Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder caused by biallelic loss-of-function mutations in the SMN1 gene on chromosome 5q13, leading to deficiency of survival motor neuron (SMN) protein and progressive degeneration of alpha motor neurons in the spinal cord and brainstem. SMA is the leading genetic cause of infant mortality, with an incidence of approximately 1 in 10,000 live births and a carrier frequency of roughly 1 in 40–60 individuals. The clinical spectrum ranges from severe neonatal presentation with death in infancy (Type 0/1) to mild adult-onset proximal weakness (Type 4). The therapeutic landscape has been transformed by three disease-modifying therapies — nusinersen, onasemnogene abeparvovec, and risdiplam — and the implementation of newborn screening has enabled presymptomatic treatment, fundamentally altering the natural history of this once-devastating disease.

Genetics & Pathophysiology

SMA results from deficiency of the survival motor neuron (SMN) protein, which is essential for motor neuron survival, axonal transport, and the assembly of small nuclear ribonucleoproteins involved in pre-mRNA splicing. The SMN1 and SMN2 genes are located in an inverted duplication on chromosome 5q13. While SMN1 produces full-length functional SMN protein, SMN2 differs by a critical C-to-T transition in exon 7 that causes predominant exon 7 skipping during splicing, resulting in a truncated, unstable protein (SMNΔ7). Only approximately 10–15% of SMN2 transcripts produce full-length SMN protein.

Classification

SMA is traditionally classified into clinical subtypes based on age of symptom onset, maximal motor milestone achieved, and natural history. This classification predates the era of disease-modifying therapy; treated patients may not follow the expected trajectory of their initial subtype.

Clinical Features

SMA Type 1 (Severe Infantile)

Type 1 is the most common and severe form, accounting for approximately 60% of all SMA cases. Infants present within the first 6 months of life with progressive, symmetric, proximal greater than distal weakness, severe hypotonia ("floppy infant"), poor head control, and absent deep tendon reflexes. A bell-shaped chest deformity results from intercostal muscle weakness with relative diaphragmatic sparing, producing paradoxical (abdominal) breathing. Tongue fasciculations are characteristic. Bulbar dysfunction leads to feeding difficulties, poor weight gain, and aspiration risk. Cognition and social engagement are preserved, with infants often appearing bright and alert despite profound motor impairment.

SMA Type 2 (Intermediate)

Children with Type 2 SMA achieve the ability to sit independently but never walk unaided. Onset is typically between 6 and 18 months. Proximal weakness predominates, with legs weaker than arms. Fine finger tremor (polyminimyoclonus) is common. Progressive scoliosis develops in nearly all patients and may require surgical intervention. Respiratory insufficiency progresses over time, with many patients eventually requiring nocturnal noninvasive ventilation. Joint contractures, particularly of the hips, knees, and elbows, are frequent.

SMA Type 3 (Mild / Juvenile)

Patients achieve independent ambulation, though many subsequently lose this ability. Type 3a (onset <3 years) has a higher risk of losing ambulation than Type 3b (onset >3 years). Weakness is proximal and symmetric, affecting legs more than arms. Gower sign is typically present. Deep tendon reflexes are diminished or absent. Calf pseudohypertrophy may occur, mimicking muscular dystrophy. Most patients have a normal lifespan, though functional limitations accumulate over decades.

SMA Type 4 (Adult Onset)

The mildest phenotype, with onset after age 21. Patients present with slowly progressive proximal weakness, exercise intolerance, and muscle cramps. The disease course is indolent, and patients generally maintain ambulation and have a normal lifespan. This form is uncommon and may be underdiagnosed.

Diagnosis

Genetic Testing

Molecular genetic testing is the gold standard for SMA diagnosis. The recommended diagnostic algorithm begins with testing for homozygous deletion of SMN1 exon 7 using multiplex ligation-dependent probe amplification (MLPA) or quantitative PCR, which identifies approximately 95% of affected individuals. In patients with a single SMN1 copy (heterozygous deletion) and a compatible phenotype, full SMN1 gene sequencing should be performed to detect point mutations on the remaining allele. SMN2 copy number determination should be performed in all confirmed cases to inform prognosis and treatment decisions.

