Spinal Muscular Atrophy (SMA) type 3, also known as Kugelberg Welander disease1, is diagnosed in fewer than 20% of patients with childhood-onset SMA.2 Patients with SMA type 3 typically will experience an insidious onset of leg weakness after they achieve independent ambulation.3
Zerres and colleagues in a 1995 publication4 noted the existence of two distinct forms of type 3 SMA, designated 3-A and 3-B; their observation was affirmed by The European Neuro Muscular Center (ENMC) International Workshop held in 2014.5 The distinguishing features between these two subtypes of type 3 SMA are age of onset and severity. Patients with SMA subtype 3-A experience segmental distal weakness and a developmental plateau beginning before 3 years of age whereas patients with SMA subtype 3-B will have an onset of segmental proximal sometime between age 3 and age 10 years old.5,6 Though patients with subtype 3-A SMA can walk, their lower extremity strength and dexterity will be poor compared to patients with subtype 3-B SMA, who may have sufficient lower extremity function to be able to play competitive sports.5 The ability to climb stairs may differentiate children with subtype 3-A from those with subtype 3-B.7 Puberty appears to be when significant motor function loss occurs in all patients with type 3 SMA, and patients with subtype 3-A may lose all ambulation ability during this time.8
The genetic basis for the difference between SMA subtypes 3-A and 3-B appears to be related to the retention of the NAIP gene and increased copy numbers of SMN2 gene in patients with subtype 3-B.7,9
Patients with type 3 SMA are expected to have a normal lifespan, and a U.S. database of SMA patients confirms the existence of patients in their sixth decade and beyond,2 but there are longitudinal differences in motor ability between subtypes 3-A and 3-B. Patients with SMA 3-B have approximately a two-fold greater likelihood of retaining ambulation at ages 20 and 40 years compared to patients with subtype 3-A.4Â Adult patients with subtype 3-B SMA may report reduced endurance and gait changes more than true weakness.10
References
1. 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.
2. 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.
3. Zerres K, Rudnik-Schoneborn S. Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications. Archives of neurology. 1995;52(5):518-523.
4. 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.
5. Gdynia HJ, Sperfeld AD, Flaith L, et al. Classification of phenotype characteristics in adult-onset spinal muscular atrophy. European neurology. 2007;58(3):170-176.
6. 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.
7. Montes J, McDermott MP, Mirek E, et al. Ambulatory function in spinal muscular atrophy: Age-related patterns of progression. PLoS One. 2018;13(6):e0199657.
8. 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.
9. Piepers S, van den Berg LH, Brugman F, et al. A natural history study of late onset spinal muscular atrophy types 3b and 4. J Neurol. 2008;255(9):1400-1404.