karakaya, Min Jeong Kye, and Natalia Mendoza-Ferreira Institute of Human Genetics, Center for Molecular Medicine Cologne and Center for Rare Diseases, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany; email: brunhilde.wirth@uk-koeln.de Annu. Rev. Genom. Hum. Genet. 2020. 21:231–61 First published as a Review in Advance on January 31, 2020 The Annual Review of Genomics and Human Genetics is online at genom.annualreviews.org https://doi.org/10.1146/annurev-genom-102319- 103602 Copyright © 2020 by Annual Reviews. All rights reserved Keywords spinal muscular atrophy, neuromuscular disorder, survival of motor neuron gene, therapy, phenotype–genotype correlation, modifiers, animal models, newborn screening, antisense oligonucleotides, gene therapy Abstract Twenty-five years ago, the underlying genetic cause for one of the most common and devastating inherited diseases in humans, spinal muscular atrophy (SMA), was identified. Homozygous deletions or, rarely, subtle mutations of SMN1 cause SMA, and the copy number of the nearly identical copy gene SMN2 inversely correlates with disease severity. SMA has become a paradigm and a prime example of a monogenic neurological disorder that can be efficiently ameliorated or nearly cured by novel therapeutic strategies, such as antisense oligonucleotide or gene replacement therapy. These therapies enable infants to survive who might otherwise have died before the age of two and allow individuals who have never been able to sit or walk to do both. The major milestones on the road to these therapies were to understand the genetic cause and splice regulation of SMN genes, the disease’s phenotype–genotype variability, the function of the protein and the main affected cellular pathways and tissues, the disease’s pathophysiology through research on animal models, the windows of opportunity for efficient treatment, and how and when to treat patients most effectively. 231 Annu. Rev. Genom. Hum. Genet. 2020.21:231-261. Downloaded from www.annualreviews.org Access provided by 2600:1700:3c30:a3d0:89dc:b3d1:ac73:5085 on 01/23/22. For personal use only. This review aims to bridge our knowledge from phenotype to genotype to therapy, not only highlighting the significant advances so far but also speculating about the future of SMA screening and treatment. THE PHENOTYPE OF SPINAL MUSCULAR ATROPHY Description and Classification Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by degeneration of alpha motor neurons in the anterior horn of the spinal cord. The characteristic symptoms are hypotonia, muscular atrophy, and weakness of proximal muscles, predominantly affecting the lower extremities. Before therapies were developed, SMA was classified into three main types (types I–III) based on the age of onset and achieved motor milestones (127). The emergence of additional phenotypes broadened this classification to include congenital (type 0) (43) and adult onset (type IV) (190). However, this classification delivers cross-sectional information and does not adequately address the dynamic changes in the clinical picture after treatment. Emerging therapeutic options and adjacent clinical trials accelerated improvements in natural history studies and led to an update of the consensus statement (54, 118, 178). Today, overlaps among SMA types are commonly observed. Furthermore, because the predictive value of a classification based solely on motor assessment at the initial
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