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Disease/ Disorder


Spinal muscular atrophy (SMA) refers to a diverse group of genetic disorders characterized by degeneration of anterior horn cells of the spinal cord and brainstem motor nuclei with resultant muscle atrophy and progressive weakness.1


SMA is categorized by its mode of inheritance and the pattern of weakness that phenotypically manifests (i.e. proximal vs. distal weakness). The most common type of SMA is autosomal recessive proximal SMA, often referred to simply as proximal SMA which accounts for 95% of cases. This form results from a homozygous deletion or mutation of the survival motor neuron 1 gene (SMN1) on chromosome 5q-13.2 It represents the most common genetic cause of death in infants3.

Epidemiology including risk factors and primary prevention

Spinal muscular atrophy disorders affect 1/6000 to 1/10,000 infants, with a carrier frequency in the general population of 1/40.5-7 SMA type 1 (SMA-1) is the most common type (60%-70% of all patients with SMA), followed by SMA-2 (20%-30%) and SMA-3 (10%-20%).8


Humans have 2 forms of the SMN gene, SMN1 and SMN2. SMN1 produces primarily full length SMN protein but the SMN2 form is able to encode a small amount of normal SMN protein (10%-15%).4 All patients with SMA lack a working SMN1 gene, and the amount of full-length protein produced by SMN2 is insufficient for normal motor neuron function.  SMN2 copy number varies in the population, and the variability of SMA disease severity is primarily related a patient’s SMN2 copy number.  However, other factors besides SMN2 copy number affect the phenotype such that prognosis cannot be fully predicted by the SMN2 copy number.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Various classification schemes exist for SMA. The International SMA Consortium scale published in 1991 is still commonly used and includes types 1, 2 and 3, based on age of onset and highest level of motor function achieved.9 Subsequent modifications have separated type 3 SMA into two subtypes based on age of onset and added groups 0 and 4. Early onset refers to Type I, late onset refers to Type II and III and adult onset is Type IV.

Table 1. Characteristics of SMA by Disease Type

Specific secondary or associated conditions and complications

Secondary conditions related to SMA include:

  • Restrictive lung disease (RLD) is most severe in SMA 0 resulting in death shortly after birth, followed by SMA 1, resulting in death within 2 years without ventilator support.  In SMA 2 restrictive lung disease may be mild, but sleep-disordered breathing conditions can result in increased pulmonary infections with increased morbidity. RLD is less problematic in individuals with SMA types 3 and 4.
  • Scoliosis occurs almost universally in SMA 2 but is rare in SMA 1.
  • Contractures may be congenital (clubfeet) or may occur over time in association with progressive weakness.
  • Constipation is common in SMA and may be due to poor abdominal muscle tone and immobility from weakness.
  • Dysphagia is most common in SMA 1 and is due to bulbar weakness.

Essentials of Assessment


  • In SMA-1 the history reveals concern for hypotonia, progressive proximal > distal weakness with legs more affected than arms, dysphagia and respiratory distress.
  • In SMA-2 progressive weakness begins occurring after 6 months; the child fails to achieve milestones of standing and has weakness in proximal > distal muscles, with legs more affected than arms.
  • In SMA-3 there is often gait difficulty and proximal weakness.
  • In SMA-4 there is mild weakness occurring in adulthood.
  • A complete family history should be obtained as well.

Physical examination

Table 2. Physical Exam

Functional assessment

Table 3.

Laboratory studies

Diagnostic Testing

In the past electromyography/nerve conduction studies (EMG/NCS) and muscle biopsy were used to identify features of denervation and were the mainstay of diagnostic workup. However molecular genetic testing has now become the standard tool for diagnosis of SMA.10 It should be considered early in any infant with weakness or hypotonia or patients with symptoms of proximal predominant weakness, reduced or absent reflexes, tongue fasciculations and/or limb tremor (polyminimyoclonus).

  • Genetic testing specifically for homozygous deletion will confirm the disease in 95% of patients.
  • If negative, genetic testing for the other SMN related SMA (compound heterozygotes) should be undertaken starting with genetic testing for a heterozygous deletion followed by possible heterozygous mutations (e.g., frameshift, nonsense or missense mutation).
  • If testing is still negative, one can consider electrodiagnostic testing, creatine kinase and imaging to assist with diagnosis.

