BioHunt – Biomarker for Hunter Disease
Hunter disease (mucopolysaccharidosis type II, MPS 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.
New methods, such as mass-spectrometry, provide a good chance of characterizing specific metabolic alterations in the blood (plasma) of affected patents that will allow us to diagnose the disease earlier in the future, with higher sensitivity and specificity. In a pilot study Compound 312 was identified as a sensitive and specific biomarker. The structure and pathophysiological role will have to be illucidated further; however, preliminary data suggests that Compound 312 is a feasible biomarker for Hunter syndrome. After the verfication of Compound 312 as a biomarker for Hunter syndrome, quantification and validation of Compound 312 in saliva will allow for an easier detection method in the future.
The validation of this new biochemical marker from the plasma and saliva of the affected patients is the goal of this study.
What is Hunter Disease?
Mutations in the IDS gene located at Xq28 cause loss of the iduronate-2-sulphatase 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% of all patients), deletions of certain exons or the entire IDS gene (10% of all patients) or small mutations including insertions, deletions and point mutations (80% of all 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-sulphatase 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.
Hunter syndrome (MPS II) affects a calculated estimate of approximately 1 in 155,000 live male births. Because Hunter syndrome is an inherited disorder (X-linked recessive) that primarily affects males, it is passed down from one generation to the next in a specific way. Nearly every cell in the human body has 46 chromosomes, with 23 derived from each parent. The I2S gene is located on the X chromosome. Females have two X chromosomes, one inherited from each parent, whereas males have one X chromosome that they inherit from their mother and one Y chromosome that they inherit from their father.
If a male has an abnormal copy of the I2S gene, he will develop Hunter syndrome. A male can obtain an abnormal copy of the I2S gene in one of two ways. His mother is often a carrier; i.e., she has one abnormal and one normal I2S gene, and she passes along the abnormal gene to him. However, during egg and sperm formation, a mutation can develop in the I2S gene on his X chromosome. In this second case, the mother is not a carrier and the risk of a spontaneous mutation occurring again in a future sibling is low but not zero. Females can carry one abnormal copy of the I2S gene and are usually not affected. Although rare, Hunter syndrome has also been reported to occur in females.