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Spinal muscular atrophy legislation, “The SMA Treatment Acceleration Act”, will soon be introduced in both the U.S House of Representatives and the U.S. Senate.
What is spinal muscular atrophy?
Spinal muscular atrophy (SMA) is an autosomal recessive (meaning the disorder is inherited by receiving one gene from both mother and father) neuromuscluar disorder that affects motor neurons of the spinal cord and brainstem. Motor neurons are responsible for supplying electrical and chemical messages to muscle cells. Without proper input from motor neurons, muscle cells don’t function properly and become much smaller (atrophy), producing symptoms of muscle weakness and affecting the ability to swallow, breath and move limbs.
SMA kills more babies than any other genetic disease and it is estimated that it occurs in between 1:6,000 and 1:20,000 births annually. Approximately 1:40 to 1:50 people are carriers of this genetic disease .
The region on human chromosome 5 that contains the SMN (survival motor neuron) gene has a large inverted duplication. This duplicated region also contains repetitive elements that make it prone to genomic rearrangements and deletions. Genes coded within this region occur twice, once within each of the duplicated regions. Thus, there are two copies of the SMN gene, appropriately named survival of motor neuron 1 (SMN1) and survival of motor neuron 2 (SMN2).
SMA is caused by loss of the SMN1 gene from both copies of chromosome 5 (remember, human cells have 23 pairs of chromosomes). SMN1 plays a role in general cellular RNA processing  and more recently has been shown to have a novel function in motor axons, the long process of a nerve fiber that conducts electrical impulses . Siblings that have lost both copies of SMN1 can have variable SMA phenotypes (meaning observable physical or biochemical characteristics), which suggests that the SMA phenotype is modifed by other factors in addition to the loss of SMN1 .
SMN2 has been shown to be a factor that modulates disease severity . Recently, it was shown that as SMN2 copy number increases, so does functional status in SMA . A study last year demonstrated that histone deacetylase inhibitors such as valproic acid (VPA) or 4-phenylbutyrate (PBA) increased SMN2-derived RNA and protein levels  and clinical trials are underway to investigate their effects on motor function in SMA patients.
SMA severity is variable and affects infants through adults. The range has been divided into four types by the level of weakness:
- Infantile SMA – Type 1 or Werdnig-Hoffmann disease (onset of symptoms 0-6 months). Children with SMA type 1 are never able to sit without assistance and are constantly at risk of respiratory infection and pneumonia. Feeding may require tubes to be placed through the nose or directly into the stomach. Recurrent respiratory problems typically result in death before 2 years of age.
- Intermediate SMA – Type 2 (onset of symptoms 7-18 months). Children with SMA type 2 are able to independently maintain a sitting position but are never able to stand and walk. Some children are free of life-threatening complications such as pneumonia while others have progressive weakness of their swallowing and respiratory muscles. Many children develop curvature of the spine and various other orthopedic problems.
- Juvenile SMA – Type 3 or Kugelberg-Welander disease (onset of symptoms >18 months). Children with SMA type 3 are able to walk independently. Many children may be able to walk for decades after the onset of symptoms while others display progressive weakening that results in the loss of independent walking. However, problems swallowing and respiratory issues are uncommon.
- Adult SMA – Type 4. Most patients notice symptoms in their mid-30’s. Their course is benign with only a small number of patients eventually requiring wheelchair assistance.
The SMA Treatment Acceleration Act has been developed through a collaborative effort of the SMA Foundation, Families of SMA and FightSMA and is modeled on other disease-specific legislation currently before Congress or that has been previously considered and became law.
Specifically, “The SMA Treatment Acceleration Act” would provide for the following:
- Federal support for a national clinical trials network for SMA.
- Federal support to enhance the existing SMA patient registry and for expanded research on the epidemiology of SMA.
- Establishes an SMA Coordinating Committee to include federal agencies, SMA researchers, and SMA families.
- Establishes a trans-Institute research collaboration at the NIH under the Director of NIH to ensure all relevant Institutes at NIH are contributing and collaborating on SMA research.
- Requires the Secretary of the U.S. Department of Health and Human Services (HHS) to study and report to Congress on ways to improve existing incentives, as well as to recommend additional incentives, necessary to promote SMA drug development among private industry.
- Provides for the Secretary of HHS to establish a program to provide information and education on SMA to health professionals and the general public.
Once the legislation is introduced in the House and Senate, FightSMA, an international organization dedicated to finding a treatment or cure for spinal muscular atrophy, will be issuing a “Nationwide Call to Action” for all SMA families, researchers and friends, to help engage every Member of Congress in support of this bill.
You can help now by simply asking your congressional representatives to join the fight against SMA.
- McAndrew et al. Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNt and SMNc gene copy number. Am J Hum Genet 1997 Jun;60(6):1411-22.
- Liu et al. The spinal muscular atrophy disease gene product, SMN, and its associated protein SIP1 are in a complex with spliceosomal snRNP proteins. Cell 1997 Sep 19;90(6):1013-21.
Carrel et al. Survival motor neuron function in motor axons is independent of functions required for small nuclear ribonucleoprotein biogenesis. J Neurosci. 2006 Oct 25;26(43):11014-22.
Helmken et al. Evidence for a modifying pathway in SMA discordant families: reduced SMN level decreases the amount of its interacting partners and Htra2-beta1. Hum. Genet. 2003 Dec;114(1):11-21.
Mailman et al. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet Med. 2002 Jan-Feb;4(1):20-6.
Swoboda et al. Natural history of denervation in SMA: relation to age, SMN2 copy number, and function. Ann Neurol. 2005 May;57(5):704-12.
Wirth et al. Spinal muscular atrophy: from gene to therapy. Semin Pediatr Neurol. 2006 Jun;13(2):121-31.