The homozygous deletion of SMN1 is essentially 100% specific for the diagnosis of SMA. Prenatal screening by chorionic villus sampling or amniocentesis is available and can potentially be used to catch the diagnosis early in a hypotonic infant in-vitro.


Imaging studies are not helpful in the diagnosis of SMA disorders but may be ordered as part of a workup for a hypotonic infant to exclude a central disorder.

Supplemental assessment tools

Electrodiagnostic (EDX) Testing

  • Previously used when molecular testing was not widely available.
  • Should be reserved only for evaluation of atypical patients and negative molecular work up (negative SMN1 deletion and SMN1mutation testing). EDX remains important for diagnostic workup in atypical cases and non-5q-related SMA to demonstrate the neurogenic etiology of the illness.
  • EDX studies show variable features of motor neuron and axonal loss consistent with loss of motor neuron function with active denervation with chronic compensatory changes of re-innervation and motor unit action potential enlargement.
  • On Electromyography (EMG), abnormal spontaneous activity (i.e. fibrillation potentials and positive sharp waves) is typically present. Delayed recruitment patterns with large motor unit action potentials (MUAPs) can be evident as well. In end stage individuals, MUAPs may lack clear neurogenic features of long duration and large amplitude and instead have reduced amplitude and durations.
  • Nerve Conduction Studies (NCS) show chronic motor axonal loss with perseveration of sensory nerve action potentials (SNAPs).
  • Conduction velocities tend to be preserved with possible slight decrease due to axonal loss.

Early predictions of outcomes

  • Outcome depends on what type of SMA the patient has; that is on severity of weakness, age at onset and on the highest functional level achieved.
  • Disease severity amongst groups of patients correlates by SMN2 copy number, however due to idiosyncratic factors of each individual it cannot predict an individual’s potential severity and prognosis.11-13 Also, knowledge of the SMN 2 copy number is important for therapeutic approaches and is currently used as a criterion for enrollment into clinical trials.14
  • Compound muscle action potential (CMAP) amplitude on NCS correlates with clinical severity, age and function and has potential to be used for prognostication.15-17
  • Serum creatinine kinase and serum creatinine may play a role in predictive and pharmacodynamic biomarkers for SMA. Some studies show it may differentiate treatment responders with nusinersen from non-responders in adults with SMA. In addition, serum creatinine is involved as a biomarker for disease progression in infants with 3 copies of SMN2. Serum creatinine is a marker of muscle mass and inversely correlates with disease severity.18
  • Neurofilament proteins are released from neurons when injured and levels may be detected in blood and CSF. These are a biomarker for disease progression, prognostic and pharmacodynamic particularly in infants with SMA. In some studies, a higher baseline of plasma NF-H (heavy chain) correlated with earlier age of diagnosis and symptom onset and a lower baseline motor function. Also, it may indicate early biochemical effects of nusinersen treatment.18


  • Individuals with SMA-1 or SMA-2 will require an environment that is wheelchair accessible.
  • It is recommended that individuals with SMA-1 and SMA-2 have a back-up electric generator in the event of a power outage, to allow functioning of respiratory support equipment.

Social role and social support system

  • In a child with a diagnosis of SMA, it is important to provide anticipatory guidance to the patient’s family concerning the child’s ongoing medical and care needs.
  • Counseling about the expectations of functional needs, and about the disease process itself, is essential to the family’s decision-making regarding care options and management of respiratory complications of SMA.
  • Cure SMA is a non-profit organization which provides support to families, promotes and supports research with the goal of eradicating SMA.

Professional issues

Controversies in the management of a child with type 1 SMA exist and relate primarily to the decision to provide invasive ventilatory support for a condition that is progressive and non-treatable. In addition, with the medical advances and accessibility to medical treatment there is an arising issue regarding if to start treatment in a patient who is in mechanical ventilation.

Rehabilitation Management and Treatments

Available or current treatment guidelines

The clinical management of SMA depends upon the severity of weakness and the degree of respiratory involvement.  In the last few years due to advancement in the understanding of SMA genetics and molecular mechanisms, genetic therapies are becoming a reality and will change the therapeutic landscape. There are commercially available medications that will likely change the survival and natural history of this disease.19 However, supportive care will continue to be a mainstream mode of management for SMA.10

Pulmonary Management

  • Restrictive lung disease is the most common cause of mortality for children with SMA. All children with SMA 1 and about 1/3rd of those with SMA-2 will develop respiratory insufficiency or failure during childhood. Therefore establishment with a pulmonary specialist is important early on during the time of initial diagnosis. Management options include noninvasive ventilatory support as well as invasive support with tracheostomy and a ventilator.
  • Immunization against influenza, pneumococcus and respiratory syncytial virus is recommended as a preventative strategy.
  • Parents should be educated about various care options and the role of invasive ventilation as well as related complications. They should also be educated about use of cough-assist devices, oral secretion management, chest physiotherapy and postural drainage.

