MPS-1 Hurler Disease

1. DEFINITION AND CLASSIFICATION

• Definition: The most severe subtype of Mucopolysaccharidosis Type I (MPS I), a progressive lysosomal storage disorder caused by deficiency of alpha-L-iduronidase.
• Classification:
  • Hurler (MPS I-H): Severe form with neurodegeneration and early death.
  • Hurler-Scheie (MPS I-H/S): Intermediate form.
  • Scheie (MPS I-S): Mild form with normal intellect and near-normal lifespan.

2. ETIOLOGY AND GENETICS

• Inheritance: Autosomal Recessive.
• Gene: IDUA gene on chromosome 4p16.3.
• Enzyme Defect: Deficiency of alpha-L-iduronidase.
• Pathophysiology:
  • Failure to degrade glycosaminoglycans (GAGs).
  • Accumulation of Dermatan Sulfate and Heparan Sulfate within lysosomes.
  • Leads to cellular dysfunction, hypertrophy, and multisystem tissue damage.

3. CLINICAL FEATURES

• General:
  • Inguinal Hernia: often the earliest presenting sign (months before other symptoms).
  • Failure to thrive and short stature (detectable by 2-3 years).
• Craniofacial:
  • Coarse Facies: Flat nasal bridge, thick lips, macroglossia.
  • Macrocephaly: Scaphocephaly due to premature suture closure.
  • Chronic nasal discharge ("snuffles").
• Ophthalmologic:
  • Corneal Clouding: Diffuse, ground-glass opacity (Universal finding).
  • Distinguishes Hurler (Cloudy) from Hunter (Clear).
  • Glaucoma and retinal degeneration.
• Skeletal (Dysostosis Multiplex):
  • Spine: Thoracolumbar kyphosis (Gibbus deformity) usually at L1-L2; often the first skeletal sign.
  • Hands: Claw-hand deformity, broad digits, proximal pointing of metacarpals.
  • Ribs: Ovoid or paddle-shaped ribs.
  • Joints: Generalized stiffness and contractures.
• Visceral:
  • Hepatosplenomegaly: Massive, due to GAG storage; abdomen is protuberant.
• Cardiorespiratory:
  • Valvular heart disease (Mitral/Aortic regurgitation or stenosis).
  • Obstructive sleep apnea due to airway narrowing and macroglossia.
• Neurologic:
  • Developmental delay (sitting/walking delayed).
  • Progressive intellectual regression after 1-2 years.
  • Communicating hydrocephalus.

4. INVESTIGATIONS

• Screening Tests:
  • Urine GAGs: Quantitative elevation of dermatan and heparan sulfate.
  • Berry Spot Test: Qualitative screening (toluidine blue).
• Confirmatory Tests:
  • Enzyme Assay (Gold Standard): Absent alpha-L-iduronidase activity in leukocytes or dried blood spots.
  • Molecular Genetics: IDUA gene sequencing (identifies mutations like W402X).
• Radiology:
  • Skeletal Survey: Reveals classical Dysostosis Multiplex.
  • Lateral Spine X-ray: Anterior beaking of vertebrae (Gibbus).

5. MANAGEMENT

• Hematopoietic Stem Cell Transplantation (HSCT):
  • Treatment of Choice for severe Hurler phenotype if diagnosed early (<2 years).
  • Prevents progressive neurocognitive decline.
  • Resolves hepatosplenomegaly and improves hearing/facial features.
  • Does not fully correct skeletal or corneal issues.
• Enzyme Replacement Therapy (ERT):
  • Agent: Laronidase (recombinant human alpha-L-iduronidase).
  • Role: Manages somatic symptoms (liver, spleen, joints) and improves respiratory function.
  • Limitation: Does not cross the blood-brain barrier; ineffective for CNS disease.
• Supportive Care:
  • Hernia repair.
  • VP shunt for hydrocephalus.
  • Corneal transplantation for severe clouding.
  • CPAP for sleep apnea.

6. PROGNOSIS

• Untreated: Progressive deterioration; death usually occurs in the first decade (age 5-10) due to respiratory obstruction or cardiac failure.
• Treated (Early HSCT): Significantly improved survival and cognitive preservation.