Spinal muscular atrophy (SMA) is a hereditary neurodegenerative disease characterized by progressive loss of motor neurons in the anterior horn of the spinal cord, resulting in muscle atrophy and weakness. It is one of the most common monogenic causes of infant mortality, with an incidence of approximately 1 in 6,000–30,000 live births and a carrier frequency of about 1 in 50 individuals [1,2,3].

The genetic basis of SMA lies in the biallelic deletion or mutation of the survival motor neuron 1 (SMN1) gene, located on chromosome 5q13. This gene encodes the SMN protein, which is critical for the maintenance of motor neurons. A paralogous gene, SMN2, produces a small amount of functional protein and modifies disease severity depending on the copy number. Increased copy number of SMN2 is associated with a milder phenotype of the disease [4].

In 1891, Guido Werdnig described two brothers who had weakness and degeneration of the anterior horn cells on autopsy. More cases were reported by Johann Hoffmann. The clinical phenotype of this, the most severe form, was consolidated, inclusive of recognition of the jug handle arm posture, intercostal weakness, sparing of the diaphragm, and absence of facial weakness. Over 60 years later, in 1956, the milder form with retained ambulation was reported by Kugelberg and Welander. In 1964, Victor Dubowitz described the first report of the intermediate form via 12 children with neurogenic muscular atrophy of infantile onset. Their course appeared to be static or with minimal progression. The group survived longer than those reported by Werdnig and Hoffmann [5]. In 1990, the gene was first mapped to chromosome 5q11.2–13.3, and 5 years later, the SMN1 gene was identified by Dr. Judith Melki and her team, marking a major breakthrough in neuromuscular genetics. This confirmed that the three apparent phenotypes represent the same disease, manifesting at different levels of severity [6,7,8].

Classification of SMA into types 1, 2, and 3 was proposed by the International Consortium on Spinal Muscular Atrophy aligning with the age of onset, severity, and motor milestones [9]. However, each SMA type exhibited clinical heterogeneity, warranting further subclassification. Dubowitz has proposed a decimal classification for each type (1.1–1.9 for type 1, 2.1–2.9 for type 2, and 3.1–3.9 for type 3) [10]. Another approach for classification is adjusting for age of onset of clinical signs, especially for type 1. The disease can be classified as 1a–1c for type 1, allowing for neonatal presentations (type 1a), disease onset after the first month without head control (type 1b), disease onset after 3 months with achieved head control (type 1c) [11]. Type 3 is subdivided into type 3a with onset before 3 years of age and type 3b with onset after 3 years of age [12]. Furthermore, genetic testing permitted confirmation that, whilst rare, very severe forms with prenatal onset have occurred (type 0) [13]. Likewise adult onset mild cases were labeled as type 4, although some consider these patients better placed as very mild type of type 3 [5]. The classification of SMA is summarized in Table 1 [14].

With the introduction of standardized care recommendations in 2007, and updated in 2018, the improvement in survival for children with SMA has been evident [15,16,17]. The guidelines illustrate how neuromuscular disorders, especially SMA, cover a broad range of systems. The guidelines focus on diagnosis and genetics, ancillary and rehabilitation, orthopedic and orthotic interventions, endocrine, pulmonary, nutrition and safe feeding, ethics, and palliative care. Also acute care interventions and medications. The recommendations illustrate the gains of multidisciplinary care with regular patient and family-focused assessments. The updated recommendations gave direction of critical disease altering complications such as scoliosis and implications for care.

The natural course of untreated SMA, especially in type 1, is devastating. Most infants with type 1 SMA die or require permanent ventilation before 2 years of age. Type 2 patients often become wheelchair-bound in childhood, while type 3 patients may retain ambulation but have reduced endurance and function over time [18]. However, the introduction of disease-modifying therapies, starting in 2016, has significantly altered the course of SMA. As a result, the traditional classification of the disease has become inadequate. To address this, a functional classification (non-sitters, sitters, and walkers) has been adopted in the updated standard care recommendations. This new classification reflects current motor abilities rather than historical expectations, enabling more accurate assessment of disease severity, treatment response, and long-term prognosis [16,17].

