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presentation is limited (147), the classical classification of SMA is becoming less practical for current clinical studies. To ensure the consistency and uniformity of outcome measures and therapy follow-up, it has been recommended to reclassify the patients as nonsitters, sitters, and walkers (54, 118, 178). This approach acknowledges the SMA phenotype as a continuum and focuses on the current functional status and the therapy response (14, 118, 178). Nevertheless, we recognize that no classification perfectly covers each presentation and disease course of SMA. Nonsitters. The majority of nonsitters have SMA type I. However, independently sitting individuals with disease onset after six months (type II) may lose that skill and revert to the nonsitter group (Figure 1). Bulbar and intercostal muscles are usually affected, resulting in feeding difficulties and respiratory insufficiency with a bell-shaped thorax deformity. The diaphragm is usually spared and is dominantly involved in paradoxical breathing. The involvement of tongue muscles often presents with fasciculations. Facial muscles are not usually affected, except in some individuals with congenital onset. On examination, the vertical suspension test reveals an absent hip flexion, a slip-down through the examiner’s hands, and a head lag due to neck flexion weakness. In the supine position, infants show a frog-leg posture and absent head control on traction (130). Nutritional and respiratory support has significantly reduced mortality in the past two decades. Despite prolonged survival after these supportive measures, affected infants do not achieve any further motor milestones and remain nonsitters (37). Sitters. This group includes type II individuals and nonambulatory type III individuals (Figure 1). They achieve sitting without help at any point in their development but either are not able to walk freely or lose the ability to walk. They exhibit generalized muscular hypotonia and weakness in the first months of life. The proximal muscular weakness is more profound in the legs than in the arms. Over time, they develop joint contractures and mandible ankyloses. Sitters frequently develop scoliosis from sitting in an upright position with weak axial muscles, and without any supportive measures, scoliosis and intercostal muscle weakness may lead to restrictive lung disease and respiratory insufficiency (130). The disease progresses between 5 and 15 years of age, especially 232 Wirth et al. Annu. Rev. Genom. Hum. Genet. 2020.21:231-261. Downloaded from www.annualreviews.org Access provided by 2600:1700:3c30:a3d0:89dc:b3d1:ac73:5085 on 01/23/22. For personal use only. 10% Type 0 0 20 40 60 80 100 1 2 3 4 >4 1 2 3 4 >4 1 2 3 4 >4 1 2 3 4 >4 Original SMA classification Nonsitters Sitters Walkers New SMA classification 7% 73% 20% <1%T transition at position +6 in exon 7 (c.840C>T) is within the coding region (Figure 2). However, it is a silent variant that causes no amino acid exchange. The remaining variants reported so far cannot be uniquely assigned to one of the two SMN copies. Two long noncoding RNAs are transcribed from the SMN locus. The antisense transcript SMN-AS1 is 1.6 kb in length and localized in intron 1, and SMN-AS2 starts in exon 8 and ends in intron 5. Both transcripts downregulate the expression of SMN (34, 187). Splicing of SMN Genes SMN1 is nearly always correctly spliced and produces full-length transcripts and protein. SMN2, by contrast, produces mainly alternatively spliced transcripts lacking exon 7 (SMN2); only approximately 10% are correctly spliced SMN2 transcripts that contain all exons and produce a fulllength protein (68, 100). Moreover, both SMN1 and SMN2 produce a small amount of transcripts lacking exon 3, exon 5, or both (58). SMN exon 7 spans 54 nucleotides and harbors a stop codon at nucleotide positions 49–51. The region encoded by exon 7 is crucial for protein oligomerization and function. Consequently, exon 7 and the surrounding introns are fully packed with cis-regulatory domains [exonic splicing enhancers (ESEs) and intronic splicing enhancers] that facilitate exon 7 inclusion in SMN1 and, to a lesser extent, SMN2. However, these domains compete against exonic splicing silencers and
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