title: Spinal muscular atrophy: from gene discovery to clinical trials.
abstract: Spinal muscular atrophy (SMA) is a common neuromuscular disorder with autosomal recessive inheritance, resulting in the degeneration of motor neurons. The incidence of the disease has been estimated at 1 in 6000-10,000 newborns with a carrier frequency of 1 in 40-60. SMA is caused by mutations of the SMN1 gene, located on chromosome 5q13. The gene product, survival motor neuron (SMN) plays critical roles in a variety of cellular activities. SMN2, a homologue of SMN1, is retained in all SMA patients and generates low levels of SMN, but does not compensate for the mutated SMN1. Genetic analysis demonstrates the presence of homozygous deletion of SMN1 in most patients, and allows screening of heterozygous carriers in affected families. Considering high incidence of carrier frequency in SMA, population-wide newborn and carrier screening has been proposed. Although no effective treatment is currently available, some treatment strategies have already been developed based on the molecular pathophysiology of this disease. Current treatment strategies can be classified into three major groups: SMN2-targeting, SMN1-introduction, and non-SMN targeting. Here, we provide a comprehensive and up-to-date review integrating advances in molecular pathophysiology and diagnostic testing with therapeutic developments for this disease including promising candidates from recent clinical trials.
authors.affiliation: Department of Community Medicine and Social Health Care, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Dian K
authors.initials: DK
authors.lastname: Nurputra
authors.forename: Poh San
authors.initials: PS
authors.lastname: Lai
authors.forename: Nur Imma F
authors.initials: NI
authors.lastname: Harahap
authors.forename: Satoru
authors.initials: S
authors.lastname: Morikawa
authors.forename: Tomoto
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Nishimura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kubo
authors.forename: Atsuko
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Toshio
authors.initials: T
authors.lastname: Saito
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takeshima
authors.forename: Yumi
authors.initials: Y
authors.lastname: Tohyama
authors.forename: Stacey K H
authors.initials: SK
authors.lastname: Tay
authors.forename: Poh Sim
authors.initials: PS
authors.lastname: Low
authors.forename: Kayoko
authors.initials: K
authors.lastname: Saito
authors.forename: Hisahide
authors.initials: H
authors.lastname: Nishio
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D018628:Gene Dosage; D005820:Genetic Testing; D006801:Humans; D009134:Muscular Atrophy, Spinal / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy*; D009154:Mutation; D055532:SMN Complex Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D055532:SMN Complex Proteins
keywords: Spinal muscular atrophy (SMA); clinical trials; diagnosis; survival motor neuron (SMN)