Spinal Muscular Atrophy (SMA) is a congenital neuromuscular disorder characterized by progressive muscle atrophy and weakness.1 Investigators generally classify SMA into types 1-3 based on age of onset and severity of disease, specifically the degree to which weakness impedes motor function.2 Approximately one third of patients with SMA have SMA type 2.3,4 The defining criterion for type 2 form of SMA is that children with type SMA 2 will not ever stand unassisted or ambulate without support, though they may achieve the ability to sit independently.4
As researchers learned more about the natural history of SMA, it became clear that there might be distinct sub-populations within the broader SMA types.5 In type 2 SMA, there are several proposed parsing schema for subtyping, the existence of which are largely driven by a need for outcome determinations for clinical trials.4 However, unlike SMA types 1 and 3, the most recent European Neuro Muscular Center (ENMC) International Workshop on Outcome Measures designates SMA type 2 as a single group without subtypes.5
International panels of experts and other investigators have divided SMA type 2 patients into “sitter” and “non-sitter” groups, corresponding to the patients’ ability to sit by as measured by clinical observation or by standardized motor scoring scales such as the Motor Function Measure (MFM).6,7 This observational classification is problematic because some type 2 patients will lose the ability to sit as SMA progresses.8 Furthermore, because of the heterogeneity in the ages at which children with SMA will achieve motor milestones, longer observation periods of type 2 patients may result in patients achieving new abilities and obligating reclassification from type 2 to type 3.9
Alternatively, investigators observing a cohort of Japanese children with SMA noted that type 2 SMA could be meaningfully differentiated based on the achievement of sitting independently at > 8 months of age (type 2A) or at ≤ 8 months of age (type 2B).4 Earlier sitting (i.e., SMA type 2B) predicted better motor function overall, higher quality of life, and was correlated with significantly higher copy numbers of the protective SMN2 gene.4 However, a phenotype-genotype correlation in type 2 SMA is not an entirely novel finding,10 and therefore it remains to be seen if the proposed 2A and 2B distinction has broader relevance and utility.
References
1. Darras BT. Spinal muscular atrophies. Pediatric clinics of North America. 2015;62(3):743-766.
2. Tizzano EF, Finkel RS. Spinal muscular atrophy: A changing phenotype beyond the clinical trials. Neuromuscular disorders : NMD. 2017;27(10):883-889.
3. Belter L, Cook SF, Crawford TO, et al. An overview of the Cure SMA membership database: Highlights of key demographic and clinical characteristics of SMA members. J Neuromuscul Dis. 2018;5(2):167-176.
4. Kaneko K, Arakawa R, Urano M, Aoki R, Saito K. Relationships between long-term observations of motor milestones and genotype analysis results in childhood-onset Japanese spinal muscular atrophy patients. Brain Dev. 2017;39(9):763-773.
5. Finkel R, Bertini E, Muntoni F, Mercuri E. 209th ENMC International Workshop: Outcome Measures and Clinical Trial Readiness in Spinal Muscular Atrophy 7-9 November 2014, Heemskerk, The Netherlands. Neuromuscular disorders : NMD. 2015;25(7):593-602.
6. Wang CH, Finkel RS, Bertini ES, et al. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007;22(8):1027-1049.
7. Chabanon A, Seferian AM, Daron A, et al. Prospective and longitudinal natural history study of patients with Type 2 and 3 spinal muscular atrophy: Baseline data NatHis-SMA study. PLoS One. 2018;13(7):e0201004.
8. Kaufmann P, McDermott MP, Darras BT, et al. Prospective cohort study of spinal muscular atrophy types 2 and 3. Neurology. 2012;79(18):1889-1897.
9. Rudnik-Schoneborn S, Hausmanowa-Petrusewicz I, Borkowska J, Zerres K. The predictive value of achieved motor milestones assessed in 441 patients with infantile spinal muscular atrophy types II and III. European neurology. 2001;45(3):174-181.
10. Watihayati MS, Fatemeh H, Marini M, et al. Combination of SMN2 copy number and NAIP deletion predicts disease severity in spinal muscular atrophy. Brain Dev. 2009;31(1):42-45.