Spinal Muscular Atrophy (SMA)


Spinal muscular atrophy (SMA) type 3, also called Kugelberg-Welander disease, is a relatively mild form of SMA characterized by muscle weakness and atrophy.

Like other types of SMA, it is caused by mutations in the SMN1 gene.1 This gene normally encodes for a protein called survival motor neuron (SMN), which is essential for the survival of nerve cells that control muscle movement. When there is a mutation in the SMN1 gene, no functional protein can be made from this gene. As a result, motor neurons die and cannot send nerve signals to muscles, which in turn also die over time.

There is a second gene called SMN2 from which some functional SMN protein can also be made. However, most of the protein made from this gene is shorter than normal and quickly degraded by cells. The copy number of the SMN2 gene varies from person to person. The more copies there are, the less severe the symptoms of SMA.

People with SMA type 3 usually have 3 to 4 copies of the SMN2 gene.2 While not enough to rescue the phenotype, the resulting SMN protein produced from these copies of SMN2 mitigates some of the disease’s severity.

SMA Type 3 Symptoms

Symptoms of SMA type 3 may vary from person to person. The main symptoms of the disease are muscle weakness and atrophy, especially in the legs. Breathing problems are usually not common. Patients have a near-normal life expectancy.

Based on the age of onset of the symptoms, SMA type 3 can be classified as SMA type 3a or SMA type 3b.3 In SMA type 3a, symptoms usually appear between ages 18 months and 3 years. Affected children can usually stand and walk but gradually experience segmental distal weakness and a developmental plateau before age 3, after which they may lose ambulation. When symptoms appear after age 3, the disease is classified as SMA type 3b. Standing and walking difficulty becomes apparent later in life than in SMA type 3a. Patients with SMA type 3b are twice as likely to retain ambulation at ages 20 and 40 years than those with SMA type 3a.4 

SMA Type 3 Diagnosis

Doctors diagnose SMA type 3 based on physical examination and family history. A definite diagnosis can be reached following genetic testing that looks for mutations in the SMN1 gene. Some doctors may also ask for nerve conduction tests and a muscle or nerve biopsy.1

The patient is said to have type 3 disease based on when their symptoms first appeared.

SMA Type 3 Treatments

Three disease-modifying treatments have been approved to treat SMA type 3. They are nusinersen (Spinraza), onasemnogene abeparvovec-xioi (Zolgensma), and risdiplam (Evrysdi).

On December 23, 2016, nusinersen became the first disease-modifying treatment approved by the US Food and Drug Administration (FDA) for the treatment of SMA.8  The therapy contains an antisense oligonucleotide that “masks” the signal in the SMN2 gene that causes the protein that it encodes to be shorter than normal, increasing the amount of functional SMN protein made from the SMN2 gene. Nusinersen is approved for patients with SMA types 1, 2, and 3 of all ages. It is an intrathecal injection given every 4 months following 4 initial doses given on days 1, 15, 30, and 60.4

Onasemnogene abeparvovec is a gene therapy that delivers a healthy copy of the SMN1 gene to the body using a modified virus.5 In clinical trials, it was shown to significantly improve patients’ motor skills. Approved by the FDA on May 24, 2019,9 the therapy is indicated to treat all types of SMA in patients aged 0 to 2 years. It is a one-time infusion into the bloodstream.

Risdiplam is the most recently approved disease-modifying therapy for SMA, approved by the FDA on August 7, 2020.10 It is a small molecule that works to correct the splicing of the SMN2 gene, allowing more full-length SMN protein to be made from it. The therapy, an oral medication taken daily for the rest of a patient’s life, can be used to treat patients aged 2 years or older with any type of SMA.6

SMA Type 3 Support

Patients with SMA type 3 may have difficulties with posture and mobility. Some may develop contractures and scoliosis. Physiotherapy and occupational therapy can help patients maintain muscle strength for as long as possible.7

Some patients may require splints to support them with standing and walking. As the disease progresses, some may need a walking frame or wheelchair. A spinal brace or jacket may be necessary to avoid scoliosis. 

An occupational therapist can help with aids and adaptations that patients may need to make their everyday activities more comfortable. These may include equipment to help with personal hygiene, dressing, cooking, and eating.

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

References

  1. Spinal muscular atrophy type 3. Genetic and Rare Diseases Information Center. Accessed May 26, 2021.
  2. 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
  3. SMA type 3 information. Spinal muscular atrophy UK. Accessed May 26, 2021.
  4. Finkel R, Bertini E, Muntoni F, Mercuri E. 209th ENMC International Workshop: outcome measures and clinical trial readiness in spinal muscular atrophy 7-9 November 2014, Heemskerk, The Netherlands. Neuromuscul Disord. 2015;25(7):593-602. doi:10.1016/j.nmd.2015.04.009. doi:10.1016/j.nmd.2015.04.009
  5. Spinraza treatment for spinal muscular atrophy (SMA) patients. Columbia University Department of Neurology. Accessed May 26, 2021.
  6. Zolgensma – one-time gene therapy for spinal muscular atrophy. Med Lett Drugs Ther. 2019;29;61(1577):113-114.
  7. Evrysdi. Cure SMA. Accessed May 26, 2021.
  8. Type 3. SMA Europe. Accessed May 26, 2021.
  9. FDA approves first drug for spinal muscular atrophy. News release. US Food and Drug Administration. December 23, 2016.
  10. FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality. News release. US Food and Drug Administration. May 24, 2019.

FDA approves oral treatment for spinal muscular atrophy. News release. US Food and Drug Administration. August 07, 2020.

READ MORE ON SMA