IDUA – Hurler syndrome

IDUA encodes the lysosomal enzyme alpha-L-iduronidase, whose deficiency causes Hurler syndrome (MPS IH), a severe autosomal recessive mucopolysaccharidosis characterized by early-onset multisystemic dysfunction. Patients present in infancy with coarse facial features, joint stiffness, umbilical hernia, and corneal clouding due to glycosaminoglycan accumulation impairing connective tissue and organ function.

Clinical Validity

The association between IDUA and Hurler syndrome is Definitive, supported by over 538 unrelated severe MPS IH probands (PMID:31194252) and extensive concordance of genotype with phenotype. Multiple families from diverse populations (at least 7 segregating kindreds) demonstrate autosomal recessive inheritance with homozygous or compound heterozygous pathogenic variants (PMID:8328452).

Genetic Evidence

Hurler syndrome follows an autosomal recessive inheritance mode, with 538 severe cases described in the International MPS I Registry (PMID:31194252). Segregation in 7 families confirmed co-segregation of IDUA variants with disease (PMID:8328452). Over 75 unique pathogenic variants have been reported, including nonsense, missense, splice-site, and frameshift alleles. A recurrent founder mutation is c.1206G>A (p.Trp402Ter), accounting for 31% of alleles in some cohorts (PMID:1301196).

Functional Evidence

Alpha-L-iduronidase activity assays consistently show absent or markedly reduced enzyme levels in patient fibroblasts, with delayed maturation of precursor forms (PMID:1627351). A knock-in mouse model carrying the analogous W402X mutation recapitulates GAG storage, skeletal dysplasia, and elevated urinary GAGs, confirming haploinsufficiency as the pathogenic mechanism (PMID:19751987). Combination therapy with enzyme replacement and hematopoietic stem cell transplantation improves biochemical and clinical outcomes, demonstrating rescue of enzyme function and clinical utility (PMID:18037941).

Integration and Clinical Utility

Collectively, genetic and experimental data establish IDUA deficiency as the root cause of Hurler syndrome, justifying newborn screening and early therapeutic intervention. Molecular diagnosis via sequencing of IDUA enables genotype-phenotype predictions, informs recurrence risk, and supports treatment decisions including enzyme replacement and transplant. Key take-home: Early genetic diagnosis of IDUA mutations in suspected Hurler syndrome guides life-saving interventions and anticipatory management.

References

• Clinical genetics • 2019 • Genotype-phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry. PMID:31194252
• American journal of human genetics • 1993 • Molecular analysis of Hurler syndrome in Druze and Muslim Arab patients in Israel: multiple allelic mutations of the IDUA gene in a small geographic area. PMID:8328452
• Human mutation • 1992 • A common mutation for mucopolysaccharidosis type I associated with a severe Hurler syndrome phenotype. PMID:1301196
• Molecular genetics and metabolism • 2010 • Characterization of an MPS I-H knock-in mouse that carries a nonsense mutation analogous to the human IDUA-W402X mutation. PMID:19751987
• Bone marrow transplantation • 2008 • Combination of enzyme replacement and hematopoietic stem cell transplantation as therapy for Hurler syndrome. PMID:18037941

Evidence Based Scoring (AI generated)