Every movement our body makes is controlled by a long, thin, tube-like structure called the “spinal cord”. The spinal cord is part of our nervous system, and it connects our brain to our lower back. It is composed of motor nerve cells that carry signals between the brain and nerves throughout our body, thereby controlling movements and sensations such as pain [1].
Spinal muscular atrophy (SMA) is characterized by the irreversible loss of motor nerve cells, leading to the muscles’ inability to receive signals to move and gradual weakening [2]. SMA ranks as the second most fatal autosomal recessive disorder in children, following only cystic fibrosis [3]. In this article, we will explore the genetics of SMA, currently available treatments, diagnosis, and promising prospects for diagnosing SMA early which can drastically change the course of the disease.
Contents
What is Spinal Muscular Atrophy (SMA)?
Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder affecting life quality and life expectancy. Even though historically, SMA has been the primary genetic cause of infant mortality, the many therapies for SMA which have recently been approved or are in clinical development are expected to increase and improve the lifespan of SMA patients [4].
What causes SMA?
SMA is caused by changes in the Survival Muscular Atrophy genes, SMN1 and SMN2, which result in extremely low amounts or complete lack of Survival Motor Neuron-SMN protein. The SMN protein plays a vital role in numerous cellular processes and pathways, including the function and maintenance of motor neurons.
- The SMN1 gene is responsible for producing the right amount of functional SMN protein. Many genetic changes in the SMN1 gene have been found to render the SMN protein non-functional, leading to the development of SMA [5].
- The SMN2 gene, known as the “backup gene”, only produces about 10% of the SMN1 protein. While the SMN1 gene is responsible for SMA’s development, the SMN2 gene influences SMA’s severity. While typically, a person has one to two copies of the SMN2 gene, some people can have up to eight copies. Usually, the more SMN2 copies, the milder the symptoms are [6]. As the SMN2 gene affects the course of the disease, it is frequently referred to as a “disease modifier” [7]. Some other disease modifiers are PLS3, NCALD, NAIP, SERF1, and GTF2H2 genes [8, 9].
How common is Spinal Muscular Atrophy?
Although SMA is considered a rare disease, it affects approximately 1 in 6,000 to 1 in 10,000 live births [10]. Worldwide, around 1 in 50 individuals are SMA carriers [11]. Carriers are unaffected and do not exhibit symptoms, but they have one healthy copy and one defective copy of the SMN gene. As SMA is inherited in an autosomal recessive pattern, parents who are both carriers have a 1 in 4 chance of having a child with SMA. Due to the high frequency of individuals being SMA carriers, the American College of Obstetricians and Gynecologists (ACOG) recommends that all women considering pregnancy or currently pregnant should be offered carrier screening for SMA [11].
A very small percentage of SMA cases occur “de novo” (spontaneously), without any of the parents being carriers [12].
Symptoms and types of SMA
The symptoms of SMA vary widely, with muscle weakness and hypotonia (decreased muscle tone) being the most common. SMA is currently classified into 5 types, according to the severity of the symptoms, the age of onset, and the number of SMN2 copies [7].
- SMA type 0, the prenatal form of SMA, is the rarest and the most severe, affecting approximately 1% of patients. Affected infants have only one copy of the SMN2 gene [13]. Symptoms could start prenatally, with low or absent fetal movement [14]. At birth, affected infants present with hypotonia, severe muscular weakness, congenital heart defects, and skin necrosis [15]. If left untreated, death can occur within weeks of birth [14].
- SMA type 1 is the most common type of SMA, affecting 60% of the cases [15]. Patients can have 2-3 SMN2 copies. Disease onset is noticeable between birth and 6 months of age [16]. Affected infants, also known as “non-sitters”, do not have head control and are unable to sit independently due to hypotonia. This subsequently leads to breathing, eating, and swallowing difficulties which puts them at risk of undernutrition and chest infections. “Frog-leg” posture when lying can also occur [16]. If left untreated, the disorder can be fatal by age 2.
- SMA type 2 patients usually have 3 copies of the SMN2 gene, and disease onset occurs between 6 and 18 months of age [13]. They are referred to as ‘sitters’ as they can sit independently, although they are not able to stand or walk. Patients exhibit milder symptoms than type 1, which include difficulty swallowing, weak arms or legs, tremors in fingers and hands, joint problems such as scoliosis, and breathing difficulties which can result in chest infections as in SMA type 1 [15]. Most patients with SMA type 2 can survive past 25 years of age, even without treatment [17].
- SMA type 3 patients have 3-4 copies of the SMN2 gene [13]. Symptoms can manifest between 18 and 3 or between 3 and 30 years of age. Patients are characterized as “walkers” are they can walk and stand independently. Typically, they do not have swallowing and feeding difficulties and they have a normal lifespan with appropriate treatment, although they may exhibit loss of balance, abnormal gait, and progressively lose the ability to walk [16].
- SMA type 4 is the adult-onset form of SMA and accounts for less than 1% of SMA cases. Patients have 4 to 8 copies of the SMN2 gene. Symptoms appear after the age of 30 and can include tremors, twitching, and leg weakness. They have a normal lifespan and can walk independently, without losing their ability to walk over time [16].
In addition to the SMA types described above, there are forms of SMA caused by genetic mutations on genes other than the SMN1:
- SMA with respiratory distress (SMARD)
- Distal SMA
- Spinal muscular atrophy with lower extremity predominant and dominant inheritance (SMA-LED)
- Spinal and bulbar muscular atrophy (SBMA) or Kennedy’s disease
- X-linked SMA [18]
How is SMA diagnosed?
