Spinal Muscular Atrophy (SMA)

Spinal muscular atrophy (SMA) is a spectrum of autosomal recessive syndromes characterized by progressive proximal muscle weakness and atrophy, possibly due to degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem. There are 5 clinical types of SMA, each with a distinctive clinical presentation unified by motor weakness. The earlier presentations are associated with more severe motor weakness affecting a child’s ability to reach the developmental milestones of sitting or walking. In the more severe types, breathing and swallowing may also become difficult as the disease progresses. The prognosis of SMA is poor. In the less severe types, adults have a normal lifespan. The initial diagnosis is made clinically and confirmed using genetic testing. Management is mostly supportive although novel therapies are being developed. The prognosis depends on the clinical type.

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Spinal muscular atrophy (SMA) is a spectrum of autosomal recessive syndromes characterized by progressive proximal muscle weakness and atrophy, possibly due to degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem.


  • Type 0: prenatal-onset SMA
    • Presence of only 1 copy of the survival motor neuron 2 gene (SMN2
    • Decreased fetal movement in late pregnancy
    • Manifests with severe, flaccid paralysis
  • Type 1: infantile SMA, also called Werdnig-Hoffman disease
    • Onset before 6 months of age
    • Never able to sit up independently
  • Type 2: intermediate form, also called Dubowitz disease
    • 20% of cases
    • Onset between 3 and 15 months of age
    • Unable to stand or walk independently
  • Type 3: juvenile form, also called Kugelberg-Welander disease
    • 30% of cases
    • Onset between 18 months and 18 years of age
    • Normal lifespan
  • Type 4: adult SMA (mildest form)
    • < 5% of cases
    • Presence of 4–8 copies of SMN2
    • Able to maintain ambulation throughout life
    • Normal lifespan


  • 2nd-most common autosomal recessive disorder (after cystic fibrosis), causing significant morbidity and mortality
  • Incidence: calculated to be 1 in 11,000 in the US among all ethnicities
  • Carrier frequency: 1 in 47 Caucasians and 1 in 72 African American individuals


  • Homozygous deletion of the survival motor neuron 1 gene (SMN1) loss of synthesis of survival motor neuron protein
  • Extra copies of SMN2 determine the phenotypic expression/clinical severity.
  • Dysfunctional SMN protein → anterior horn cells in the spinal cord and motor nuclei in the lower brainstem undergo degeneration → progressive muscle weakness
  • Mechanisms by which the lack of normal SMN protein causes SMA pathology are unclear.
  • Pathophysiology in a mouse model (2014) shows skeletal muscle damage preceding motor neuron damage.

Clinical Presentation

Spinal muscular atrophy presents as a lower motor neuron lesion syndrome with muscle weakness, which is more severe in types 0, 1, and 2.

Type 0: decreased fetal movement in late pregnancy

  • Documented polyhydramnios, fetal growth restriction, and pulmonary hypoplasia
  • After birth:
    • Severe hypotonia and weakness
    • Areflexia
    • Facial diplegia (paralysis on both sides)
    • Arthrogryposis (multiple joint contractures)
    • Congenital heart defects
    • No motor milestones are achieved.

Type 1: presents before age 6 months of age

  • Severe and symmetric flaccid paralysis
  • Infants do not achieve the ability to sit without support.
  • “Frog-like” posture with hips abducted
  • Bulbar weakness: 
    • Weak cry
    • Poor sucking and swallowing reflexes
    • Pooling of secretions
    • Tongue fasciculations
    • Increased risk of aspiration and FTT
  • Progressive respiratory failure
  • Bell-shaped chest
  • Cranial nerves are spared:
    • Preserved eye movement
    • Normal expression/facial muscles

Type 2: presents at 3–15 months of age

  • Progressive proximal weakness in legs > arms:
    • The ability to sit independently is delayed and then lost in teenage years.
    • Inability to stand or walk
  • Sparing of the face and eye muscles
  • Tongue fasciculations
  • Areflexia
  • Muscular weakness → progressive scoliosis
  • Small amplitude myoclonic tremor-like movements of the hands (polyminimyoclonus) 
  • Ankylosis of the mandible
  • Joint contractures
  • Respiratory muscle weakness and scoliosis from progressive muscular weakness → restrictive lung disease

Type 3: presents from 18 months of age to the end of adolescence

  • Achieve independent ambulation → later presents with progressive proximal muscle weakness in legs > arms
    • Falls
    • Difficulty climbing stairs
  • May develop foot deformities
  • Most individuals do not develop scoliosis or respiratory muscle weakness.
  • Many individuals become wheelchair-bound as the disease progresses.

Type 4 (mildest phenotype): presents in adulthood

  • Mild proximal muscle weakness (lower extremities)
  • Ambulation is usually maintained.


Spinal muscular atrophy should be suspected in any infant with unexplained weakness or hypotonia. Definitive diagnosis requires genetic testing.

