Mucopolysaccharidosis Type I

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disease due to deficiency of alpha-L-iduronidase (IDUA, 4p16.3), which leads to accumulation of the glycosaminoglycans dermatan sulfate and heparan sulfate. Incidence is about 1 in 100,000 live births. The clinical spectrum is continuous: Hurler syndrome (severe), Hurler-Scheie (intermediate) and Scheie syndrome (attenuated). More than 100 IDUA variants exist; common variants are W402X and Q70X (severe, particularly in Europeans).

• Severe (Hurler): normal at birth, with symptoms emerging at 6 to 12 months: coarse facies, macrocephaly with frontal bossing, corneal clouding, hepatosplenomegaly, umbilical and inguinal hernias, recurrent upper respiratory and ear infections, thick secretions, skeletal dysplasia (dysostosis multiplex; gibbus deformity, claw hand), joint stiffness, hydrocephalus, developmental regression from age 2 to 3 years, cardiac valve disease and cardiomyopathy, airway obstruction and sleep apnoea, hearing loss, and death in childhood (before age 10) if untreated
• Hurler-Scheie: later onset (3 to 8 years), with milder or absent cognitive impairment, but significant somatic disease (joint stiffness, corneal clouding, cardiac valve disease, airway disease)
• Scheie: onset after 5 years, with normal intelligence, corneal clouding, joint stiffness, cardiac valvular disease, carpal tunnel syndrome, and near normal lifespan

1. Urinary glycosaminoglycans (elevated dermatan and heparan sulfate), quantified and with electrophoresis; screening only, with possible false negatives.
2. Enzyme assay of alpha-L-iduronidase in leucocytes, fibroblasts, or dried blood spot (deficient or absent activity; diagnostic).
3. IDUA genotyping (to predict phenotype and for family studies).
4. Newborn screening is now available in some programmes (dried blood spot enzyme).
5. Baseline assessment: skeletal survey, echocardiography, spinal MRI (cervical cord compression at C1 and C2, odontoid hypoplasia), brain MRI, ophthalmology, audiology, polysomnography, and neurocognitive testing.

• Haematopoietic stem cell transplantation (HSCT; the standard treatment for severe MPS I before 2 years of age, ideally before 24 months and before developmental decline, with developmental quotient above 70): preserves cognition, reduces airway disease, hydrocephalus and hepatosplenomegaly, and improves survival; limited effect on skeletal, corneal and valvular disease. Engraftment with donor enzyme competent cells; outcomes are best with matched donors and cord blood.
• Enzyme replacement therapy with laronidase (recombinant human alpha-L-iduronidase) 0.58 mg/kg IV weekly, given over 3 to 4 hours (premedicate with antihistamine and antipyretic; anaphylaxis monitoring): improves walking capacity, liver and spleen size, joint mobility, and sleep apnoea; does not cross the blood brain barrier; used as bridging therapy before HSCT and as the primary therapy for attenuated disease. Antibody formation is common.
• Supportive care: management of hydrocephalus (ventriculoperitoneal shunt), carpal tunnel decompression, cervical spine decompression and fusion, hip and knee orthopaedic surgery, corneal transplantation, valve replacement, tonsillectomy and adenoidectomy, tracheostomy and CPAP, grommets and hearing aids, and anaesthetic risk planning (difficult airway, cervical instability, cardiopulmonary risk).
• Gene therapy trials are ongoing (lentiviral HSC gene therapy and AAV).
• Genetic counselling: 25% recurrence risk; prenatal diagnosis by enzyme assay or molecular analysis.