Natural history of infantile‐onset spinal muscular atrophy

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Spinal muscular atrophy (SMA) is the leading genetic cause of infant death with an incidence of 1 in 11,000 live births.1 Infantile‐onset or type 1 SMA is characterized by muscle weakness, respiratory insufficiency, and premature death.3 SMA is a recessive disorder caused by deletion or mutation in the SMN1 (survival motor neuron 1) gene and retention of one or more copies of a nearly identical gene, SMN2 (survival motor neuron 2), which results in reduced expression of full‐length SMN protein.5SMN2 differs from SMN1 by a nucleotide substitution that results in exclusion of exon 7 in approximately 90% of transcripts.7 The messenger RNA (mRNA) that results, SMNΔ7, produces a nonfunctional truncated protein targeted for degradation.9SMN2 copy number correlates inversely with clinical severity in humans and motor function and survival in murine models.11 An understanding of the molecular genetics, and the ability to produce faithful SMA animal models, has led to the development of small‐molecule, therapeutic antisense oligonucleotides (ASOs) and gene replacement therapies.15 Nusinersen, an ASO that alters SMN2 splicing to favor expression of full‐length SMN protein,17 was approved by the US Food and Drug Administration (FDA) in December 2016 and European Commission in June 2017 and is the first of many promising SMN disease‐modifying therapies.
To identify and compare effective therapies expeditiously requires accurate, reliable natural history data. Initial studies in SMA type 1 demonstrated shortened life span, with 68% mortality within the first 2 years of life.3 Standardized care guidelines19 have helped reduce mortality of SMA type 1 at age 2 years to 30%, but nearly half of these infants are dependent upon noninvasive ventilation.20 More recently, SMA infants with 2 copies of SMN2 and symptom onset preceding 6 months were shown to have poor motor function and significant motor unit loss electrophysiologically, with a median age of death (or at least 16 hours/day required noninvasive ventilation) at age 10.5 months.22 In a retrospective study, no SMA type 1 infants achieved major motor milestones such as rolling over or sitting independently.23 A critical challenge for the use of natural history data in infantile‐onset SMA is that data are often wholly or partially retrospective, are collected at one or a few specialty academic sites in a nonsystematic fashion, and have no comparison control group.
The National Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) SMA Infant biomarker Study was initiated in 2012 to describe and prospectively compare the natural history of motor function assessments during the first 2 years of life in SMA and healthy infants enrolled before age 6 months and to model the design of interventional studies in infantile‐onset SMA.24 In addition to creating novel data sets, a primary goal was to examine correlations between candidate physiological and molecular biomarkers with motor function scores to inform the use of these measures in future clinical trials and clinical management.
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