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Hunter Disease

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

Background

Hunter disease (mucopolysaccharidosis type II) is a lysosomal storage disease caused by deficiency of the enzyme iduronate-2-sulphatase. Deficiency of iduronate sulphatase enzyme causes accumulation of the products dermatan sulphate and heparan sulphate in lysosomes leading to cell death. Hunter disease can vary from mild to severe, depending on the level of enzyme deficiency. Features of the disease include dwarfism, enlarged liver and spleen, cardiovascular disorders and deafness.

Mutations in the IDS gene located at Xq28 causes loss of the iduronidate sulfatase enzyme. A pseudogene IDS2 also exists 20 kb from the active IDS gene. The pseudogene IDS2 shares homology to exon 2, intron 2, exon 3, intron 3 and intron 7 of the IDS gene.

Mutations that have been reported in the IDS gene in Hunter patients include gene rearrangements caused by recombination with the IDS2 gene (10 per cent patients), deletions of certain exons or the entire IDS gene (10 per cent patients) or small mutations including insertions, deletions and point mutations (80 per cent patients). To detect all possible types of mutations in the IDS gene causing Hunter disease, three procedures are necessary. These include Southern blot to look for gene rearrangements, multiplex dosage analysis to detect large deletions and DHPLC and sequencing to detect small mutations.

An accurate biochemical test is available for the diagnosis of Hunter disease consisting of the analysis of iduronate-2-sulfatase activity in plasma, leucocytes or cultured cells. This test should be considered before molecular analysis is undertaken. Molecular identification of the mutation in individuals with a confirmed diagnosis can be used for carrier testing and prenatal diagnosis in the family. The biochemical test is not reliable for identifying carriers.

Who should be tested

• individuals clinically and/or biochemically suspected of being affected with Hunter disease
• women with a family history of Hunter disease, to determine the carrier status of unaffected individuals
• pregnancies at risk due to a family history of Hunter disease

Testing Methodology

Direct Mutation Analysis: This assay consists of two stages:

• Direct sequence analysis to identify any point mutations or small insertions/deletions.
• Southern blot analysis to detect rearrangements between the IDS gene and the IDS2 pseudogene or
• Dosage analysis to detect large scale deletions in the IDS gene

Potential Outcomes & Interpretation of Test Results

Cautions

• Current molecular testing will not detect all possible mutations in this gene. A negative test, therefore, does not rule out the diagnosis of Hunter disease, or eliminate the possibility the individual is a carrier.
• We strongly recommend that biochemical analysis be done on these patients, as it can be a useful complement to molecular testing.
• It is helpful to first identify the mutation(s) in an affected family member or in the parent of the affected family member. If the familial mutation can be identified in this way, the molecular test is conducted only for the familial mutation.
• 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 # 309900
• Understanding Gene Testing
• To locate a genetics center near you, please visit Canadian Association of Genetic Counsellors website.