Spinal Muscular Atrophy (SMA) type 1, also known as Werdnig-Hoffmann disease, is the most common diagnosed form of SMA, accounting for approximately half of all patients with SMA.1 SMA type 1 is a degenerative neuromuscular condition and without life-prolonging interventions such as mechanical ventilation, this form of SMA is nearly universally fatal before age 2 years.2
There are several ratings systems to categorize phenotypes in type 1 SMA.3 The goal of these systems had been to provide prognostic information to clinicians and families, but, with the advent of approved therapies for SMA, investigators are using these classifications to determine whether there are different therapeutic windows within the SMA subtypes.4,5
There are three subtypes of type 1 SMA (subtypes 1A-C) currently recognized by an international consortium of neuromuscular experts, and these subtypes correspond to the observed ages of onset of weakness observed in patients, from birth through 6 months of age.6 An alternative sub classification system advanced by Mercuri et al., which also utilizes 1A-1C nomenclature, combines age of onset and achievement of head control as the differentiating factors between patient groupings.3 Dubowitz proposed a classification system for SMA that utilizes a decimal system with nine subtypes (1.1-1.9),7 but collapsing this more complicated rating scheme into the other three category systems is common.4,6
The most severe form of type 1 SMA, subtype 1A, is apparent within the first two weeks of infancy, if not at birth.6 Infants with SMA type 1A have global weakness, profound hypotonia, feeding difficulties, and respiratory insufficiency.6 These infants will not make any significant motor milestone gains and will have the shortest lifespan of SMA type 1 patients.8 In the sub classification scheme proposed by Mercuri et al., an infant with subtype 1A will experience neonatal onset and will not acquire head control.3
Patients with the 1B subtype of SMA type 1 will experience an onset of severe generalized weakness and hypotonia by age 3 months.6 The patients with type 1B will often have the bell-shaped thorax and paradoxical breathing pattern caused by accessory muscle use to compensate for chest wall muscle weakness.6 Patients with type 1B may experience some motor development but will not roll or sit without support.6,9 The Mercuri et al. SMA 1B sub classification stipulates an onset after the neonatal period and absence of head control.
The 1C subtype of SMA features general weakness with more proximal involvement that is greatest in the lower extremities.6 The onset of signs and symptoms in subtype 1C will be after 3 months and usually before 6 months of age.6 Motor development may occur in patients with SMA 1C, but these patients will never sit unsupported.10 The SMA 1C sub classification proposed by Mercuri and colleagues states that these patients with SMA will experience an onset of weakness after the neonatal period, and, unlike other subtypes of type 1 SMA, these children will acquire good head control.3
The genetic basis for the differences between the patients with subtypes 1A-1C appears to be related to the copy number of the protective SMN2 gene, but the copy number of SMN2 is not entirely predictive of subtype so other factors have a role in determining age of onset and severity.4,10
References
1. D’Amico A, Mercuri E, Tiziano FD, Bertini E. Spinal muscular atrophy. Orphanet journal of rare diseases. 2011;6:71.
2. 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.
3. Mercuri E, Bertini E, Iannaccone ST. Childhood spinal muscular atrophy: controversies and challenges. The Lancet Neurology. 2012;11(5):443-452.
4. De Sanctis R, Pane M, Coratti G, et al. Clinical phenotypes and trajectories of disease progression in type 1 spinal muscular atrophy. Neuromuscular disorders : NMD. 2018;28(1):24-28.
5. Tizzano EF, Finkel RS. Spinal muscular atrophy: A changing phenotype beyond the clinical trials. Neuromuscular disorders : NMD. 2017;27(10):883-889.
6. 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.
7. Dubowitz V. Chaos in the classification of SMA: a possible resolution. Neuromuscular disorders : NMD. 1995;5(1):3-5.
8. De Sanctis R, Coratti G, Pasternak A, et al. Developmental milestones in type I spinal muscular atrophy. Neuromuscular disorders : NMD. 2016;26(11):754-759.
9. Kolb SJ, Kissel JT. Spinal Muscular Atrophy. Neurologic clinics. 2015;33(4):831-846.
10. Finkel RS, McDermott MP, Kaufmann P, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014;83(9):810-817.