Spinal Muscular Atrophy (SMA)

Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease caused by mutations in the SMN1 gene and characterized by the degeneration of lower motor neurons in the spinal cord and brainstem.1 

The disease typically affects infants and children. However, there are also other forms of SMA with phenotypes ranging from life-threatening to mild, where affected individuals have a normal life expectancy. The mildest form of SMA is called SMA type 4 or adult-onset SMA.2

Symptoms of Adult SMA

The first symptoms of this type of SMA appear in adulthood, usually after age 30, in the form of weakness in the proximal musculature and functional impairments.

Motor symptoms include hypotonia, proximal muscle weakness especially in the hips and shoulders, and impaired function such as altered gait, difficulty rising from low surfaces, and inability to run, climb stairs, raise the arms over the head, or carry heavy objects.3

Other symptoms may include finger trembling, fasciculation, and calf hypertrophy.2

Prognosis of Adult SMA

Adult-onset SMA is not life-threatening, and affected individuals have the same life expectancy as that of unaffected individuals.1 As the disease progresses, some patients may need a wheelchair for mobility but this usually happens later in life. The disease does not usually affect the respiratory muscles.

Prevalence of Adult SMA

Adult-onset SMA accounts for less than 5% of all SMA cases.4 Prevalence is estimated at about 1/300,000.2

Causes of Phenotypes in SMA

SMA is classified according to the age at onset of clinical symptoms and the maximum motor function achieved by the patient.1 Even though most forms of SMA are caused by mutations in the SMN1 gene, varying clinical manifestations and severities are reported.

The wide range of clinical severity is the result of the presence of other genetic modifiers.5 Humans have a second highly homologous copy of the SMN1 gene called SMN2, which differs by only 5 nucleotides.6 One of these nucleotides creates a new exonic splice silencer, which results in 90% of SMN2 pre-mRNAs being alternatively spliced and subsequently lacking exon 7. Only 10% of the transcripts are full-length and can produce functional proteins. The copy number of the SMN2 gene differs between individuals, and a higher copy number is correlated with milder disease. People with adult SMA usually have 4 or more copies of the SMN2 gene.7

Other protective genetic modifiers include PLS3, which codes for plastin 3, and ZPR1, which codes for zinc finger protein 1.5 Plastin 3 plays a role in the formation and stabilization of actin bundles, while zinc finger protein 1 is thought to interact with the SMN protein and stabilize the protein.

Other Forms of Adult SMA

There are other, rarer forms of adult SMA not caused by mutations in the SMN1 gene. These include spinal and bulbar muscular atrophy, also known as Kennedy’s disease, late-onset spinal motor neuronopathy, and progressive muscular atrophy or sporadic lower motor neuron syndromes.8 The motor neuron damage seen in these diseases is caused by various genetic mutations and governed by complex molecular pathways. Their inheritance patterns may also differ from SMA caused by SMN1 mutations.

Management of Adult SMA

In most cases, the symptoms of adult SMA are mild enough that patients might not need treatment. However, some patients may benefit from physiotherapy and occupational therapy.3 

Physiotherapy can maximize function, strength, and endurance through a range of motion, positioning, and exercise programs that include strengthening and aerobic exercise to maximize function and prevent deconditioning. Aquatic therapy, which makes use of the buoyancy of water to support the body weight and allow movements not possible against gravity, can also help. 

Occupational therapy can offer fall prevention programs and suggest mobility aids such as walkers and wheelchairs to maintain independence, as well as equipment for self-care needs, assistive technology, and durable medical equipment for traveling.

Adults with SMA should be offered genetic counseling and family planning. 

Preliminary studies have indicated that valproic acid could improve quantitative muscle strength as well as subjective motor function in patients with adult SMA.9

There are currently no data available about the potential benefits of nusinersen (Spinraza®) or risdiplam (Evrysdi™) in adults with SMA.10

Reviewed by Michael Sapko, MD on 7/1/2021


  1. Kolb SJ, Kissel JT. Spinal muscular atrophy. Neurol Clin. 2015;33(4):831-46. doi:10.1016/j.ncl.2015.07.004
  2. Spinal muscular atrophy type 4. Genetic and Rare Diseases Information Center. Accessed June 10, 2021.
  3. Souza PVS, Pinto WBVR, Ricarte A, et al. Clinical and radiological profile of patients with spinal muscular atrophy type 4. Eur J Neurol. 2021;28(2):609-619. doi:10.1111/ene.14587
  4. Arnold WD, Kassar D, Kissel JT. Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve. 2015;51(2):157-167. doi:10.1002/mus.24497
  5. Lamar KM, McNally EM. Genetic modifiers for neuromuscular diseases. J Neuromuscul Dis. 2014;1(1):3-13. doi:10.3233/JND-140023
  6. Wirth B, Mendoza-Ferreira N, Torres-Benito L. Chapter 12 – spinal muscular atrophy disease modifiers. In: Sumner CJ, Paushkin S, Ko CP, eds. Spinal Muscular Atrophy: Disease Mechanisms and Therapy. New York: Elsevier Inc.; 2017:191-210. doi:10.1016/B978-0-12-803685-3.00012-4
  7. Butchbach MER. Copy number variations in the survival motor neuron genes: implications for spinal muscular atrophy and other neurodegenerative diseases. Front Mol Biosci. 2016;3:7. doi:10.3389/fmolb.2016.00007
  8. Juntas Morales R, Pageot N, Taieb G, Camu W. Adult-onset spinal muscular atrophy: an update. Rev Neurol (Paris). 2017;173(5):308-319. doi:10.1016/j.neurol.2017.03.015
  9. Weihl CC, Connolly AM, Pestronk A. Valproate may improve strength and function in patients with type III/IV spinal muscle atrophy. Neurology. 2006;67(3):500-501. doi:10.1212/01.wnl.0000231139.26253.d0
  10. Proximal spinal muscular atrophy type 4. Orphanet. Updated January 2021. Accessed June 10, 2021.