Annual Review of Genomics and Human Genetics

Abstract

Twenty-five years ago, the underlying genetic cause for one ofthe most com- mon 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 strate- gies, 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 pathophysiol- ogy 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 high- lighting the significant advances so far but also speculating about the future ofSMA screening and treatment. THE