Electrodiagnostic Studies

Nerve conduction studies show normal sensory responses and normal or reduced motor amplitudes (reflecting motor neuron loss). Electromyography (EMG) demonstrates denervation changes with fibrillation potentials, positive sharp waves, and large-amplitude, long-duration motor unit potentials with reduced recruitment. These findings support a motor neuron or motor axon process but are not specific to SMA and have been largely supplanted by genetic testing for diagnosis.

Other Investigations

• Creatine kinase (CK): Normal or mildly elevated (typically <5 times upper limit of normal); markedly elevated CK should prompt consideration of muscular dystrophy
• Muscle biopsy: Rarely needed in the era of genetic testing; shows grouped atrophy with groups of hypertrophied (Type 1) fibers — a pattern of neurogenic atrophy
• Pulmonary function testing: Baseline and serial assessment in all patients; FVC declines over time, particularly in Types 1 and 2

Newborn Screening

SMA was added to the United States Recommended Uniform Screening Panel (RUSP) in July 2018, following evidence that presymptomatic treatment produces dramatically superior outcomes compared with treatment initiated after symptom onset. As of 2024, over 90% of US states and territories have implemented SMA newborn screening, and numerous countries worldwide have adopted or are piloting screening programs.

Disease-Modifying Therapies

Three disease-modifying therapies are currently approved for SMA, each increasing functional SMN protein through a distinct mechanism. The choice of therapy depends on the patient's age, weight, disease type, functional status, and practical considerations including route of administration and access. All three therapies demonstrate greatest benefit when initiated early, particularly in the presymptomatic period.

Nusinersen (Spinraza)

Nusinersen is an antisense oligonucleotide (ASO) that modifies SMN2 pre-mRNA splicing to promote inclusion of exon 7, thereby increasing production of full-length, functional SMN protein. It is administered intrathecally and was the first disease-modifying therapy approved for SMA (FDA approval December 2016).

Dosing: 12 mg administered intrathecally. Loading doses on days 0, 14, 28, and 63, followed by maintenance doses every 4 months. Treatment is lifelong.

Pivotal trials:

• ENDEAR (Type 1): Phase 3, randomized, sham-controlled trial in 122 infants with SMA Type 1. At final analysis, 51% of nusinersen-treated infants achieved motor milestone responses versus 0% in the control group. Event-free survival (HR 0.53, p=0.005) and overall survival (HR 0.37, p=0.004) were significantly improved. The trial was terminated early due to overwhelming efficacy.
• CHERISH (Types 2/3): Phase 3, sham-controlled trial in 126 children with later-onset SMA aged 2–12 years. Nusinersen-treated patients showed a 5.9-point improvement on the HFMSE versus sham control (p<0.0001). 57% of nusinersen-treated patients achieved a ≥3-point HFMSE improvement versus 21% of controls.
• NURTURE (presymptomatic): Phase 2, open-label trial in 25 presymptomatic infants. All 25 achieved sitting independently, 92% achieved walking with assistance, and 88% achieved independent walking. All remained alive without permanent ventilation at last follow-up.

Onasemnogene Abeparvovec (Zolgensma)

Onasemnogene abeparvovec is a gene replacement therapy using an adeno-associated virus serotype 9 (AAV9) vector to deliver a functional copy of the SMN1 gene. It is administered as a single intravenous infusion (FDA approval May 2019). The AAV9 vector crosses the blood–brain barrier and transduces motor neurons, enabling sustained SMN protein expression from the transgene.

Dosing: Single IV infusion at a dose of 1.1 × 10¹⁴ vg/kg. Systemic corticosteroids (prednisolone 1 mg/kg/day) are administered for at least 2 months following infusion to mitigate the immune response to the viral capsid.

Eligibility: Approved for patients <2 years of age with biallelic SMN1 mutations. Clinical experience and safety data are most robust in patients weighing <13.5 kg. Pre-existing anti-AAV9 antibodies should be assessed before treatment, as high titers may reduce efficacy.

Pivotal trials:

• START (Phase 1): Open-label trial in 15 SMA Type 1 infants. At the therapeutic dose, all patients survived and were free of permanent ventilation at 5-year follow-up, with sustained motor function improvements.
• STR1VE-US (Phase 3): 22 SMA Type 1 patients with 2 SMN2 copies; 91% survived without permanent ventilation and 59% achieved independent sitting at 18 months of age.
• STR1VE-EU: 33 SMA Type 1 patients; 97% survived at 18 months of age.

