alfaLiduronidase

Alpha-L-iduronidase is a lysosomal hydrolase encoded by the IDUA gene in humans. It catalyzes the hydrolysis of terminal alpha-L-iduronosidic bonds in the glycosaminoglycans dermatan sulfate and heparan sulfate, enabling their degradation within lysosomes. Deficiency of this enzyme leads to mucopolysaccharidosis type I (MPS I), a spectrum of disorders ranging from the severe Hurler phenotype to the milder Scheie phenotype.

Genetics and biochemistry: The IDUA gene is located on chromosome 4p16.3. The enzyme is synthesized as a precursor protein that is trafficked to lysosomes via the mannose-6-phosphate receptor pathway and processed to the mature active form. Deficiency causes accumulation of dermatan sulfate and heparan sulfate in lysosomes, leading to multi-organ dysfunction.

Clinical features: MPS I presents with progressive somatic symptoms such as coarse facial features, hepatosplenomegaly, skeletal dysplasia, joint stiffness, corneal clouding, and recurrent respiratory infections. Cognitive impairment is common in severe forms. Onset and severity vary with residual enzymatic activity.

Diagnosis and treatment: Diagnosis relies on measuring alpha-L-iduronidase activity in leukocytes or fibroblasts, urinary glycosaminoglycan quantification, and IDUA gene sequencing. Enzyme replacement therapy with recombinant human alpha-L-iduronidase (iduronidase), marketed as Aldurazyme, reduces non-neurological disease manifestations but does not prevent neurological decline because the enzyme does not cross the blood–brain barrier. Hematopoietic stem cell transplantation may be considered in selected cases and earlier intervention can improve somatic outcomes. Research continues into newer therapies and gene therapy.