Spinal muscular atrophy (SMA) is a rare and debilitating genetic disorder that primarily exerts influence on the motor neurons in the spinal cord, leading to muscle atrophy and weakness. This disorder has garnered significant attention in recent years due to the development of groundbreaking treatments, such as gene therapies, which have the potential to change the prognosis for individuals affected by SMA (1). SMA is a heterogeneous group of inherited neuromuscular disorders characterized by the progressive degeneration of motor neurons in the spinal cord. The condition’s prevalence and incidence can vary significantly based on geographic and ethnic factors, making it a complex subject for epidemiological study (2). The estimated global prevalence of SMA ranges from 1 in 6,000 to one in 10,000 live births, with variations in different populations and regions. This range represents a significant burden for affected families and healthcare systems (3). This condition is an autosomal recessive disorder resulted by mutations in the survival motor neuron 1 (SMN1) gene. The incidence of SMA depends on the carrier frequency of these mutations in a given population (4). SMA is classified into different divisions based on the age of onset and clinical severity, which also have implications for epidemiology. SMA type I, with an early outbreak and severe phenotype, is often the most common, while SMA type IV, with adult onset and milder symptoms, is rarer (5). There may be variations in the prevalence and incidence of SMA across different countries and regions. For example, some studies suggest a higher prevalence in certain European populations. Research is ongoing to understand these variations better (6). Addressing the impact of SMA on families and healthcare systems necessitates a multifaceted approach that includes comprehensive support services, caregiver education and training, psychosocial interventions, financial assistance programs, and healthcare system reforms to improve access to specialized care (7, 8). Collaboration among healthcare providers, lawmakers, advocacy organizations, and community stakeholders is critical for reducing the effect of SMA and improving the well-being of afflicted individuals and their families (9). In this review, we discussed the epidemiology and clinical classification of SMA, shedding light on the latest research, rehabilitation and clinical findings.

In 1891, SMA first came to light through the observations of Guido Werdnig in two infant brothers (10). Over the subsequent nine years, Johann Hoffmann documented an additional seven cases. The traditional framework for classifying SMA was built upon the timing of symptom onset and the highest level of motor function achieved. While the cases they scrutinized had intermediate symptom severity, the term “Werdnig-Hoffmann disease” was coined to denote the more severe manifestations of SMA (11). The year 1899 saw Sylvestre and Beevor describe severe forms of SMA, further delineating the spectrum. In 1964, Dubowitz contributed to the field by detailing intermediate forms of SMA in 12 patients and naming this variant “Dubowitz disease” (11–13). Additionally, in 1955, the discovery of a milder form of SMA was made, with Kugelberg and Welander providing a comprehensive description one year later (14). This division of kinds of SMA is based on the age of symptom when its starts, the highest motor function achieved, and the severity of muscle weakness. Research into the epidemiology of SMA is vital for understanding the wide prevalence of disease, its occurrence, and natural evolution. These studies provide beneficial insights into the biological, ecological, and demographic factors that drive the development and progression of SMA in populations. The International Standard of Care Committee for SMA (ISCCSMA) has classified SMA into five primary types, as shown in the Figure 1, which include:

The SMN1 gene encodes the survival motor neuron (SMN) protein, which is essential for the normal functioning of motor neurons in the spinal cord (20, 21). SMN, a foundational protein within the SMN-Gemin multiprotein complex, serves as a core component. Additionally, it actively engages in various physiological functions, including responding to cellular stress, facilitating axon transport, regulating cytoskeletal dynamics, modulating mitochondrial and bioenergy pathways, and participating in ubiquitin pathways. Consequently, SMN emerges as a significant molecule, intricately involved in a multitude of essential activities that underpin human existence (22). These SMN genes are found within the 5q13 region, which harbors inverted repeats and multiple gene copies (20, 23, 24). The telomeric version of SMN1, with its nine exons, generates a functional 294-amino acid, 38 kDa SMN protein as shown in Figure 2. Typically, this protein is found in both organalles that is the cytoplasm and nucleus, specifically in the Gemini of coiled bodies compartment, which forms Cajal bodies holding high concentrations of small ribonucleoproteins (snRNPs) along with pre-mRNAs (25). SMN contains crucial and highly conserved domains that are essential for its cellular functions. Any kind of mutations occurring within these domains of SMN1 result in the production of an inefficient protein (26). The SMN2 is a centromeric gene which is a paralog of SMN1, having almost identical sequences with SMN1 except for 5 nucleotide differences. To understand the contributions of the survival motor neuron 2 (SMN2) gene to spinal muscular atrophy (SMA) pathology, it’s important to grasp its differences in alternative splicing compared to SMN1 and how these differences impact disease severity and progression. The one of these changes leads to the exclusion of exon number 7 in approximately 90% of the transcripts through alternative splicing (27). SMN2 is located 875 kb far from SMN1 and originates from a duplication of an ancestral gene which is unique to the human lineage (28). Both SMN1 and SMN2 genes encode the survival motor neuron (SMN) protein, which is crucial for the survival and function of motor neurons. However, a critical difference between SMN1 and SMN2 lies in a single nucleotide difference within exon 7, resulting in a C-to-T transition in SMN2. This single nucleotide change in SMN2 affects the alternative splicing pattern, leading to the exclusion (skipping) of exon 7 in a significant proportion of transcripts. Exon 7 skipping results in the production of an isoform of the SMN protein lacking exon 7 (SMNΔ7), which is less stable and less functional compared to the full-length SMN protein produced by SMN1. The exclusion of exon 7 in a substantial portion of SMN2 transcripts results in reduced levels of functional SMN protein in cells, contributing to the pathogenesis of SMA. While SMN2 can partially compensate for the loss of SMN1 function, the lower levels of full-length SMN protein produced by SMN2 are insufficient to fully support motor neuron survival and function. The severity and progression of SMA are influenced by the number of copies of SMN2 present in the genome. Individuals with fewer copies of SMN2 typically produce lower levels of functional SMN protein and tend to have more severe forms of the disease, whereas those with more copies of SMN2 may produce higher levels of functional SMN protein and exhibit milder symptoms. The unique alternative splicing pattern of SMN2 has made it a primary target for therapeutic interventions aimed at increasing the production of full-length SMN protein. SMA symptoms manifest when there is a deficiency of proper functional SMN protein, usually stemming from minimum one copy of the SMN1 (29). However, around 10% of full-length SMN2 transcripts, often present in multiple copies within the genome, provide some degree of protection against motor neuron degeneration (30). The more SMN2 copies a patient possesses, the more they can compensate for the absence of SMN1 (31). Consequently, in rare cases, individuals with 6 or more copies can exhibit milder symptoms appearing after the age of 30, characterized by mild muscle weakness and retained full mobility. Most type I SMA patient’s carries either one or two SMN2 copies (32). While the number of SMN2 gene copies strongly correlates with disease severity, some studies suggest that it may not always be a definitive indicator of severity, especially in SMA patients who retain one SMN1 allele (33). Additionally, even when SMN is expressed normally, point mutations in SMN can affect protein functionality and stability, leads to the disorder, along with genetic and epigenetic factors, as well as environmental influences, may modulate disease (34). Approaches such as antisense oligonucleotide (ASO) therapy and small molecule drugs target the splicing machinery to promote the inclusion of exon 7 in SMN2 transcripts, thereby increasing the production of functional SMN protein. These therapies aim to augment the levels of functional SMN protein in motor neurons, potentially ameliorating disease symptoms and improving outcomes for individuals with SMA.

