The first clinical descriptions of MPS I and MPS II recognising the whole phenotype as a disease date back almost a century, preceding the first classification of mucopolysaccharidoses (MPSs) and the discovery of the lysosome by more than three decades.1

The term MPS originated in 1952 after it was discovered that excessive amounts of glycosaminoglycans (GAGs), previously called mucopolysaccharides, were present in urine samples from patients with severe forms of MPS I. Mucopolysaccharidoses were originally thought to result from GAG overproduction. The concept of MPSs as disorders of enzyme deficiency was first proposed by Van Hoof and Hers in 1964 with observations of dramatically enlarged lysosomes in hepatocytes from patients with severe MPS I. Four years later, kinetics studies performed by Fratantoni and co-workers provided proof of impaired enzymatic degradation of GAGs in severe MPS I and MPS II.2 This finding formed the basis of the modern classification of MPSs according to the specific enzyme deficiency involved.1

Recognition of MPS I and MPS II as distinct diseases

Due to their similar clinical presentations, severe phenotypes of MPS I (Hurler syndrome) and MPS II (Hunter syndrome) were not historically recognised as distinct diseases. Patients were often referred to as having Hurler syndrome or Hurler-Hunter syndrome.3 Two different forms were recognised; one that appeared to be inherited in an autosomal recessive fashion and another that appeared to be X-linked. By 1956, these two forms were recognised as Hurler and Hunter syndrome, respectively. However, it wasn’t until the early 1970s that the specific enzyme deficiencies involved in Hurler (α-L-iduronidase) and Hunter syndrome (iduronate-2-sulphatase) were identified.4,5

Historical perspective of MPS I classification

The three subcategories of MPS I (Hurler, Hurler-Scheie and Scheie syndromes; see Disease spectrum & progression) are historical remnants of earlier understanding of the disease aetiology. Hurler syndrome (severe MPS I) was first described by Dr Gertrud Hurler in 1919 and Scheie syndrome (attenuated MPS I) by Dr Harold Scheie in 1962. Although Scheie syndrome was described as resembling a mild version of Hurler syndrome, it was thought to have a distinct aetiology and designated MPS V. However, in 1972, both syndromes were found to be due to a deficiency of the same enzyme (α-L-iduronidase). It was hypothesised that individuals with Hurler syndrome would be homozygous for a severe allele at the α-L-iduronidase locus while Scheie patients would be homozygous for a mild allele. This would explain the observed intermediate phenotype, classified Hurler-Scheie syndrome, which was thought to occur in individuals heterozygous for the Hurler and Scheie alleles.6

Today it is recognised that MPS I represents a continuous spectrum of mild to severe clinical phenotypes caused by more than 100 different alleles of the α-L-iduronidase gene. Although the three subcategories of MPS I are still used in diagnosis, the distinction between the clinical phenotypes is not always clear.6 It has become favourable to classify MPS I into two categories, severe (Hurler syndrome) and attenuated (Hurler-Scheie and Scheie syndromes).7


  1. 1.Coutinho MF, Matos L, Alves S. (2015) From bedside to cell biology: a century of history on lysosomal dysfunction. Gene 555(1): 50-58.
  2. 2.Fratantoni JC, Hall CW, Neufeld EF. (1968) The defect in Hurler's and Hunter's syndromes: faulty degradation of mucopolysaccharide. Proc Natl Acad Sci U S A 60(2): 699-706.
  3. 3.Martin R, Beck M, Eng C, et al. (2008) Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics 121(2): e377-386.
  4. 4.Bach G, Eisenberg F, Jr., Cantz M, Neufeld EF. (1973) The defect in the Hunter syndrome: deficiency of sulfoiduronate sulfatase. Proc Natl Acad Sci U S A 70(7): 2134-2138.
  1. 5.McKusick VA. Am J Hum Genet. 1978; 30: 105-122.
  2. 6.Muenzer J. Rheumatology (Oxford). 2011; 50 Suppl 5: v4-12.
  3. 7.Muenzer J, et al. Pediatrics. 2009; 123: 19-29.