The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved three therapies to date, which have action of either direct gene replacement of the defective SMN1 gene or upregulating the SMN2 gene to produce full-length SMN protein. The use of adeno-associated viral vectors allows for effective SMN1 gene delivery [19,20,21].

Carrier screening for SMA aims to identify individuals or couples at risk of having a child affected by SMA. The identification of SMA carriers is important because the carrier frequency of SMA is approximately 1 in 50 healthy individuals in the population. The American College of Medical Genetics and Genomics and the American College of Obstetricians and Gynecologists recommend routine SMA carrier screening for all individuals who are planning a pregnancy or are currently pregnant [36,37]. Quantitative polymerase chain reaction (PCR) or next-generation sequencing is used to determine SMN1 gene copy number. Identifying carriers allows for informed reproductive choices, such as prenatal or preimplantation genetic diagnosis.

Combination therapy strategies are being explored, such as using nusinersen or risdiplam after gene therapy. Early data suggest potential additive benefits, though more research is needed [38]. Other novel therapies are also under exploration, namely using fast skeletal troponin activators or targeting myostatin as a potent negative regulator of skeletal muscle growth [39]. SRK-015 is a fully human anti-pro-myostatin monoclonal antibody currently under investigation. Attempts to increase the transcription of SMN2, to stabilize residual SMN protein, protect motor neurons from oxidative damage or replace motor neurons with stem cells have not been effective. Studies are underway aimed at mitigating neuromuscular junction defects or increasing muscle mass and/or contractility in combination with gene therapy and antisense oligonucleotides. Biomarkers such as SMN protein levels, neurofilament light chain (NfL), and electromyography are being studied to assess disease activity and response to therapy. Imaging modalities like muscle magnetic resonance imaging (MRI) also offer non-invasive insights into muscle health [40]. The new therapies have changed the progression and expression of the disease and, whilst truly disease modifying, are not curative. With the prolonged survival and growth infants with SMA type 1 are now faced with challenges of chronic disease complications such as progressive scoliosis [41]. SMA type 2 children may acquire ability to walk but still need specific orthotic devices to support them. Especially for one-time AAV9 gene therapy, true durability over decades and re-treatment feasibility are unresolved; for all three therapies, extensions and registries continue to accrue data. For nusinersen delivery issues (lifelong repeated lumbar punctures, difficulties after scoliosis surgery), for onasemnogene abeparvovec the probability of serious liver injury, adverse effects of long-term steroid use on growing children and the necessity for acceptable anti-AAV9 titers, and for risdiplam reproductive safety questions and lifelong daily adherence are still controversial aspects of these SMA therapies. Big data on these patients is needed to collate accurate information on care needs and how to ensure optimal outcomes.

The ethics of access to orphan drugs is a major challenge especially in resource-limited settings [42]. Managed access programs whilst allowing wider distribution of these life-changing interventions have been extremely limited in regions such as Africa [43]. The cost of the interventions is preclusive and highly unlikely to be taken on by the state sector. This means that the treatment gaps only widen in these regions.

Lastly, patient advocacy organizations and SMA family associations play an important role in supporting individuals and families affected by SMA. For example, Cure SMA in the United States offers education, counseling, financial aid, and clinical resources while leading efforts for universal newborn screening and influencing federal and state health policies [44]. SMA Europe, a network of national SMA groups, funds patient-centered research, promotes equitable access to diagnosis, treatment, and care [45].

The rapid expansion of the therapeutic options and the impressive clinical responses are significant in the field of SMA. New therapies are providing novel understandings about the biology and pathogenesis of SMA. This includes the onset of the disease, the evolution of the progressive muscle weakness, and whether the pathological process is reversible or attenuated, especially in the setting of early intervention. As some of these novel therapies address SMN deficiency only in the central nervous system (CNS) and others address both peripheral and CNS deficiency, this will eventually add to the knowledge of the roles of peripheral and central SMN. As such, these novel disease-modifying therapies for SMA will eventually clarify the pathogenesis of the disease. Care for children with SMA, especially type 1, has evolved from primarily being palliative or reactive, to a more proactive approach, inclusive of the multimodal care.