Genetics

MPS I is seen in all populations at a frequency of approximately 1:100,000 to 1:280,000, with roughly equal proportions of the severe and attenuated forms. The estimated incidence of a small subset of individuals with a less severe form of attenuated MPS I (Scheie syndrome) is 1:500,000 ^[1,2,3].

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 siblings of each parent have a 50% chance of being a heterozygote 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 spans 19 kb and includes 14 exons ^[4,5]. It is present on chromosome 4 (locus 4p16.3) ^[6,7]. Two major alleles, W402X and Q70X, and a minor allele, P533R, account for over half of the MPS I alleles in the Caucasian population ^{[8, 9]}. None of these alleles produce functional α-L-iduronidase enzyme, and if present singly or in combination, these alleles will give rise to a severe phenotype of MPS I. A comprehensive review in 2003 listed ~100 disease-causing mutations and 30 nonpathogenic sequence variants^[9] ; these numbers will most likely increase as more populations are studied.

References

1. Lowry, R.B., and Renwick, D.H.G. (1971) Relative frequencies of the Hurler and Hunter syndromes. N Engl J Med 284: 221.

2. Lowry, R.B., Applegarth, D.A., Toone, J.R., MacDonald, E., and Thunem, N.Y. (1990) An update on the frequency of the mucopolysaccharide syndromes in British Columbia. Hum Genet 85: 389.

3. Neufeld, E.F., and Muenzer, J. (2001) The mucopolysaccharidoses. In: The Metabolic and Molecular Bases of Inherited Disease. Scriver, C.R., Beaudet, A.L., Sly, W.S., Valle, D., Childs, B., Kinzler, K.W., and Vogelstein, B. (eds.). 8th edition, Vol. III. McGraw-Hill, Medical Publishing Division, pp. 3421.

4. Scott, H.S., Guo, X.H., Hopwood, J.J., and Morris, C.P. (1992a) Structure and sequence of the human α-l-iduronidase gene. Genomics 13: 1311.

5. Scott, H.S., Litjens, T., Nelson, P.V., Brooks, D.A., Hopwood, J.J., and Morris, C.P. (1992b) a-l-iduronidase mutations (Q70X and P533R) associate with a severe Hurler phenotype. Hum Mut 1: 333

6. Scott, H.S., Ashton, L.J., Eyre, H.J., Baker, E., Brooks, D.A., Callen, D.F., Sutherland, G.R., Morris, C.P., and Hopwood, J.J. (1990) Chromosomal location of the human a-l-iduronidase gene (IDUA) to 4p 16.3. Am J. Hum Genet 47: 802.

7. MacDonald, M.E., Scott, H.S., Whaley, W.L., Pohl, T., Wasmuth, J.J., Lehrach, H., Morris, C.P., Frischauf, A.-M., Hopwood, J.J., and Gusella, J.F. (1991) Huntington disease–linked locusD4S111 exposed as the alpha-l-iduronidase gene. Somat Cell Mol Genet 17: 421.

8. Clarke, L.A. and Portigal, C. (2002) Mucopolysaccharidosis type I. Gene Reviews (submitted).

9. Terlato, NJ and Cox GF (2003) Can mucopolysaccharidosis type I disease severity be predicted based on a patient's genotype? A comprehensive review of the literature.

Genet Med. Jul-Aug;5(4):286-94. Review