Genetics and MPS I

MPS I is seen in all populations at a frequency of approximately 1:100,000.[1] There are severe and attenuated forms, (historically known as Hurler, Hurler-Scheie, and Scheie) that occur in roughly equal proportions.

The estimated incidence of a small subset of individuals with a less severe form of attenuated MPS I (Scheie syndrome) is 1:500,000.[2],[3],[4]


                        Fig.1) Inheritance Pattern of MPS I.

MPS I is inherited in an autosomal recessive manner (Fig. 1). Thus, the disease occurs in an individual who inherits two defective copies of the α-L-iduronidase gene. Based on the frequency of the disease in the population, it is estimated that 1:160 individuals carry a defective allele.

Each of the parents of a child affected with MPS I is typically an obligate heterozygote (carrier) for a disease-causing mutation in the α-L-iduronidase gene. In this situation, the parents will have one normal gene and one mutant gene; as such, they will be asymptomatic, since the one functional copy of the gene allows the individual to produce sufficient quantities of α-L-iduronidase enzyme. Each child of a couple in which both parents are heterozygotes for a disease-causing mutation in the α-L-iduronidase gene has a 25% chance of being affected with MPS I, a 50% chance of being an unaffected heterozygote carrier, and a 25% chance of being an unaffected homozygote non-carrier. The unaffected sibling of an individual with MPS I has a 67% chance of being a heterozygote carrier and a 33% chance of being an unaffected non-carrier. Within the same family, all affected siblings will have the same genotype. However, striking variations in disease manifestations have been reported in affected siblings with the same mutations.

The gene encoding α-L-iduronidase (IDUA) spans 19 kb and includes 14 exons.[5],[6] It is present on chromosome[5] (locus 4p16.3), the region associated with Huntington disease.[7],[8] Two major alleles, W402X and Q70X, and a minor allele, P533R, account for over half of the MPS I alleles in the Caucasian population.[4],[9] None of these alleles produce functional α-L-iduronidase enzyme, and if present singly or in combination, these alleles will give rise to severe MPS I. A comprehensive review in 1995 listed 46 disease-causing mutations and 30 nonpathologic polymorphisms;[10] these numbers will most likely increase as more populations are studied.


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