MPS I Disease History

Mucopolysaccharide storage disease was first described clinically in 1917, when Charles Hunter, a Canadian physician, described two brothers with enlarged livers and coarse facial features ^[1]. In 1919, Gertrud Hurler, a German physician, described two unrelated boys with coarse facial features, mental retardation and hepatomegaly^[2]. The diseases described by doctors Hunter and Hurler are now known as mucopolysaccharidoses (MPS) II and I, respectively. Interestingly, in 1962 Harold Scheie, an American ophthalmologist, described a patient with corneal clouding and joint disease which he felt was a forme fruste of Hurler disease. This symptom complex was initially termed MPS V, a designation which was later dropped when Scheie syndrome was confirmed to be a mild form of MPS I.

It was many years after these initial clinical observations, in the late 1960s, when researchers began to elucidate the underlying basis of lysosomal storage disorders ^[3]. This first involved understanding the lysosome’s key role in degradative processes that occur as a normal part of tissue growth and homeostasis; later, specific degradative functions were characterized, which was followed by the identification of individual lysosomal enzymes. From 1968 to 1970, Drs. Fratantoni, Hall, Wiesmann and Neufeld made several significant breakthroughs in determining the etiology of the mucopolysaccharidoses. They showed that cells from MPS-affected patients were unable to degrade glycosaminoglycans. Moreover, the co-cultivation of fibroblasts from Hurler and Hunter patients caused mutual correction (“cross-correction”), thus overcoming the defect that caused intracellular accumulation of mucopolysaccharide. This was a highly significant finding since it demonstrated that Hunter and Hurler syndromes were caused by separate and distinct genetic defects in glycosaminoglycan degradation ^[4,5]. No cross-correction was achieved when fibroblasts from patients with Scheie and Hurler syndromes were co-cultivated, indicating that these diseases were caused by defects of the same gene ^[6]. Finally, researchers began to relate different disease conditions with specific lysosomal enzyme deficiencies. For example, the diseases described by Drs. Hunter and Hurler are caused by deficiencies of the lysosomal enzymes iduronate sulfatase and α-L-iduronidase, respectively ^{[7, 8, 9, 10]}. In addition, some conditions such as Hurler and Scheie syndromes were found to represent different extremes of the spectrum of disease associated with a single enzyme deficiency ^[11]. The discovery that a specific deficiency in α-l-iduronidase is the underlying cause of MPS I made it possible to diagnose the disease by measuring the activity of α-l-iduronidase in the leukocytes, plasma and cultured fibroblasts of affected patients.

In 1991-1992, the full-length cDNA was isolated and the entire sequence of the human α-l-iduronidase gene was determined ^{[12, 13]}. The identification of mutations in the gene that lead to deficiency of the α-l-iduronidase enzyme has provided important insights into the molecular and biochemical basis of MPS I ^{[12,13,14,15,16,17,18,19]}.The precise identification of the underlying cause of MPS I at the molecular, biochemical and cellular levels, and the availability of new molecular genetic techniques, have fueled research on several disease-specific therapeutic strategies currently at various stages of development. With potential advances in enzyme replacement and gene therapies, early clinical diagnosis of disease remains paramount in directing the application of therapeutics and appropriate genetic counseling ^[9].

References

1. Hunter, C.A. (1917) A rare disease in two brothers. Proc Roy Soc Med 10: 104.

2. Hurler, G. (1919) Uber einen Typ multiper Abartungen, vorwiegend am Skelettsystem. Z Kinderheilk 24: 220.

3. Hopwood, J.J., and Brooks, D.A. (1997). An introduction to the basic science and biology of the lysosome and storage diseases. In: Organelle Diseases. Clinical Features, Diagnosis, Pathogenesis and Management. Applegarth, D.A., Dimmick, J.E., and Hall, J.G. (eds.). Chapman and Hall Medical, London, pp. 7.

4. Fratantoni, J.C., Hall, C.W., and Neufeld, E.F. (1968a) Hurler and Hunter syndromes: Mutual correction of the defect in cultured fibroblasts. Science 162: 570.

5. Fratantoni, J.C., Hall, C.W., and Neufeld, E.F. (1968b) The defect in Hurler’s and Hunter’s syndromes: Faulty degradation of mucopolysaccharide. Proc Natl Acad Sci USA 60: 699.

6. Wiesmann, U., and Neufeld, E.F. (1970) Scheie and Hurler syndromes: apparent identity of the biochemical defect. Science 169: 72.

7. Fratantoni, J.C., Hall, C.W., and Neufeld, E.F. (1969a) The defect in Hurler’s and Hunter’s syndromes. Deficiency of specific factors involved in mucopolysaccharide degradation. Proc Natl Acad Sci USA 64: 360.

8. Barton, R.W., and Neufeld, E.F. (1971) The Hurler corrective factor: purification and some properties. J Biol Chem 246: 7773.

9. Clarke, L.A. (1997) Clinical diagnosis of lysosomal storage diseases. In: Organelle Diseases. Clinical Features, Diagnosis, Pathogenesis and Management. Applegarth, D.A., Dimmick, J.E., and Hall, J.G. (eds.). Chapman and Hall Medical, London, pp. 37.

10. 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.

11. Wiesmann, U., and Neufeld, E.F. (1970) Scheie and Hurler syndromes: apparent identity of the biochemical defect. Science 169: 72.

12. Scott, H.S., Anson, D.S., Orsborn, A.M., Nelson, P.V., Clements, P.R., Morris, C.P., and Hopwood, J.J. (1991) Human a-L-iduronidase: cDNA isolation and expression. Proc Natl Acad Sci USA 88: 9695.

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

14. Scott, H.S., Litjens, T., Nelson, P.V., Thompson, P.R., Brooks, D.A., Hopwood, J.J., and Morris, C.P. (1993a) Identification of mutations in the a-l-iduronidase gene (IDUA) that cause Hurler and Scheie syndromes. Am J Hum Genet 53: 973.

15. Scott, H.S., Nelson, P.V., Litjens, T., Hopwood, J.J., and Morris, C.P. (1993b) Multiple polymorphisms within the a-l-iduronidase gene (IDUA): Implications for a role in modification of MPS-I disease. Hum Mol Genet 2: 1471.

16. Scott, H.S., Bunge, S., Gal, A., Clarke, L.A., Morris, C.P., and Hopwood, J.J. (1995) Molecular genetics of mucopolysaccharidosis type I: Diagnostic, clinical, and biological implications. Hum Mutat 6: 288.

17. Clarke, L.A., and Scott, H.S. (1993) Two novel mutations causing mucopolysaccharidosis type I detected by single strand conformation analysis of the a-l-iduronidase gene. Hum Mol Genet 2: 1311

18. Clarke, L.A., Nelson, P.V., Warrington, C.L., Morris, C.P., Hopwood, J.J., and Scott, H.S. (1994). Mutation analysis of 19 North American mucopolysaccharidosis type I patients: Identification of two additional frequent mutations. Hum Mutat 3: 275.

19. Bunge, S., Kleijer, W.J., Steglich, C., Beck, M., Zuther, C., Morris, C.P., Schwinger, E., Hopwood, J.J., Scott, H.S., and Gal, A. (1994). Mucopolysaccharidosis type I: Identification of 8 novel mutations and determination of the frequency of the two common a-l-iduronidase mutations (W402X and Q70X) among European patients. Hum Mol Genet 3: 861.