The underlying molecular mechanisms of SMA revolve around the loss of functional SMN protein and its impact on motor neurons and muscle cells. The reduction in functional SMN protein in motor neurons results in their degeneration (35). Motor neurons are responsible for transmitting signals from the spinal cord to muscles, and without proper functioning SMN protein, these neurons become vulnerable to damage and eventual death. This leads to muscle weakness and atrophy (36). SMN protein plays a crucial role in the assembly of snRNPs, which are essential for mRNA splicing (37). Impaired snRNP assembly due to SMN deficiency leads to widespread splicing defects in various genes, further exacerbating motor neuron dysfunction (38). While SMA is primarily a disorder of motor neurons, the resulting muscle atrophy and weakness are critical clinical features. The lack of neural input from affected motor neurons causes muscle disuse, contributing to muscle wasting (39). The neuromuscular junction, where motor neurons communicate with muscle cells, is also affected in SMA (40). The loss of functional motor neurons disrupts this communication, leading to muscle weakness and contractures (41).

SMA presents with a spectrum of clinical features, ranging from severe, early-onset forms to milder, adult-onset forms. The key clinical manifestations include muscle weakness, atrophy, and hypotonia. Patients with SMA may also exhibit respiratory difficulties, joint contractures, and scoliosis (42). It is essential to recognize these clinical signs early, as timely intervention can significantly impact the prognosis and quality of life for affected individuals.

There are several treatments approaches for the SMA such as (Table 1).

Nusinersen (marketed as Spinraza^®) was the first FDA-approved disease-modifying treatment for SMA having obtained approval in December 2016 and by the EMA in 2017 for both infant and adult (56). This innovative therapeutic approach, which involves the intrathecal administration of a 2′-O-methoxyethyl phosphorothioate modified antisense oligonucleotide (ASO), focuses on enhancing the incorporation of exon 7 into mRNA transcripts of SMN2 (57). The intrathecal route of administration is crucial for nusinersen’s effectiveness in treating SMA because it allows for targeted delivery to the site of pathology, bypasses the blood-brain barrier, optimizes concentration at the target site, minimizes systemic side effects, and provides a longer duration of action within the central nervous system (57). By administering nusinersen directly into the central nervous system (CNS) through the intrathecal route, the medication effectively suppresses the activity of certain splice-factors and binds to a specific intronic splice-silencing site within intron 7 of SMN2 (58). This intervention substantially increases the probability of exon 7 being included in the mRNA, ultimately enabling the translation of a more substantial quantity of fully functional SMN protein (27). This enhanced production has demonstrated significant improvements in both survival and the overall condition of various experimental models of SMA. Importantly, nusinersen’s journey to approval and commercialization has been bolstered by a multitude of studies confirming its efficacy, without any notable drug-related adverse events (59). Due to ASOs’ inability to traverse the blood-brain barrier, nusinersen was consistently administered intrathecally in all clinical trials. During the initial loading phase, it was administered four times over two months, and in the maintenance phase, it was given once every four months (60). The standard dosage of nusinersen typically amounts to 12 milligrams (61). Studies on nusinersen have revealed the potential for some patients to regain lost abilities, such as sitting up, standing, and walking, without the need for therapy. Furthermore, early initiation of this treatment has demonstrated positive outcomes in individuals with SMA types I, II, and III (62). It is worth noting that a notable drawback of this therapy is the possibility of side effects, including constipation and upper and lower respiratory tract infections (63).

