Spinal muscular atrophy (SMA) is inherited in an autosomal recessive manner and is caused by abnormalities in the survival motor neuron 1 (SMN1) gene. The overwhelming majority of patients with SMA have a homozygous deletion of the gene; only 5% of cases have a heterozygous deletion and a point mutation.
“The SMN protein is critical for motoneuron development and maintenance, with highest levels of expression during fetal development and early postnatal period,” Servais and colleagues wrote in Expert Opinion on Investigational Drugs.
Throughout life, SMN expression is needed for the same purpose, albeit at lower levels. The lack of the SMN protein results in the characteristic motor weakness seen in patients with SMA. The quantity of SMN protein produced is driven by the amount of SMN2 copies an individual has. However, measurements of the number of SMN2 copies lack standardization, sometimes differing according to the laboratory in which investigations are carried out.
The phenotypic spectrum of SMA is wide and is best described as a continuum. Current classifications of SMA depend on the age of onset and motor milestones achieved. Over 50% of patients present with the severe phenotype of the disease, with symptom onset occurring within the first few months of life.
Read more about SMA etiology
The most severely impacted patients are characterized by a “floppy infant” presentation. These infants are often observed to have contractures and a reduction in spontaneous movements. Within 6 months, these patients are often diagnosed with dysphagia and respiratory insufficiency. Without medical intervention, they never acquire the skill to sit independently and have a median life expectancy of only 12 months.
There are 2 primary treatment strategies physicians pursue, almost always simultaneously: 1) the management of muscle weakness and decreased mobility and 2) therapies designed to increase the levels of the SMN protein.
“While being a monogenetic neuromuscular disease, the resulting phenotypic spectrum is complex and SMA is generally perceived as a systemic disease,” Schorling and colleagues wrote in the Journal of Neuromuscular Diseases. “Accordingly, caring for patients with SMA requires the interdisciplinary management of respiratory, nutritional and gastroenterological, orthopedic, and psychosocial issues.”
The severity of symptoms also depends largely on the age of symptom onset. Patients who begin experiencing symptoms before 6 months typically have the worst prognosis, as mentioned earlier. Patients who experience symptom onset between the ages of 6 and 18 months can typically sit but not walk. They also experience delays in motor development, difficulties in coughing, and scoliosis, as well as joint contractures.
If a patient with SMA experiences symptom onset between 18 months and 18 years, they are typically able to walk independently. However, they may experience variable levels of muscle weakness, joint contractures, and scoliosis. Patients who experience symptom onset after their 18th birthday are mostly able to walk independently, experiencing variable but mild muscle weakness.
This means the clinical manifestations in a patient with SMA can vary greatly, and physicians will benefit from taking a detailed medical history to gauge the spectrum of symptoms that have to be addressed.
The most common ways to manage the symptoms of SMA are twofold: physiotherapy to maximize mobility, and psychological/social support to deal with the emotional impact of the disease. Physicians from specialized disciplines may need to be involved if particular systems are pathologically affected.
Increasing Levels of SMN
Many treatment methods to increase levels of the SMN protein have been developed relatively recently.
Nusinersen was the first disease-modifying drug made available for the treatment of SMN. Its efficacy has been clearly demonstrated through a number of trials that indicate considerable efficacy in a wide range of patients. Importantly, nusinersen has been shown to improve the clinical outcomes in infants who received treatment prior to symptom onset.
Risdiplam, like nusinersen, modifies SMN2 pre-mRNA splicing. It differs from nusinersen in that it crosses the blood-brain barrier and is administered orally. It is approved by the US Food and Drug Administration (FDA) for use in pediatric patients older than 2 months of age.
Read more about SMA patient education
Gene replacement therapy is also the subject of intense research in the treatment of SMA. It is an intuitive therapeutic approach, given that the genetic components of the disease have been well-established.
Onasemnogene abeparvovec, a gene therapy, “is a recombinant self-complimentary adeno-associated virus serotype 9 (scAAV9) vector carrying cDNA that encodes a fully functional human SMN protein,” Servais and colleagues explained.
This drug works rather elegantly. Once the vector enters into cells and is translocated into the nucleus, SMN protein expression is kickstarted. Intravenous injections allow it to cross the blood-brain barrier and interact with motoneurons in the central nervous system. This allows SMN to be ubiquitously expressed throughout the body. Onmasnogene abeparvovec is approved by the FDA for use in pediatric patients under 2 years of age.
This two-pronged strategy of symptomatic relief and increasing SMN levels is the standard of care for SMA today, but their therapeutic implications are limited because they do not represent a cure. However, having a strategy is better than none, and the introduction of powerful disease-modifying drugs such as nusinersen continues to change patient outcomes for the better.
Schorling DC, Pechmann A, Kirschner J. Advances in treatment of spinal muscular atrophy – new phenotypes, new challenges, new implications for care. J Neuromuscul Dis. 2020;7(1):1-13. doi:10.3233/JND-190424
Servais L, Baranello G, Scoto M, Daron A, Oskoui M. Therapeutic interventions for spinal muscular atrophy: preclinical and early clinical development opportunities. Expert Opin Investig Drugs. 2021;30(5):519-527. doi:10.1080/13543784.2021.1904889