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Spinal and Bulbar Muscular Atrophy (SBMA)

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

Background

Spinal and bulbar muscular atrophy (SBMA or Kennedy disease) is an X-linked recessive motor neuron disease that occurs in one in 50,000 males. It is characterized by slowly progressive muscle weakness associated with mild insensitivity to the hormone androgen. Symptoms typically begin between the ages of 20 and 50 years with difficulty walking and a tendency to fall. Some patients have muscle cramps, while others complain of action tremors. Patients often show breast development, testicular atrophy and reduced fertility due to androgen insensitivity. The vast majority of patients with SBMA have a normal life expectancy and do not die from direct complications of their disease.

The principal mutation causing SBMA is an increase in the number of CAG repeats within the androgen receptor (AR) gene located on the X chromosome (specifically Xq11-q12). The normal gene contains a three base pair sequence that is repeated on each X chromosome (called a CAG trinucleotide repeat). Although variable in the general population, the number of repeats is usually inherited without change from generation to generation. In unaffected individuals, this region ranges in size from 9 to 34 repeats, whereas individuals affected with SBMA have 36-66 repeats (full mutation).

Males normally have one X chromosome in each cell. If that X chromosome carries the expansion mutation in the AR gene, the boy will have SBMA. Affected males who are fertile pass the expanded gene to each daughter. As a result, all daughters of affected fathers are carriers. Males do not pass an X chromosome to their sons. As a result, the sons of affected fathers do not receive the expanded gene, and are not affected. Females normally have two X chromosomes in each cell. If one X chromosome carries the mutation in the AR gene and the other one does not, the girl will be a carrier of SBMA. Carriers do not have and will not develop SBMA. Carrier females may, however, transmit the repeat expansion in the AR gene to their children. Each son of a carrier mother has a 50 per cent risk of being affected. Each daughter of a carrier mother has a 50 per cent risk of being a carrier.

Who should be tested

• individuals clinically suspected of being affected with SBMA.
• individuals with a family history of SBMA, to determine the carrier status of unaffected individuals.

Testing Methodology

Direct Mutation Analysis: PCR analysis across the CAG repeat is used to measure the number of repeats in the androgen receptor (AR) gene.

Test Sensitivity: Expansion of the AR repeat occurs in 99 per cent of individuals affected with SBMA. These cases will be detected by current testing procedures in place in the Molecular Genetics Laboratory.

• Approximately one per cent of SBMA cases are caused by other types of mutation in the AR gene. These cases will not be detected by this analysis.
  • For example, of 100 people affected with Spinal bulbar and muscular atrophy, 99 per cent will be detected by this test; one affected individual would not be detected

Potential Outcomes & Interpretation of Test Results

Caution:

• 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:

• Online Mendelian Inheritance in Man - Item 313200
• GeneReviews online clinical information resource
• Understanding Gene Testing
• To locate a genetics center near you, please visit Canadian Association of Genetic Counsellors website.