Onasemnogene abeparvovec (Zolgensma), an advanced gene therapy: In May 2019, the FDA granted approval to AVXS-101, also known as Zolgensma is a gene therapy approved for the treatment of SMA, developed by AveXis, a subsidiary of Novartis (56). This approval followed the release of favorable outcomes from the phase one clinical trial known as START (Identifier: NCT01547871). This trial assessed the drug’s safety and effectiveness when administered as a one-time infusion to infants with SMA symptoms appearing before six months of age. Subsequently, in March 2020, Zolgensma received conditional marketing authorization, and in May 2020, it was granted approval by the European Medicines Agency (EMA) as well (Zolgensma, 2020a; Novartis, 2020) (64). The adeno-associated virus 9 (AAV9) capsid is used to transport the SMN-encoding complementary DNA (cDNA) to the motor neurons that need it (65–67). A single dose of AVV9 administered intravenously (IV) is sufficient to transport a functional copy of the SMN1 gene over the blood-brain barrier and into patient cells, where it may stimulate the production of SMN protein (27). The SMN1 trans gene and synthetic promoter based on AVV9 are also crucial components in maintaining SMN protein synthesis throughout time (68). Although it successfully corrects the underlying molecular defect in SMA, it has a deleterious effect on the liver by elevating serum amino transferase (69). However, prednisone is effective at reducing elevated liver enzymes. Therefore, at least three months after administration, patients should be monitored for liver function (70, 71). The long-term durability of the benefits of Zolgensma (onasemnogene abeparvovec) is still being actively studied and monitored. Zolgensma is a gene therapy approved for the treatment of spinal muscular atrophy (SMA) in pediatric patients, and it has shown remarkable efficacy in improving motor function and survival in clinical trials. While the initial data from clinical trials and real-world experience have shown sustained benefits of Zolgensma treatment over several years, including improvements in motor function and survival, more long-term follow-up is needed to fully understand the duration of these benefits. Clinical trials and observational studies are ongoing to assess the durability of Zolgensma’s effects, including its impact on motor function, respiratory function, quality of life, and survival rates over extended periods. These studies involve monitoring patients treated with Zolgensma for several years to track their progress and detect any potential changes in treatment outcomes over time. It’s important to note that as research continues and more data become available, our understanding of the long-term benefits and potential limitations of Zolgensma treatment will continue to evolve. Patients and caregivers should work closely with healthcare providers to stay informed about the latest research findings and recommendations regarding the use of Zolgensma in the management of SMA (65, 72).

Risdiplam (Evrysdi^™) was authorized by the FDA as of 7 August 2020, as the first oral medication for children as young as 2 months old and adults with SMA. It is a collaborative development effort involving Roche, PTC Therapeutics Inc., and the SMA Foundation, aimed at addressing spinal muscular atrophy (56, 73). Risdiplam serves as a modifier of mRNA splicing that leads to an elevation in SMN protein expression (74). It is a tiny molecule that changes the splicing of the SMN2 by binding to two locations in the SMN2 pre-mRNA. These sites are known as the 5′ splice site (5′ ss) of intron number 7 and the exon splicing enhancer 2 (ESE2) of exon 7 (75). Increases in full-length SMN mRNA and protein levels are caused by the unique specificity of binding two sites, which also reduces impact on other pre-mRNA splicing and prevents the likelihood of off-target effects (76). According to preclinical studies, risdiplam can reach the central nervous system and peripheral organs in vivo and can result in a significant increase of SMN protein in the blood, brain, and muscles, as well as an increase in survival in various SMA mouse models (77). While risdiplam’s systemic distribution in preclinical tests with oral administration allowed for the possibility of an impact on other tissues, nusinersen’s intrathecal delivery method mostly limited its effect to motoneurons of the central nervous system (78). Previous studies in human and murine models suggest that SMA may in fact be considered a multi-system disorder involving the neuromuscular junction, cardio-vascular system, lung, gastrointestinal-tract, and liver (79). Risdiplam has shown significant improvements in motor function and has the advantage of being an oral therapy, making it a more convenient option for many patients (80).