SMA is usually suspected when there is a family history, presence of hypotonia symptoms, such as low or absent motor strength, and failure to reach development motor milestones in infancy. As the symptoms of SMA are often very similar to other neuromuscular disorders, apart from physical examination, genetic testing of SMN1 and SMN2 is recommended as a first-line investigation to confirm SMA diagnosis, evaluate disease severity and determine prognosis [19]. While SMN1 testing is used for diagnosis, testing for SMN2 is also vital, as determining the number of SMN2 copies is currently used as a criterion for the enrollment of patients into clinical trials [20, 21].
Early diagnosis of SMA
Early identification and diagnosis of affected patients is undoubtedly of critical importance, not only because the damage to motor neurons is irreversible, but also because it opens the doors to clinical trials, life-saving treatment, and access to multidisciplinary care to help them meet motor development milestones. For this reason, SMA is beginning to be included in more and more national newborn screening programs throughout the world.
Newborn screening for SMA was included in the Recommended Uniform Screening panel (RUSP), a list according to the ACOG recommendations, in July 2018 [22]. Since then, 48 of 50 US states have included SMA in their newborn screening programs and as a result, 99% of babies born in the US today are screened for SMA. In New York state, 32 of 34 infants diagnosed with SMA via newborn screening in the first 3 years of screening received treatment and showed improved motor outcomes [23].
In Europe, it is estimated that 65% of children are screened for SMA at birth. There are many countries that include SMA in their national newborn screening programs, such as Germany, Belgium, Italy, and Ukraine, while others are adding it as a pilot program. The European Alliance for Newborn Screening demands that by 2025, newborn screening programs in all European countries include a test for SMA for all newborn children [24].
Is there a treatment for SMA?
For more than a century, SMA had been regarded as an untreatable disease. This changed following the discovery of the SMN gene’s function, and several gene-specific approaches have since been developed. Most of the treatments focus on increasing the SMN protein expression either by re-expressing the SMN1 gene, or by changing the structure of the SMN2 gene to produce more functional SMN protein.
Different eligibility criteria, such as the patient’s age, weight, or SMN2 gene copy numbers are in place for each trial, but the primary key to the most effective treatment and improved quality of life is timing
[25, 26, 27]. When treatment initiation happens before or soon after the onset of symptoms, several treatment approaches have shown significant improvements, such as preserving motor neurons and maximizing motor function development.
Treatment examples include:
- Nusinersen (Spinraza)
The US Food and Drug Administration (FDA) approved Spinraza as the first drug for the treatment of SMA in late December 2016 [28], with the European Medicines Agency (EMA) authorizing it a year later [29]. Spinraza targets the SMN2 gene by increasing the synthesis of functional SMN protein. It has shown safety, considerable and meaningful efficacy on motor skills, respiratory function, and survival among other benefits, in infants, children, and adults [7]. A 5-year study of Spinraza treatment in SMA type 1 and 2 patients before any symptoms appeared was recently published. In contrast to the expected course of SMA type 1 and 2 patients, the results indicated normal motor development and improvements in motor skills. Importantly, all children with three SMN2 gene copies participating in the study achieved all World Health Organization (WHO) motor milestones [30].
- Onasemnogene abeparvovec (Zolgensma)
Zolgensma is the first approved gene therapy for a neuromuscular disease. FDA- and EMA- approved in 2019 and 2022 respectively, the drug is administered once in a lifetime intravenously, and contains a functional copy of the SMN1 gene, replacing the needed SMN protein expression [26, 31]. Early administration to children under two years old has shown improved outcomes for head control and the ability to sit independently and speak [32].
- Risdiplam (Evrysdi)
In 2020, the FDA approved Evrysdi for SMA treatment, and the European Commission authorized it in 2021 for the treatment of SMA in patients older than 2 months of age [33, 34]. Like Spinraza, Evrysdi increases the production of SMA protein leading to achievements in sitting, lack of dysphagia, and improvement in motor function and development milestones with high safety and efficacy [27].
Additional therapeutic approaches in clinical trials include various approaches that block myostatin, a hormone that inhibits muscle growth, with or without the use of the drugs mentioned above [35, 36].
Artificial intelligence for diagnosis and treatment of SMA
Another exciting new direction of neuromuscular diseases research is the usage of digital biomarkers, Artificial Intelligence (AI), and Machine Learning (ML) for disease management. These methods are being developed to help healthcare professionals assess the severity of neuromuscular disorders more accurately, as well as assist them in providing personalized treatments by taking into consideration each patient’s disease progression. Currently, an application designed to be used as a self-assessment tool to measure motor function is under investigation for its reliability and validity compared to conventional clinical evaluations [37]. Another study trained a ML model to predict individualized disease progression based on the patient’s characteristics. This holds many benefits not only for prognostic assessment but also for predicting patient outcomes from commercially available new therapies, as well as clinical trial design [38]. As AI is becoming more and more powerful, its role in diagnosis and treatment of SMA holds a lot of promise.
Conclusion
In the last 10 years, great progress has been made with FDA and EMA-approved therapies, the inclusion of SMA into national newborn screening programs, and the number of clinical trials investigating SMA treatments. Although we still have a long way to go to find a cure, SMA is a pivotal example that highlights how advocacy and awareness can propel the public, national, and scientific framework for advancing disease management and treatment.
To learn more about SMA and how you can help, please visit curesma.org/
The content of this article is for informational purposes and is not intended to replace medical advice. Please visit your healthcare provider if you have concerns about your health and well-being.
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