Risdiplam (Evrysdi)

Risdiplam is a small-molecule SMN2 pre-mRNA splicing modifier administered orally once daily (FDA approval August 2020). It promotes exon 7 inclusion in SMN2 transcripts, increasing full-length SMN protein production both centrally and peripherally. It is approved for patients ≥2 months of age with all SMA types.

Dosing: Oral liquid, administered once daily. Dose is weight-based: 0.2 mg/kg/day for patients aged 2 months to <2 years; 0.25 mg/kg/day for patients ≥2 years weighing <20 kg; 5 mg/day for patients ≥2 years weighing ≥20 kg. Treatment is lifelong.

Pivotal trials:

• FIREFISH (Type 1): Phase 2/3 trial in infants with SMA Type 1 (2–3 SMN2 copies). At 24 months, 29% of infants achieved sitting independently for ≥5 seconds (versus 0% in untreated natural history). 85% were alive and free of permanent ventilation.
• SUNFISH (Types 2/3): Phase 3, double-blind, placebo-controlled trial in patients aged 2–25 years with Type 2 or non-ambulant Type 3 SMA. At 12 months, the Motor Function Measure-32 (MFM-32) treatment difference was 1.55 points in favor of risdiplam (p=0.0156). Improvements were sustained and continued through 4-year follow-up.

Comparison of Disease-Modifying Therapies

Supportive Care

Comprehensive multidisciplinary care remains the cornerstone of SMA management alongside disease-modifying therapy. The 2017 international consensus standards of care, updated in 2018 by Mercuri et al., define evidence-based recommendations across multiple domains. The treatment landscape has evolved from purely supportive to a combination of disease-modifying therapy and proactive multisystem management.

Respiratory Management

• Serial monitoring of respiratory function (FVC, peak cough flow, nocturnal oximetry/capnography)
• Noninvasive ventilation (BiPAP) for nocturnal hypoventilation; may progress to daytime use in more severe phenotypes
• Mechanical insufflation–exsufflation (cough assist) for airway clearance
• Proactive management of respiratory infections with aggressive chest physiotherapy and early antibiotic therapy
• Influenza and pneumococcal vaccination; palivizumab or nirsevimab for RSV prophylaxis in high-risk infants
• Discussion of tracheostomy and long-term ventilation options, particularly in SMA Type 1 with respiratory failure

Nutritional Management

• Swallowing assessment and monitoring for aspiration risk, especially in Types 1 and 2
• Gastrostomy tube placement (G-tube or GJ-tube) when oral feeding is unsafe or insufficient for growth
• Monitoring for overweight/obesity in less severely affected patients, particularly with reduced mobility
• Bone health assessment (DEXA scan) and supplementation with calcium and vitamin D for osteopenia, which is common due to reduced weight-bearing
• Management of gastroesophageal reflux and constipation, which are frequent comorbidities

Orthopedic & Rehabilitative Care

• Scoliosis surveillance: progressive neuromuscular scoliosis develops in nearly all non-ambulant patients; surgical fusion may be indicated when curves exceed 40–50 degrees
• Hip subluxation monitoring, particularly in Type 2 patients
• Joint contracture prevention with range-of-motion exercises, splinting, and serial casting
• Adaptive equipment: custom seating, standing frames, power wheelchairs
• Physical and occupational therapy to optimize function, endurance, and quality of life
• Aquatic therapy for strengthening and mobility in a reduced-gravity environment

Adult SMA Considerations

Adults with SMA include those with Type 3 or 4 who have had long-standing disease, as well as an emerging population of Type 1 and 2 patients surviving into adulthood with disease-modifying therapy and improved supportive care. Key considerations include:

• Transition of care: Structured transition from pediatric to adult neuromuscular services, with attention to the multidisciplinary needs that persist across the lifespan
• Respiratory decline: Progressive respiratory insufficiency may develop or worsen in adulthood, requiring initiation or escalation of noninvasive ventilation
• Scoliosis and pain: Chronic musculoskeletal pain is common and often undertreated; may be related to scoliosis, joint contractures, or chronic postural strain
• Fatigue: Significant contributor to reduced quality of life; management includes energy conservation, pacing, and optimization of respiratory support
• Psychosocial factors: Depression, anxiety, social isolation, and vocational challenges require proactive screening and intervention
• Pregnancy: Women with SMA can conceive and carry pregnancies successfully, but require close monitoring of respiratory function; risdiplam is contraindicated in pregnancy due to teratogenicity
• Treatment access: All three therapies are now being used in adults, though data are more limited; nusinersen and risdiplam have the broadest adult approval