Gastro-intestinal (GI) & Nutrition Management

  • Dysphagia due to bulbar dysfunction can occur. Possible options for management include modification of diet consistencies to compensate for poor swallowing and protect against aspiration.
  • For malnutrition due to poor oral intake, potential use of a gastrostomy tube can be considered.
  • Constipation is a common complication due to immobility and can be managed by placement on a bowel program and encouraging mobility.

Musculoskeletal Management

  • In non-ambulatory patients, contracture prevention and management is important. This can be treated with regular stretching, bracing, serial casting, physical and occupational therapy. Adaptive equipment for mobility and ADL needs may include medical strollers, manual or power wheelchairs and any other related home medical equipment.
  • Non-ambulatory patients will benefit from referral to a physical and occupational therapist for evaluation of adaptive equipment for mobility and ADLs, which may include an adaptive stroller, manual wheelchair or bath equipment. Some young children may use a supine standing frame if they have adequate trunk control, although tolerating this frame is difficult for older children who have developed lower extremity contractures.
  • Physical exercise and therapy can optimize both endurance and strength. Patients should be encouraged to continue being as physically active as possible and encouraged to be involved in aqua-therapy and adaptive sports.
  • Scoliosis, a likely complication in non-ambulatory patients, should be monitored regularly and treated as indicated with bracing for early stages or spinal fusion surgery for more severe cases. Spinal fusion surgery is the most effective and definitive treatment option.


Communities and home set-ups that are wheelchair accessible are important for individuals with SMA 1 and SMA 2. Additionally, it is recommended that individuals with SMA 1 and SMA 2 have a back-up electric generator in the event of a power outage to allow functioning of respiratory support equipment.

Coordination of care

Multidisciplinary care is recommended. It is typically performed in a clinic setting with a neurologist, physiatrist, pulmonologist and orthopedist available. Patients benefit from early referral to physical and occupational therapists.

Patient & family education

Patient/family education and anticipatory guidance is critical due to the serious implications of a diagnosis of SMA. Counseling about the expected functional needs, goals and disease process itself is essential in order for the family to make decisions regarding care options.

Emerging/unique interventions

Standard outcome measures have not yet been established. Physiologic measures such as motor unit number estimation, compound motor action potentials and MRI have been used. Non-disease specific functional outcome measures that have been used include the Alberta Infant Motor Scale, Wee Functional Independence Measure (WeeFIM), the Hammersmith scale and CHOP INTEND.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Cognition is not affected in SMA, but children with SMA may be placed in inappropriate, cognitively unchallenging class settings due to the severity of their motor impairments. It is important to advocate for testing so that they are placed in the least restrictive setting to achieve optimal academic achievement.

Emerging/unique interventions

  • The disease-modifying antisense oligonucleotide therapy (ASO), nusinersen (Spinraza®, Biogen, Cambridge, MA), was FDA approved for the treatment of all types of SMA related to loss of SMN1 This ASO increases SMN protein expression from the SMN2 gene which is now in clinical useand commercially available in several countries. Nusinersen is administered intrathecally due to poor blood brain barrier penetration, which requires adequate facility for administration and post-procedure monitoring. 21,22
  • Small molecule therapies to induce full length SMN expression from the SMN2 gene working as SMN2exon 7 splice modifier. Generic name is risdiplam and commercially known as Evrysdi by Genentech, Inc. 23-25
  • Gene replacement therapy commercially known as Zolgensma was approved by FDA in 2019. Manufactured by Novartis Gene Therapies, Inc.
  • Recent studies have shown dysfunction of the neuromuscular junction in SMA which may contribute to weakness and fatigability in these patients. Arnold WD, Severyn S, Zhao S, et al 2021 published adults with SMA had significant neuromuscular junction transmission defects that were not corrected with 14 months of nusinersen treatment. 26 Clinical trials are exploring the effect of pyridostigmine (anti-cholinesterase) and impact on motor performance and fatigue in spinal muscular atrophy type 2-4. (ClinicalTrials.gov identifier: NCT02227823)
  • Clinical trials studying if the combination of risdiplam and investigational anti-myostatin antibody in ambulatory SMA children has the potential to improve motor function. ClinicalTrials.gov identifier: NCT05115110
  • Clinical trials are ongoing evaluating the intrathecal administration of onasemnogene abeparvovec in SMA patients with 3 copies of SMN2 and deletion of SMN1. (ClinicalTrials.gov Identifier: NCT03381729)
  • Clinical trials exploring oral reldesemtiv on measures of skeletal muscle function or fatigability in patients with SMA. Reldesemtiv is an investigational drug intended to slow the rate of calcium release from the regulatory troponin complex of fast skeletal muscle fibers. (ClinicalTrials.gov identifier: NCT02644668)