SMA treatments have evolved notably in recent years, particularly as previously stated gene therapies like Zolgensma and disease-modifying drugs like Spinraza (nusinersen). Much more significant perspective, which should consider insurance coverage, availability across regions, and efforts to improve access to SMA treatments. While these drugs offer a promising treatment option for children with SMA, they are highly costly, as seen in Table 1. According to studies, certain governments have made efforts to design policies for such disease treatments, such as: The Department of Revenue, Ministry of Finance, govt. of had issued Notification No. 46/2021-Customs dated 30.09.2021, which waives all Basic Customs Duty (BCD) and Integrated Goods and Services Tax (IGST) on drugs imported (personal use only) for the treatment of spinal muscular atrophy (SMA) rare disease, making medicines for SMA rare disease more affordable (81). Government of India also made a provision for financial assistance of up to Rs. 50 lakhs to patients suffering from any category of Rare Diseases such as SMA and for treatment at any of the Centres of Excellence (CoE) identified in the NPRD-2021, outside of the Rashtriya Arogaya Nidhi umbrella scheme (82). The National Health Service (NHS) England, for example, states that Biogen (the pharmaceutical company that manufactures treatment for SMA) will make the treatment for spinal muscular atrophy (SMA) available to the youngest and most severely affected (SMA type 1) patients immediately, with NHS England offering funding contingent on the National Institute for Health and Care Excellence (NICE) publication of final guidance. In Singapore, the Rare Disease pay has been established to pay five drugs to treat three rare diseases. In Malaysia and Australia, qualifying patients are given discounted access to pricey and life-saving medications (83).

In addition to disease-modifying treatments, SMA management often involves a multidisciplinary approach as shown in Figure 3 that focuses on addressing the symptoms and complications associated with the disease. Supportive care strategies aim to improve the quality of life for individuals with SMA and include:

Research into SMA continues, with several promising therapies under investigation. These therapies include small molecule drugs, gene-editing technologies, and exon-skipping therapies, among others. The goal is to further enhance the disease-modifying potential and offer a more comprehensive treatment approach for SMA. Advances in genetic testing have made it easier to diagnose SMA accurately and offer prenatal testing for at-risk pregnancies. These advancements include: NGS has become a powerful tool in identifying rare or atypical mutations in the SMN1 gene and other related genes. It can uncover genetic variations that were previously challenging to detect (114, 115). Techniques like chorionic villus sampling and amniocentesis allow for the diagnosis of SMA in the fetus, enabling informed reproductive decisions and early intervention if the fetus is affected (116, 117).

Thirty years after the discovery of the SMN gene, global scientific efforts have successfully transformed spinal muscular atrophy (SMA) into a manageable condition. Three distinct drugs utilizing cutting-edge technology—gene therapy, antisense oligonucleotides (ASOs), and small molecules focused on SMN2 splice correction—have gained approval from both the FDA and EMA, demonstrating remarkable enhancements, particularly when administered prior to the onset of symptoms. SMA, known for its substantial economic impact, has become even more financially demanding with the introduction of these novel therapies. Addressing the considerable economic burden associated with these treatments has led to an increasing advocacy for the inclusion of SMA in newborn screening (NBS) programs. While the existing therapies are likely sufficient for immediate administration after birth in cases of intermediate and mild SMA, questions arise regarding whether individuals with only two SMN2 copies will follow a trajectory similar to their age-matched counterparts and if they may require additional SMN-independent therapies. Comprehensive longitudinal studies are imperative to explore potential new phenotypes linked to these innovative therapies. Despite the presence of biomarkers associated with disease progression, further investigations are needed to identify potential non responders, enabling them to transition to alternative therapies. SMA treatments are often expensive, prompting concerns regarding equal access for all patients, especially in low-income areas or nations with limited healthcare resources. Addressing pricing and guaranteeing access to these life-changing medications for all SMA patients worldwide remains a serious concern. Numerous unanswered questions persist, necessitating meticulous future research. Nonetheless, SMA stands as a model illustrating how genetic insights can pave the way for the development of targeted therapies.

PB: Formal analysis, Data curation, Writing – original draft. SS: Writing – review & editing, Supervision, Writing – original draft. GR: Writing – review & editing, Supervision. SK: Writing – original draft, Visualization. AS: Writing – review & editing, Supervision, Formal analysis.