Spinal muscular atrophy type 1 (SMA1) is a rare neuromuscular disease that causes muscle weakness and atrophy. It is inherited in an autosomal recessive manner and is caused by a homozygous mutation or deletion in the survival motor neuron 1 (SMN1) gene.
Type 1 is the most severe form of SMA and carries a mortality rate of 50% at 2 years of life. The lethality of SMA1 lies in its ability to impair the function of the respiratory muscles, leading to respiratory distress and infections. The most important initial clinical sign of SMA1 is hypotonia, which can be observed in 60% of cases. In addition, it causes problems in the gastrointestinal system, resulting in dysphagia and aspiration pneumonia.
Diagnosis of SMA1 is greatly enhanced by neonatal screening for this disease, which is already routinely carried out in many countries. Neonatal screening offers the best opportunity for early detection and treatment. In fact, studies have shown that it is possible to begin treatment even before symptoms emerge, thus giving children the best chance for a normal course of neurodevelopment.
Read more about SMA epidemiology
Researchers from the University of Milan, Italy, recently conducted a review of what we know about the management of SMA1 and published their findings in Pediatrics Gastrointestinal Pain and Nutrition. The purpose of the review was to “provide the clinician with a practical and usable tool about SMA1 patient care,” according to the authors of the study.
The incredible progress in SMA1 therapeutics over the last few years is deeply encouraging, and a diagnosis of SMA1 in a child needs no longer be a definite death sentence. In fact, the thrust of medical progress in treating SMA1 is now to bring it into the realm of rare but manageable diseases, offering children the best shot at a relatively normal life.
But more work needs to be done. Here we will summarize a few key therapies highlighted by the authors of the study that are currently under investigation and may prove to be central to treating SMA1 in the future.
Improving Management of SMA1
Olesoxime is a steroid-like molecule that has yielded promising results in studies on mice. It works by delaying neuronal damage and glial activation. Studies in humans showed olesoxime was associated with greater neurological improvement and stability compared to the control.
Another approach to treating SMA1 is to take a closer look at existing drugs and to see if their use can be extrapolated to treating SMA1. One such class of drugs is those known to be neuroprotective. An example of this is docosahexaenoic acid (DHA), which is known to play a key role in neuroprotection and neuronal development. “An interesting starting point for future research will therefore be to evaluate whether, with the same basic treatment and starting clinical conditions, the use of neuroprotective therapies could improve neurological and muscular outcome,” the authors of the study wrote.
Nutritional modification could be another approach to treating SMA1. If effective, it would represent the least invasive (and least costly) form of management. Studies have suggested that a ketogenic diet can have a neuroprotective effect; it has already been demonstrated to be useful in drug-resistant epilepsy, Parkinson’s disease, Alzheimer’s disease, stroke, and trauma.
Read more about SMA therapies
How does a ketogenic diet confer neuroprotection? The jury is still out, but scientists have hypothesized that it creates an antioxidant and anti-inflammatory environment by helping axons develop resistance to metabolic challenges. If so, this diet is worth further investigation into its usefulness in treating SMA1 as well.
If therapies that promote neuroprotection deserve a closer look, then so do those that enhance muscular response. There are many drugs known to promote muscular function that have yet to be tested in earnest in treating SMA1. An example of this is tirasemtiv, a drug that increases the capacity for muscular contraction by slowing the release of calcium from muscle cells. Rodent studies indicate that it promotes exercise tolerance. This promising finding suggests it may be useful in treating SMA1 as well.
“It therefore becomes increasingly important to understand which therapies can be used in order to optimize the effect of disease modifying therapies and above all to ensure that the effect can last over time,” the authors of the study wrote. This neatly summarizes a path forward in SMA1 therapeutics: understanding what currently works for neuroprotection and muscular enhancement, and carrying out the necessary research to ascertain their crossover efficacy in treating SMA1.
Medical Innovation Driving Progress
If we can combine that approach with nutritional modification, as well as gastroenterological, metabolic, and endocrine management, we can finally achieve a truly multidisciplinary approach to treating SMA1. Indeed, the future of medicine, in any field and in any disease, is multidisciplinary. The challenge will be to work together across specialties to achieve something together that might not be possible separately.
Despite the poor prognosis of SMA1, recent developments in neonatal screening and a pivot from palliative therapy to targeted therapy mean we are making progress in treating this disease. Medical innovations in SMA1 therapeutics will offer children with this diagnosis the best chance at survival and a brighter future.
Corsello A, Scatigno L, Pascuzzi MC, et al. Nutritional, gastrointestinal and endo-metabolic challenges in the management of children with spinal muscular atrophy type 1. Nutrients. Published online July 13, 2021. doi:10.3390/nu13072400
Mercuri E, Pera MC, Scoto M, Finkel R, Muntoni F. Spinal muscular atrophy – insights and challenges in the treatment era. Nat Rev Neurol. 2020;16(12):706-715. doi:10.1038/s41582-020-00413-4