Prognosis & Natural History vs. Treated Outcomes

The natural history of SMA has been profoundly altered by disease-modifying therapies. In the pre-treatment era, SMA Type 1 had a median age of death of approximately 10 months, with fewer than 10% surviving beyond 2 years without permanent ventilation. The introduction of nusinersen, onasemnogene abeparvovec, and risdiplam has transformed survival and motor outcomes across all SMA types.

Emerging Therapies & Future Directions

The SMA therapeutic pipeline continues to expand beyond SMN-targeted approaches. Apitegromab, an anti-myostatin antibody, received FDA priority review as an adjunctive therapy aimed at enhancing muscle growth and function independently of SMN protein levels. Combination therapy strategies — using an SMN-targeting agent alongside a muscle-targeting agent — represent a promising frontier. Long-term follow-up studies continue to define the durability and optimal timing of current therapies, while next-generation gene therapies and intrathecal delivery approaches are under investigation. The evolving classification system for SMA is also being reconsidered, as newborn screening and early treatment are producing phenotypes that do not fit traditional categories.

References

1. Lefebvre S, Bürglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155–165.
2. Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008;371(9630):2120–2133.
3. Feldkotter M, Schwarzer V, Wirth R, et al. Quantitative analyses of SMN1 and SMN2 based on real-time LightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Am J Hum Genet. 2002;70(2):358–368.
4. Prior TW, Leach ME, Finanger E. Spinal muscular atrophy. In: Adam MP, Feldman J, Mirzaa GM, et al., eds. GeneReviews. University of Washington, Seattle; 1993–2024.
5. Calucho M, Bernal S, Alias L, et al. Correlation between SMA type and SMN2 copy number revisited: an analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases. Neuromuscul Disord. 2018;28(3):208–215.
6. Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017;377(18):1723–1732.
7. Mercuri E, Darras BT, Chiriboga CA, et al. Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med. 2018;378(7):625–635.
8. De Vivo DC, Bertini E, Swoboda KJ, et al. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the phase 2 NURTURE study. Neuromuscul Disord. 2019;29(11):842–856.
9. Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017;377(18):1713–1722.
10. Mendell JR, Al-Zaidy SA, Lehman KJ, et al. Five-year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy. JAMA Neurol. 2021;78(7):834–841.
11. Day JW, Finkel RS, Chiriboga CA, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021;20(4):284–293.
12. Baranello G, Darras BT, Day JW, et al. Risdiplam in type 1 spinal muscular atrophy. N Engl J Med. 2021;384(10):915–923.
13. Mercuri E, Deconinck N, Mazzone ES, et al. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2022;21(1):42–52.
14. Wang CH, Finkel RS, Bertini ES, et al. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007;22(8):1027–1049.
15. Mercuri E, Finkel RS, Muntoni F, et al. Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28(2):103–115.
16. Finkel RS, Mercuri E, Meyer OH, et al. Diagnosis and management of spinal muscular atrophy: part 2: pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018;28(3):197–207.
17. Glascock J, Sampson J, Haidet-Phillips A, et al. Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. J Neuromuscul Dis. 2018;5(2):145–158.
18. Chien YH, Chiang SC, Weng WC, et al. Presymptomatic diagnosis of spinal muscular atrophy through newborn screening. J Pediatr. 2017;190:124–129.e1.
19. Kraszewski JN, Kay DM, Stevens CF, et al. Pilot study of population-based newborn screening for spinal muscular atrophy in New York state. Genet Med. 2018;20(6):608–613.
20. Kolb SJ, Coffey CS, Yankey JW, et al. Natural history of infantile-onset spinal muscular atrophy. Ann Neurol. 2017;82(6):883–891.
21. Darras BT. Spinal muscular atrophies. Pediatr Clin North Am. 2015;62(3):743–766.
22. Darras BT, Masson R, Mazurkiewicz-Beldzinska M, et al. Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls. N Engl J Med. 2021;385(5):427–435.
23. Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat. 2000;15(3):228–237.