Newborn screening · Other inherited disorder
Spinal Muscular Atrophy · SMA
SMN1 deletion. Three approved disease-modifying therapies. Pre-symptomatic treatment changes the disease.
Description
Spinal muscular atrophy, SMA, is an autosomal recessive motor neuron disorder caused by loss of function of the SMN1 gene on chromosome 5q13. SMN1 encodes the survival motor neuron protein, which is required for the assembly of small nuclear ribonucleoproteins and for the maintenance of alpha motor neurons in the anterior horn of the spinal cord. Without sufficient SMN protein, motor neurons degenerate, and the muscles they innervate become progressively weak and atrophic.
A nearly identical paralogous gene, SMN2, sits next to SMN1 on the same chromosome. SMN2 differs from SMN1 by a single nucleotide that disrupts splicing of exon 7, so most SMN2 transcripts produce a truncated, unstable protein and only a small fraction produce full-length SMN. The number of SMN2 copies a person carries, ranging from 0 to 4 or more, modifies disease severity. More SMN2 copies generally produce more functional SMN protein and a milder phenotype.
The historical clinical classification runs from type 0, with prenatal onset and severe weakness at birth, through type 1, with onset before 6 months and inability to sit unsupported, type 2, with onset between 6 and 18 months and inability to stand or walk unaided, type 3, with onset after 18 months and ambulation that may be lost over years, and type 4, adult onset. Type 1 is historically the most common severe form and, untreated, leads to death or permanent ventilation by age 2 in most children. Approximately 95 percent of SMA cases result from homozygous deletion of SMN1 exon 7; the remainder carry small intragenic SMN1 variants. Live-birth incidence is approximately 1 in 10,000.
Detection is by newborn screening on the dried blood spot using a PCR assay for homozygous SMN1 exon 7 deletion. SMA was added to the Recommended Uniform Screening Panel in July 2018. Confirmatory testing reports SMN1 status and SMN2 copy number, which guides treatment urgency and informs prognosis.
Treatments to date
Three disease-modifying therapies are FDA approved. Nusinersen, an antisense oligonucleotide that promotes inclusion of SMN2 exon 7 to increase full-length SMN protein, was approved in December 2016 under the brand name Spinraza. It is delivered by intrathecal injection on a loading and maintenance schedule. The pivotal infant trial, ENDEAR, reported by Finkel and colleagues in the New England Journal of Medicine in 2017, showed improved motor milestone achievement and survival in symptomatic type 1 infants compared with sham control.
Onasemnogene abeparvovec, a one-time intravenous AAV9-delivered SMN1 gene replacement therapy, was approved by the FDA in May 2019 under the brand name Zolgensma for children under 2 years of age. The pivotal study, STR1VE, reported by Day and colleagues in Lancet Neurology in 2021, showed event-free survival and motor function gains substantially above natural history in type 1 infants treated under 6 months. Risdiplam, an oral small-molecule SMN2 splicing modifier, was approved by the FDA in August 2020 under the brand name Evrysdi for SMA at any age and was extended to infants under 2 months in 2022.
Outcomes depend on when treatment starts. Pre-symptomatic treatment delivered through newborn screening produces the largest functional gains. The NURTURE study of pre-symptomatic nusinersen, reported by De Vivo and colleagues in Neuromuscular Disorders in 2019, showed that infants with two SMN2 copies, the genotype that predicts type 1 disease, sat, stood, and walked when treated before symptoms appeared. These milestones are almost never observed in untreated type 1.
Multidisciplinary care continues alongside disease-modifying therapy. Pulmonary support, nutrition and feeding management, orthopedic surveillance for scoliosis and contractures, and physical and occupational therapy are coordinated through neuromuscular clinics, with intensity calibrated to the child's trajectory after treatment.