The Pathophysiology of Spinal Muscular Atrophy (SMA)
Diana Castro, MD, founder of the Neurology Rare Disease Center in Dallas, Texas discusses the pathophysiology of spinal muscular atrophy (SMA).
SMA is a rare inherited neuromuscular disorder caused by an inadequate level of the survivor motor neuron (SMN) protein due to mutations in the SMN1 gene. The SMN protein appears to play a role in regulating small nuclear ribonucleoproteins complexes, and while its exact function remains unclear, the absence of the SMN protein leads to cellular imbalances in motor neurons that in turn causes the motor neuron endplates to not properly connect to muscle and the motor neurons die.
Interestingly, there is more than one gene that encodes for the SMN protein. The predominate gene responsible for producing SMN protein is the SMN1 gene. However, there is a second gene, SMN2 gene, that can also produce a form of SMN protein. The presence (or absence) of this second gene play an important role in the severity of the SMA symptoms (see Table 1).
Table: SMA Subtypes
| SMA type | Onset | Number of SMN2 gene copies |
| 0 (or IA) | Prenatal | 1 |
| IB | <3 months | 2 |
| IC | >3 months | 3 |
| II | >6 months | 3 |
| IIIA | 18 – 36 months | 3 |
| IIIB | >3 years | 3-4 |
| 4 | >10 – 20 years | 4 |
SMA is a progressive disorder. Therefore, the sooner a person with SMA can be diagnosed and be given proper treatment, the better the chances they have of maintaining a certain level of activity and quality of life.
Once a person has been diagnosed with SMA—often by newborn screening—there are several approved treatments available to delay (nusinersen, risdiplam) or possibly stop (onasemnogene abeparvovec-xioi) disease progression.
For more information about SMA and other rare neuromuscular disorders, visit checkrare.com/diseases/musculoskeletal-diseases.
