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Spinal Muscular Atrophy (SMA type 1, 2 & 3)

Background
Who should be tested?
Testing Methodology
Potential Outcomes & Interpretation of Test Results
Cautions
For More Information

Background

Spinal muscular atrophy (SMA) is a recessively inherited neuromuscular disorder caused by the progressive degeneration of cells in the spinal cord and brainstem. The onset of weakness ranges from before birth to young adulthood, and progresses with age. SMA affects children with varying severity, ranging from the severe and usually fatal SMA type 1 (Werdnig-Hoffman disease) to milder forms that are associated with longer survival but significant morbidity.

Spinal muscular atrophy is caused by a mutation in the survival motor neuron (SMN) gene on chromosome 5. People normally have two copies of the SMN_tel gene. Molecular studies have shown that approximately 95 per cent of SMA patients have deletions in both of the SMN_tel genes (homozygous deletions). The remaining SMA patients do not have a homozygous deletion of SMN_tel , but carry a deletion of the SMN_tel gene on one chromosome and a point mutation of the SMN_t gene on the other chromosome.

If one chromosome carries a deletion in the SMN_tel gene and the other copy is normal, the individual will be a carrier of SMA. Carriers do not have, and will not develop, spinal muscular atrophy. However, carriers may pass the mutation on to their children. If two individuals are carriers, there is a 25 per cent chance they will have an affected child. There is a 75 per cent chance their children will be unaffected. De novo mutational events occur in two per cent of patients with SMA, meaning that only one parent is a carrier and a new mutation in the offspring resulted in SMA.

Who should be tested

• individuals clinically suspected of being affected with SMA upgrading your existing skills
• individuals with a family history of SMA and their spouses, to determine the carrier status of unaffected individuals
• pregnancies at risk due to a family history of SMA

Testing Methodology

Dosage Analysis: A PCR-based dosage assay of exon 7 and 8 of both the SMN_tel and SMN_cen genes is used to determine the number of gene copies present in an individual.Approximately five per cent of carriers have point mutations in the SMN_tel gene, or carry a deletion of SMN_tel with a duplication of SMN_tel on the other chromosome. These individuals will not be detected by this test.

Sensitivity of the Test: Deletion analysis will detect the 95 per cent of individuals with SMA who have homozygous deletions of exon 7 of the SMN_tel gene located on chromosome 5. Dosage analysis will detect the 95 per cent of SMA carriers who have a deletion in one copy of the SMN_tel gene.

• About five per cent of affected individuals and five per cent of carriers do not have deletions, but have other types of mutations in SMN_tel. These mutations are not detected by current diagnostic procedures used in the Molecular Genetics Laboratory.
  • For example, of 100 people with SMA, 95 will be detected by deletion analysis. Of 100 people who are carriers of SMA, 95 will be detected by the dosage analysis.

Linkage analysis: In cases where there is clinical evidence of SMA in the family, but there is no detectable deletion in the SMN_tel gene, or when prenatal assessment is requested, linkage analysis is used to compare DNA markers associated with the SMN_tel gene in affected and unaffected family members. This family history is used to calculate the likelihood that a person is a carrier or is affected, and the risk of recurrence.

Potential Outcomes & Interpretation of Test Results

Cautions

• Molecular testing will not detect all possible mutations in this gene. A negative result does not rule out the possibility that the individual may carry a rare SMNtelmutation not detectable by the diagnostic procedures currently in place in the Molecular Genetics Laboratory.
• Individuals with two copies of SMNtel could, in rare cases, have a point mutation or deletion of SMNtel on one chromosome with a duplication of SMNtel on the other. These cases will not be detected by the diagnostic procedures currently in place in the Molecular Genetics Laboratory. However, these individuals are carriers and may transmit the mutation to their offspring.
• Affected individuals who have 1 copy of SMNtel may have a deletion of SMNtel on one chromosome and a point mutation of SMNtel,on the other chromosome. It may be necessary to send samples for point mutation analysis in a research laboratory in these situations.
• De novo mutational events occur in two per cent of patients with SMA, meaning that only one parent is a carrier.
• Linkage analysis may be used to assess carrier risk when mutations are not detected in families with a clear clinical history of SMA. Linked markers provided an assessment of risk, but are not an absolute diagnosis, due to the possibility of recombination between the marker loci and the disease locus.
• Test results should be interpreted in the context of clinical findings, family history and other laboratory data.
• This test was developed and its performance characteristics validated by the Molecular Genetics Laboratory at the Hospital for Sick Children. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. This test is used for clinical purposes.

For More Information:

• GeneReviews online clinical information resource
• Rochette CF, Surh LC, Ray PN, McAndrew PE, Prior TW, Burghes AH, Vanasse M, Simard LR. (1997) Molecular diagnosis of non-deletion SMA patients using quantitative PCR of SMN exon 7. Neurogenetics 1: 141-7.
• To locate a genetics center near you, please visit the Canadian Association of Genetic Counsellors website.