Twenty-Five Years of Spinal Muscular Atrophy Research: From Phenotype to Genotype to Therapy, and What Comes Next

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...

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Bibliographic Details
Published in:Annual review of genomics and human genetics 2020-08, Vol.21 (1), p.231-261
Main Authors: Wirth, Brunhilde, Karakaya, Mert, Kye, Min Jeong, Mendoza-Ferreira, Natalia
Format: Article
Language:English
Subjects:
Animal models
Antisense oligonucleotides
Copy number
Disease
Gene regulation
Gene therapy
Genetic variability
Genotype & phenotype
Genotypes
Hereditary diseases
Infants
modifiers
neuromuscular disorder
newborn screening
Pathophysiology
phenotype-genotype correlation
Phenotypes
SMN protein
Spinal muscular atrophy
survival of motor neuron gene
therapy
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Summary: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.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.
ISSN:1527-8204
1545-293X
DOI:10.1146/annurev-genom-102319-103602