Cutting Edge/ Emerging and Unique Concepts and Practice

Cutting edge concepts and practice

  • Advances in our understanding of the genetics of SMA have led to an improved understanding of the pathophysiology of the various forms of SMA.
  • An ASO therapy, nusinersen, was recently approved by FDA in December 2016. Nusinersen treatment has shown benefit in alteration of natural history of the disease including fewer respiratory complications, improvement in motor function, and improvement of quality of life particularly in patients with later-onset SMA. Medication is administered intrathecally with four initial loading doses and then three times per year. The potential risks are thrombocytopenia, coagulation abnormalities and renal toxicity.27
  • Gene replacement therapy (onasemnogene abeparvovec, previously known as AVXS-101) based on the transfer of a functional SMN gene using adeno-associated virus (AAVP-9) in SMA type 1 infants with biallelic mutations of SMN1 gene and one or two SMN2 gene copies. This is a one-time intravenous infusion commercially known as Zolgensma with clinical trials showing it reduced pulmonary and nutritional support requirements, improved motor function, and decreased hospitalization rate.28 Also, it was studied in pre-symptomatic patients with SMA type 1 showing achievement of age-appropriate motor milestones up to 14 months.29 Zolgensma was approved by FDA in May 2019 for patients with biallelic mutations of SMN1 with less than 2 years old.  This treatment may be ineffective in patients with antibodies to AAV-9. The potential risks are liver toxicity, thrombocytopenia, and elevate troponin-I. Another important consideration is the high cost of $2.1 million for a single dose.27
  • Risdiplam is a small molecule which is brain penetrant and works as an SMN2exon 7 splice modifier. The commercial name is Evrysdi and is orally available. Risdiplam was approved by FDA on August 2020 for patients with SMA of 2 months old or older. Clinical trials show improvement in motor and respiratory function. SMA Type 1 patients did not required ventilation support at 28 months old while using risdiplam. Also, SMA Type 2 and 3 showed significant improvements in motor function and it was sustained after 12 months of using risdiplam. The potential risks are harm to fetal development and male fertility.27
  • The need for pre-symptomatic genetic testing is now a pressing issue in light of the development of effective therapies that are now in clinical use.
  • An anti-myostatin monoclonal antibody known as Myostatin Inhibitor Apitegromab (SRK-015) is being investigated to improve motor function in SMA type 2 and 3.

Gaps in the Evidence-Based Knowledge

  • The reason why low levels of SMN protein are insufficient for normal motor neuron function remains uncertain.
  • Larger studies are needed to establish the role of nusinersen and risdiplam in adults with SMA. However, limited studies show there is clinical meaningful improvement in adults with nusinersen.30
  • Many advances in treatment for patients with SMA have occurred recently and the best outcomes have been observed the earlier the treatment is started. In utero therapy is an idea that has been presented.31
  • Animal studies have shown dual therapeutic approach (nusinersen and risdiplam) successfully increases SMN protein and rescues motor function.32 Future studies are needed of its benefits in humans as dual therapeutic approach.


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Original Version of the Topic

Suzanne Woodbury, MD. Spinal Muscular Atrophy (SMA). 11/14/2011

Previous Revision(s) of the Topic

William Arnold, MD, Monal Desai, MD. Spinal Muscular Atrophy (SMA). 11/28/2017.

Author Disclosures

Edwardo Ramos, MD
Nothing to Disclose

Laura M Serrano-Ortiz, MD
Nothing to Disclose