Spinal Muscular Atrophy


Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder characterized by muscle weakness and atrophy. It is the most common genetic cause of childhood mortality, yet there is a wide range of symptom severity. Its incidence is estimated to be 1 in 6,000-10,000 live births.  


Clinical Manifestations

The symptoms associated with SMA are due to the degeneration of anterior horn cells in the spinal cord and lower motor neurons. This leads to progressive, symmetric weakness that is more pronounced in the proximal than distal muscles. It also tends to affect the lower limbs more than the upper limbs.

Location of neurons affected by spinal muscular atrophy in the spinal cord


SMA has historically been classified into different types depending on age of onset, symptom severity, and life expectancy.

Type Age of onset Can sit Can stand Can walk Life expectancy
0 Prenatal No No No <6 months
1 <6 months No No No <2 years
2 6-18 months Yes No No 10-40 years
3 >18 months Yes Yes With help Almost normal
4 >5 years Yes Yes Yes Normal

Other clinical features include:

  • Hypotonia
  • Loss of motor milestones 
  • Areflexia or hyporeflexia
  • Respiratory insufficiency or failure 
  • Poor suck and swallow
  • Tongue fasciculations
  • Hand tremor
  • Joint contractures



SMA is an autosomal recessive disorder caused by the deletion or mutation of SMN1 (survival of motor neuron gene). 95-98% of those with SMA are homozygous but 2-5% are compound heterozygotes. SMN1 is located on chromosome 5q13.2 in a region of genomic instability. It encodes SMN protein that is present in all tissue and functions in essential intracellular processes including pre-mRNA splicing, mRNA transport, and formation of small nuclear ribonucleoprotein (snRNP) complexes. Complete absence of SMN is lethal and the severity of SMA is inversely related to SMN protein levels. 

Spinal muscular atrophy has an autosomal recessive pattern of inheritance.

Humans also have SMN2, a 500 kb inverted duplication of SMN1. A single point mutation in exon 7 that affects exon splicing is responsible for making the protein product of SMN2 unstable. ~90% of SMN2 transcription results in mRNA transcripts missing exon 7 that render nonfunctional protein. The remaining ~10% of transcripts are full-length and tranlated into SMN protein.   

chrom 5 prot_1_0.jpghttps://www.frontiersin.org/articles/10.3389/fmolb.2016.00007/full

SMN2 functions as a rescue gene in the absence of SMN1, yet the sharply reduced level of SMN leads to SMA. The copy number of SMN2 varies within the population and dictates the severity of SMA. 


SMN2 Copy Number

SMA Clinical Phenotype

SMA 1 (severe)

SMA 2 (intermed)

SMA 3/4 (mild)



















SMA should be suspected based on clinical presentation but must be confirmed with genetic testing

  • PCR-targeted mutation analysis +/- sequence analysis
    • Specific to exon 7
    • 95% sensitivity for homozygotes
    • Unable to detect heterozygotes
  • Carrier testing
    • SMN1 gene dosage analysis
  • Newborn screening
    • Added to Recommended Uniform Screening Panel in 2018
    • Detects ~95% of cases


Differential Diagnosis

The differential is based on age of onset of symptoms.

Prenatal to 6 months:

  • X-linked infantile spinal muscular atrophy
  • Congenital myasthenic syndrome
  • Congenital myopathy
  • Congenital myotonic dystrophy
  • Hypoxic-ischemic myopathy
  • Traumatic myelopathy
  • Glycogen storage disease
  • Prader-Willi syndrome
  • Zellweger syndrome
  • Arthrogryposis multiplex congenita

Six months to childhood:

  • Duchenne and Becker muscular dystrophy
  • Limb-girdle muscular dystrophy
  • Myasthenia gravis
  • Guillain-Barre syndrome
  • Non-5q forms of spinal muscular atrophy
  • Late onset hexosaminidase A deficiency

Adult onset:

  • Amyotrophic lateral sclerosis
  • Spinobulbar muscular atrophy


Disease Complications and Supportive Therapy


Progressive decline in pulmonary function due to weakened respiratory muscles leads to impaired cough with inadequate secretion clearance, hypoventilation during sleep, and frequent pneumonia. Respiratory failure is the most common cause of death in SMA 1 and 2. 

  • Chest physiotherapy and other airway clearance techniques
  • Ventilator support

Nutrition and Gastrointestinal

Bulbar dysfunction causes impaired feeding, risk of aspiration, and failure to thrive. Other GI issues include reflux, constipation, and delayed gastric emptying.

  • Alteration of food consistency to improve food intake and protect from aspiration 
  • Gastrostomy can be considered in severe cases

Orthopedic and Musculoskeletal

Patients at risk for scoliosis, hip dislocation, joint contractures, and thoracic kyphosis. Progressive scoliosis may impair lung function and in severe cases cause decreased cardiac output.

  • Physical therapy
  • Spinal bracing to delay progression of scoliois (must be used cautiously because it can reduce expiratory tidal volume) 
  • Surgical repair (poor evidence of efficacy)


Disease Modifying Therapy

Nusinersen (Spinraza) is an antisense oligonucleotide that binds SMN2 pre-mRNA and promotes inclusion of exon 7 in mature mRNA strand, which increases functional SMA protein production. 

  • Approved in 2016 for use in both pediatric and adult populations
  • Intrathecal injection every 4 months
  • Cost: $125,000 per dose


Onasemnogene abeparvovec (Zolgensma) is a recombinant adeno-associated viral vector with SMN1 DNA that inceases production of functional SMN protein. 

  • Approved in 2019 for children <2 years old
  • One-time IV infusion
  • Cost: $2,125,000


Patient and Family Resources

Click on the logos below for more information about organizations involved in patient support and SMA research.  

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Arnold ES, Fischbeck KH. Geschwind DH, Paulson HL, Klein C. Handbook of Clinical Neurology. Cambridge, MA: Elsevier; 2018. Spinal muscular atrophy; pp. 591–601. Neurogenetics, Part II, Vol. 148. 3rd series.

Bodamer, OA. Spinal muscular atrophy. J Dashe (Ed.), UpToDate. Updated October 1, 2019.  https://www.uptodate.com

Kolb SJ, Kissel JT. Spinal Muscular Atrophy. Neurol Clin. 2015;33(4):831–846. doi:10.1016/j.ncl.2015.07.004

Markowitz, J.A.; Singh, P.; Darras, B.T. Spinal muscular atrophy: A clinical and research update. Pediatric Neurol. 2012, 46, 1–12.

Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med. 2017 02;377(18):1713–22.

Verhaart IEC, Robertson A, Wilson IJ, Aartsma-Rus A, Cameron S, Jones CC, Cook SF, Lochmüller H. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy - a literature review. Orphanet J Rare Dis. 2017;12:124.