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MPS Reference
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MPS I: an overview

Patients with mucopolysaccharidosis (MPS) I are at increased risk for severe morbidity and early mortality1

MPS I is a progressive condition2 that has been divided into 3 subtypes known as Hurler syndrome (MPS I-H), Hurler-Scheie syndrome (MPS I-H/S), and Scheie syndrome (MPS I-S).3 All subtypes of MPS I are caused by a deficiency of the enzyme α-L-iduronidase, which is required for the degradation of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate,2,4 with resulting progressive, multisystemic manifestations.2

  • MPS I-H typically presents within the first 2 years of life with developmental delay, cognitive decline and rapid progression.2
  • MPS I-H/S typically presents between the ages of 3 and 7 with mild or absent cognitive decline and slower progression.2
  • MPS I-S typically presents between the ages of 5 and 13 with no cognitive decline and slower progression.2

Observed presentation

  • Symptoms appear at varying ages depending on the specific enzyme deficiency and rate of disease progression1:
    • H, ages 0 to 2
    • H/S, ages 3 to 7
    • S, ages 5 to 13
  • Observed presentation includes the following5:
    • Change in facial features
    • Restricted joint movement
    • Skeletal deformity
    • Macrocephaly
    • Frequent respiratory infections
    • Cardiomyopathy
    • Recurrent ear infections
    • Hernias
    • Kyphosis/gibbus deformity
  • Specific recommendations for consideration of MPS I include the following6:
    • Children with gibbus deformity, enlarged tongue, and/or 2 or more surgeries before 18 months should prompt diagnostic testing.
    • Children over 2 years of age with claw hands, cardiac problems, and/or 2 or more surgeries before age 10 should prompt diagnostic testing.

Disease progression

  • Overall disease burden:
    • Patients experience multiorgan dysfunction and have a high disease burden.1
    • This progressive, debilitating disease also puts psychological and financial burdens on patients and their families.5
  • Hurler (H):
    • Symptoms appear shortly after birth, progress rapidly and typically include the following1:
      • Developmental delay and cognitive decline
      • Coarse facial features
      • Joint stiffness and contractures
      • Short stature
      • Hepatosplenomegaly
      • Respiratory and cardiac disease
    • Left untreated, patients typically die within the first decade of life, often due to cardiorespiratory failure and neurological disease.1,5
  • Hurler-Scheie (H/S) and Scheie (S):
    • Symptom presentation varies according to age7:
      • Hernia typically occurs before age 5.
      • Joint contractures and dysostosis multiplex typically arise between the ages of 5 and 12.
      • Scoliosis, carpal tunnel syndrome and congestive heart failure often occur in adolescence.
      • Glaucoma, cardiomyopathy and myelopathy typically arise in early adulthood.
    • Left untreated, patients with MPS I-H/S typically die within the second or third decade of life.1
    • Left untreated, patients with MPS I-S usually sustain significant morbidity.1
  • Patients with MPS I have a high surgical burden, which may include the following6:
    • Myringotomies
    • Hernia surgery, often with repeat procedures
    • Adenoidectomy
    • Tonsillectomy
    • Ventriculoperitoneal shunt
    • Spinal procedures
    • Carpal tunnel surgery
    • Orthopaedic surgeries of hip, knee and foot
  • Because patients with MPS I often experience anaesthetic complications due to obstructed airways, special care must be taken when undergoing surgery.8

Genetic information

  • MPS I is caused by mutations in the α-L-iduronidase gene, IDUA.4
  • There are over 100 known pathogenic variants within IDUA.9
  • These mutations lead to accumulation of the GAGs heparan and dermatan sulfate.4

Key management considerations

  • The potential use of enzyme replacement therapy and haematopoietic stem cell transplantation (HSCT) are both important considerations in the management of MPS I1,5:
  • Patients with the Hurler phenotype diagnosed before 2 years should be treated with HSCT.10
  • All other patients should be treated with enzyme replacement therapy.10
  • Available treatment and management recommendations:
    • Martins AM, Dualibi AP, Norato D, et al. Guidelines for the management of mucopolysaccharidosis type I. J Pediatr. 2009;155(4)(suppl 2):S32-S46. doi:10.1016/j.jpeds.2009.07.005.
    • Muenzer J, Wraith JE, Clarke LA, International Consensus Panel on the Management and Treatment of Mucopolysaccharidosis I. Mucopolysaccharidosis I: management and treatment guidelines. Paediatrics. 2009;123(1):19-29. doi:10.1542/peds.2008-0416.
    • de Ru MH, Boelens JJ, Das AM, et al. Enzyme replacement therapy and/or haematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure. Orphanet J Rare Dis. 2011;6(55):1-9. doi:10.1186/1750-1172-6-55.
    • Langereis EJ, Borgo A, Crushell E, et al. Treatment of hip dysplasia in patients with mucopolysaccharidosis type I after haematopoietic stem cell transplantation: results of an international consensus procedure. Orphanet J Rare Dis. 2013;8(155):1-16. doi:10.1186/1750-1172-8-155.
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References:  1. Beck M, Arn P, Giugliani R, et al. The natural history of MPS I: global perspectives from the MPS I Registry. Genet Med.2014;16(10):759-765. doi:10.1038/gim.2014.25.  2. Clarke LA, Wraith JE, Beck M, et al. Long-term efficacy and safety of laronidase in the treatment of mucopolysaccharidosis I. Pediatrics. 2009;132(1):229-240. doi:10.1542/peds.2007-3847.  3. Yasuda E, Mackenzie WG, Ruhnke KD, et al. Long-term follow-up of post hematopoietic stem cell transplantation for Hurler syndrome: clinical, biochemical, and pathological improvements. Mol Genet Metab Rep. 2015;2:65-76. doi:10.1016/j.ymgmr.2014.12.006.  4. Shapiro EG, Nestrasil I, Rudser K, et al. Neurocognition across the spectrum of mucopolysaccharidosis type I: age, severity, and treatment. Mol Genet Metab. 2015;116(1-2):61-68. doi:10.1016/j.ymgme.2015.06.002.  5. Muenzer J, Wraith JE, Clarke LA, International Consensus Panel on the Management and Treatment of Mucopolysaccharidosis I. Mucopolysaccharidosis I: management and treatment guidelines. Pediatrics. 2009;123(1):19-29. doi:10.1542/peds.2008-0416.  6. Arn P, Wraith JE, Underhill L. Characterization of surgical procedures in patients with mucopolysaccharidosis type I: findings from the MPS I Registry. J Pediatr.2009;154(6):859-864.e3. doi:10.1016/j.jpeds.2008.12.024.  7. Thomas JA, Beck M, Clarke JTR, Cox GF. Childhood onset of Scheie syndrome, the attenuated form of mucopolysaccharidosis I. J Inherit Metab Dis. 2010;33(4):421-427. doi:10.1007/s10545-010-9113-7.  8. Semenza GL, Pyeritz RE. Respiratory complications of mucopolysaccharide storage disorders. Medicine. 1988;67(4):209-219.  9. Clarke LA, Heppner J. Mucopolysaccharidosis type I. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews®. Seattle, WA: University of Washington, Seattle; 2002. http://www.ncbi.nlm.nih.gov/books/NBK1162/?report=reader. Accessed July 31, 2015.  10. de Ru MH, Boelens JJ, Das AM, et al. Enzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure. Orphanet J Rare Dis. 2011;6(55):1-9. doi:10.1186/1750-1172-6-55.