Spinal Muscular Atrophy: Prognosis

Spinal Muscular Atrophy: Prognosis

The disease course and prognosis of spinal muscular atrophy (SMA) depends heavily on the clinical classification in a particular patient. For example, the prognosis of children with SMA type 0 is very poor while the prognosis in SMA type 4 patients is relatively good. When discussing prognosis with patients, healthcare providers should consider that prognosis is, at its heart, just a guess. Nonetheless, there has been considerable research about the natural history of SMA1,2 such that one can confidently discuss these delicate and important issues with patients and caregivers. 

As mentioned, the prognosis for children with type 0 SMA is quite poor. Symptoms begin before birth and children with this form of the disease require respiratory support at the time of delivery. They are never able to sit, stand, or walk, and their life expectancy is less than six months.1 

In children with SMA type 1, symptoms usually emerge before six months of age. Like type 0, children with SMA type I are not expected to sit, stand, or walk at any point in their lives. Moreover, average life expectancy in this group is less than two years.1 The age of symptom onset correlates with life expectancy, i.e. The earlier that symptoms first present, the shorter the child’s life expectancy is.3,4,5  The number of SMN2 gene copies is a strong predictor of survival in children with SMA type I; children with two copies of the gene deteriorate more rapidly than children with three copies do.3,6 On the other hand, supportive care can prolong survival in these patients. For instance, nutritional support and early non-invasive ventilation measures such as bi-level positive airway pressure can increase survival substantially.5,7,8 To obtain this survival benefit, however, children in this group often become dependent upon a gastrostomy tube and non-invasive ventilation/ventilator support via a tracheostomy interface.2

Patients with type 2 SMA exhibit symptoms between six and 18 months of age. Children in this group are generally expected to be able to sit, but will generally not be able to stand or walk. Life expectancy in this group is highly variable, but generally much longer than in children with more severe forms of the disease.2 Indeed, most patients with type 2 SMA live into their third decade2 with median life expectancy beyond age 40.9

Patients with type 3 or type 4 SMA live into adulthood. Researchers have reported a 100% survival rate at age 409, suggesting an essentially normal life span.10 Patients with type 3 SMA are able to sit and stand without assistance. In type 3 patients, a discussion of prognosis is less about survival and more about the ability to ambulate.  Zerres and colleagues studied the probability of becoming ambulatory in type 3 SMA patients.10 They divided the cohort into SMA Type IIIa and SMA Type IIIb. For the purposes of this study, SMA Type IIIa patients are those who had disease onset before the age of three and SMA Type IIIb patients were those who had their first symptoms after the age of three. The probability that SMA Type IIIa patients will walk at 10 years after disease onset is 70.3% and 22% at age 40. On the other hand, the probability that SMA Type IIIb will walk at 10 years after the onset of SMA is 96.3% and 58.7% at age 40.10

Patients with type 4 SMA have symptoms that emerge in adulthood. They live relatively normal lives and are able to sit, stand, and walk without assistance.

An important caveat is the natural history and prognostic data described above were collected before the widespread use of disease-modifying therapy, nusinersen (Spinraza). Currently there is insufficient data to show whether nusinersen broadly changes the survival trajectory of patients with SMA; however, the clinical trials performed pursuant to FDA approval of the medication should be considered.  Nusinersen-treated children with infantile SMA (most likely SMA Type 1) had a 47% reduction in the risk of death or permanent ventilation compared to control (p=0.005). Moreover, nusinersen treatment was associated with a 63% reduction in the risk of death compared to sham treatment during the ~60 week trial period (16% vs. 39%; ITT population; p=0.004).11 

References

1. Butchbach MER. Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases. Frontiers in Molecular Biosciences. 2016;3:7. doi:10.3389/fmolb.2016.00007 

2. Finkel RS, Sejersen T, Mercuri E, et al. 218th Enmc International Workshop:: Revisiting the Consensus on Standards of Care in Sma Naarden, the Netherlands, 19–21 February 2016. Neuromuscular Disorders. 2017;27(6):596-605. 

3. Rudnik-Schöneborn S, Berg C, Zerres K, et al. Genotype–Phenotype Studies in Infantile Spinal Muscular Atrophy (Sma) Type I in Germany: Implications for Clinical Trials and Genetic Counselling. Clinical Genetics. 2009;76(2):168-178. doi:doi:10.1111/j.1399-0004.2009.01200.x 

4. Ge X, Bai J, Lu Y, Qu Y, Song F. The Natural History of Infant Spinal Muscular Atrophy in China:A Study of 237 Patients. Journal of Child Neurology. 2012;27(4):471-477. doi:10.1177/0883073811420152 

5. Ioos C, Leclair-Richard D, Mrad S, Barois A, Estournet-Mathiaud B. Respiratory Capacity Course in Patients with Infantile Spinal Muscular Atrophy. Chest. 2004;126(3):831-837. doi:https://doi.org/10.1378/chest.126.3.831 

6. 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. doi:10.1212/wnl.0000000000000741 

7. Chung BHY, Wong VCN, Ip P. Spinal Muscular Atrophy: Survival Pattern and Functional Status. Pediatrics. 2004;114(5):e548-e553. doi:10.1542/peds.2004-0668 

8. Park HB, Lee SM, Lee JS, et al. Survival Analysis of Spinal Muscular Atrophy Type I. Korean J Pediatr. 2010;53(11):965-970. doi:10.3345/kjp.2010.53.11.965 

9. Farrar MA, Vucic S, Johnston HM, du Sart D, Kiernan MC. Pathophysiological Insights Derived by Natural History and Motor Function of Spinal Muscular Atrophy. The Journal of Pediatrics. 2013;162(1):155-159. doi:https://doi.org/10.1016/j.jpeds.2012.05.067 

10. Zerres K, Rudnik-Schöneborn S, Forrest E, Lusakowska A, Borkowska J, Hausmanowa-Petrusewicz I. A Collaborative Study on the Natural History of Childhood and Juvenile Onset Proximal Spinal Muscular Atrophy (Type Ii and Iii Sma): 569 Patients. Journal of the Neurological Sciences. 1997;146(1):67-72. doi:https://doi.org/10.1016/S0022-510X(96)00284-5 

11. Finkel RS, Mercuri E, Darras BT, et al. Nusinersen Versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017;377(18):1723-1732. doi:10.1056/NEJMoa1702752