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]

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 altered 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 an altered 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), present on chromosome (locus 4p16.3), extends 19 kb and includes 14 exons. Two major IDUA alleles, W402X and Q70X, and a minor IDUA allele, P533R, account for more than 50% of the MPS I alleles in the Caucasian demographic. These alleles result in a nonfunctional α-L-iduronidase enzyme, and if present individually or in combination, these alleles could lead to the severe MPS I phenotype.[4] More than 200 pathogenic variants have been reported;[5] these numbers will most likely increase as research is conducted.

Did You Know?

Genetic counselors are health professionals who are trained to help families understand genetic disorders such as MPS I disease. A genetic counselor can help you determine if you are a carrier of a gene defect that causes MPS I and can provide valuable information and support for family planning. To learn more, click here.

References

  1. Meikle, P.J. et al., Prevalence of lysosomal storage disorders. JAMA 1999; 281: 249-254.
  2. Lowry, R.B., and Renwick, D.H.G. (1971) Relative frequencies of the Hurler and Hunter syndromes. N Engl J Med. 284: 221.
  3. 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.
  4. Neufeld EF, Muenzer J. The Mucopolysaccharidoses. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G. eds. The Online Metabolic and Molecular Bases of Inherited Disease New York, NY: McGraw-Hill; 2014. https://ommbid.mhmedical.com/content.aspx?bookid=971&sectionid=62642135. Accessed February 2019.
  5. Poletto E, Pasqualim G, Giugliani R, Matte U, Baldo G. Worldwide distribution of common IDUA pathogenic variants. Clinical genetics. 2018 Jul;94(1):95-102.