Genetic testing

  • Gold standard
  • Targeted mutation analysis to confirm SMN1 deletion
  • For parents of an affected child: autosomal recessive mode of inheritance → 
    • 25% chance of an affected child
    • 50% chance of a carrier
    • 25% chance of an unaffected child
  • Slight deviation with SMA:
    • 2% of affected individuals have a de novo SMN1 variant with only 1 parent being a carrier of that variant →
    • Siblings are not at increased risk for SMA.
  • Carrier testing is indicated for at-risk relatives.
  • Prenatal testing is indicated for women having a family member with a confirmed diagnosis of SMA (by genetic testing).
  • Newborn screening was added to the Recommended Uniform Screening Panel (RUSP) in 2018, and SMA screening is being conducted in many states.
    • The RUSP consists of a list of disorders recommended by the US Department of Health and Human Services for newborn screening in the state.
    • Only tests for SMA due to homozygous deletion of exon 7 in SMN1

Electromyography (EMG) and muscle biopsy

  • Formerly, a standard component of diagnostic evaluation
  • Rarely used now because of the availability of molecular genetic testing
Muscle biopsy in SMA

Muscle biopsy at 10 months of age (H&E, ×200) with marked perimysial and endomysial fibrosis and fatty infiltration with groups of small fibers and scattered hypertrophic fibers

Image: “Muscle biopsy in SMA” by . License: CC BY 2.5


Current management is mostly supportive and multidisciplinary (including palliative care).

Supportive care

  • Respiratory support:
    • Noninvasive: BiPAP
    • Invasive:
      • Tracheostomy/ventilation
      • Considered when noninvasive ventilation is insufficient
    • Chest physiotherapy for secretion mobilization and clearance
    • Tracking of forced vital capacity
  • Nutritional support:
    • Early gastrostomy for growth failure in types 1 and 2
    • Supplemented nutrition reduces the likelihood of aspiration.
  • Orthopedic support:
    • Physical therapy
    • Spinal bracing for scoliosis

Disease-modifying therapy

Gene therapy: 3 agents are now available in the US.

  • Nusinersen (Spinraza): antisense oligonucleotide that increases SMN protein synthesis
    • Administered by intrathecal injection
    • Direct comparisons with other agents are not yet available.
  • Onasemnogene abeparvovec (Zolgensma): 
    • 1-time IV infusion for children < 2 years of age
    • Recombinant viral vector containing complementary DNA that encodes normal human SMN protein
  • Risdiplam (Evrysdi):
    • Oral medication for all types of SMA in individuals > 2 months
    • Corrects SMN2 splicing errors and increases the concentration of SMN protein


  • Failure to thrive (FTT) in infants:
    • Bulbar dysfunction affects swallowing.
    • → Growth failure due to inadequate caloric intake
  • Respiratory complications:
    • Aspiration
    • Mucus plugging
    • Recurrent infections
    • Restrictive lung disease
  • GI complications:
    • Constipation
    • Delayed gastric emptying
    • Gastroesophageal reflux with potential aspiration
  • Musculoskeletal complications:
    • Scoliosis
    • Joint contractures
    • Hip subluxation
    • Susceptibility to fractures
  • Sleep difficulties


  • Types 0, 1, and 2: death due to restrictive respiratory disease and respiratory failure
    • Type 0: death at birth or in the 1st month of life
    • Type 1: death at < 2 years of age
    • Type 2: Life expectancy is variable and ⅔ of individuals live up to 25 years of age.
  • Type 3: slowly progressive worsening of motor weakness, but individuals have a normal lifespan
  • Type 4: normal lifespan

Differential Diagnosis

  • Prader-Willi syndrome: a condition associated with the loss of the paternal chromosome 15q11-13 region, which manifests as intellectual disability, short stature, underdevelopment of sexual organs, and obesity in newborns. At birth, Prader-Willi syndrome presents with hypotonia and lethargy, and feeding and breathing difficulties similar to those in SMA. Diagnosis is made based on DNA methylation testing to detect parent-specific imprinting of specific regions of chromosome 15. Management is supportive.
  • Duchenne muscular dystrophy: an X-linked recessive genetic disorder in children caused by a mutation in the DMD gene, leading to muscle-fiber destruction and replacement with fatty or fibrous tissue. Affected boys present with progressive proximal muscle weakness that eventually leads to loss of ambulation, and contractures, scoliosis, cardiomyopathy, and respiratory failure. Diagnosis is based on laboratory and genetic testing. Management is supportive and aimed at slowing disease progression and complications.
  • ALS (Lou Gehrig’s disease): a sporadic or inherited neurodegenerative disease in adults that affects the upper motor neurons (UMNs) and lower motor neurons (LMNs). Amyotrophic lateral sclerosis is characterized by symptoms indicating that both the UMNs and LMNs are affected concurrently. The diagnosis is made clinically. Management is supportive and symptomatic, progressing to end-of-life care.


  1. Burr, P., Reddivari, A.K.R. (2021). Spinal Muscle Atrophy. StatPearls. Retrieved August 9, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK560687/
  2. Bodamer, O.A. (2021). Spinal muscular atrophy. UpToDate. Retrieved August 9, 2021, from https://www.uptodate.com/contents/spinal-muscular-atrophy
  3. Kolb, S.J., Kissel, J.T. (2015). Spinal muscular atrophy. Neurologic Clinics, 33, 831–846. https://doi.org/10.1016/j.ncl.2015.07.004
  4. Prior, T.W., et al. (2020). Spinal Muscular Atrophy. GeneReviews. Accessed August 19, 2021, from PubMed, http://www.ncbi.nlm.nih.gov/books/NBK1352/
  5. Fayzullina, S., Martin, L.J. (2014). Skeletal muscle DNA damage precedes spinal motor neuron DNA damage in a mouse model of spinal muscular atrophy (SMA). PloS One, 9(3), e93329. https://pubmed.ncbi.nlm.nih.gov/24667816/

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