A 3-year-old boy is brought to the pediatric clinic with severe global developmental delay. On examination, he has coarse facial features, hepatosplenomegaly, and a heart murmur. Biochemical investigations reveal elevated urinary glycosaminoglycans. Genetic testing confirms mucopolysaccharidosis type I (MPS I). What is the drug of choice for disease-modifying therapy in this child?

Explanation

## Mucopolysaccharidosis Type I (MPS I) — Enzyme Replacement Therapy ### Disease Pathophysiology MPS I results from deficiency of alpha-L-iduronidase, leading to accumulation of heparan sulfate and dermatan sulfate in lysosomes. This causes progressive somatic and neurological deterioration, cardiac valve disease, and skeletal dysplasia. ### Drug of Choice: Laronidase **Key Point:** Laronidase is a recombinant human alpha-L-iduronidase administered as intravenous enzyme replacement therapy (ERT). It is the FDA-approved and gold-standard first-line treatment for MPS I. **High-Yield:** Laronidase dosing is 0.58 mg/kg IV weekly. It reduces urinary glycosaminoglycan excretion, improves hepatosplenomegaly, enhances cardiac function, and slows progression of skeletal disease when started early. **Clinical Pearl:** ERT is most effective in attenuated forms of MPS I (Scheie and Hurler-Scheie variants) and in early-stage Hurler disease. It does NOT cross the blood-brain barrier, so neurological manifestations in severe Hurler disease progress despite ERT; hematopoietic stem cell transplantation (HSCT) is preferred in those cases. ### Comparison of MPS I Treatment Options | Agent | Mechanism | Indication | Route | Limitation | | --- | --- | --- | --- | --- | | **Laronidase** | Recombinant alpha-L-iduronidase | MPS I (attenuated & early Hurler) | IV weekly | No CNS penetration | | Genistein | Substrate reduction (inhibits glycosaminoglycan synthesis) | Experimental; MPS I adjunct | Oral | Limited evidence; not standard | | Idebenone | Mitochondrial electron transport enhancer | Friedreich ataxia, other mitochondrial disease | Oral | No role in MPS I | | Miglustat | Iminosugar; glucosylceramide synthase inhibitor | Gaucher disease, Niemann-Pick C | Oral | Not indicated for MPS I | **Warning:** Do NOT confuse ERT (laronidase) with substrate reduction therapy (genistein). Genistein is experimental and not first-line for MPS I. ### When to Use HSCT Instead If the child has severe Hurler disease (neuronopathic form) with rapid CNS decline, HSCT is preferred because it can provide enzyme-producing cells that cross the blood-brain barrier and halt neurological progression.