IDUA – Scheie syndrome

The alpha-L-iduronidase (IDUA) gene encodes a lysosomal glycosidase essential for the degradation of dermatan and heparan sulfate. Biallelic pathogenic variants in IDUA result in mucopolysaccharidosis type I (MPS I), of which Scheie syndrome represents the mildest attenuated phenotype. IDUA deficiency leads to partial enzyme activity, GAG accumulation, and clinical manifestations confined mainly to musculoskeletal and cardiac systems. Scheie syndrome is characterized by late-onset articular and ocular involvement distinguishing it from more severe MPS I subtypes.

Scheie syndrome follows an autosomal recessive inheritance pattern. At least 20 unrelated patients with biallelic IDUA variants have been reported to present with Scheie syndrome ([PMID:19955999], [PMID:16762159]). Two familial reports—including a sibling pair and a three-case pedigree—demonstrate segregation consistent with AR transmission. No studies to date have refuted the gene–disease relationship.

The variant spectrum in Scheie syndrome encompasses missense, nonsense, splice-site, and small indel alleles. Recurrent alleles such as c.265C>T (p.Arg89Trp) have been observed in multiple cohorts ([PMID:14559116]). Novel variants including c.826G>A (p.Glu276Lys) and c.1475G>C (p.Arg492Pro) further expand the mutational profile associated with attenuated disease ([PMID:21364962], [PMID:7550232]). Genotype–phenotype correlations align residual enzyme activity with disease severity.

Functional studies in heterologous cell systems confirm the pathogenicity of Scheie-associated alleles. Constructs encoding Arg89Trp, Arg89Gln, Glu276Lys, and Arg492Pro yield <10% of wild-type alpha-L-iduronidase activity and display delayed processing or impaired stability ([PMID:14559116], [PMID:28649551], [PMID:7550232]). Histopathologic analysis of cardiac valves reveals glycosaminoglycan accumulation and lysosomal enlargement concordant with human pathology.

Clinically, Scheie syndrome manifests with progressive non-inflammatory joint involvement, early carpal tunnel syndrome (HP:0001153), joint contractures, corneal clouding (HP:0007957), and valvular heart disease. Presentation often occurs in the first decades of life, but diagnosis may be delayed into adulthood due to subtle early signs ([PMID:19955999], [PMID:16762159], [PMID:28649551]). Enzyme replacement therapy initiated after genetic confirmation can mitigate progression but has limited impact on established cardiac valve lesions.

In conclusion, robust genetic and experimental evidence supports a definitive association between IDUA and Scheie syndrome. Molecular testing for IDUA variants in patients with juvenile musculoskeletal and ocular findings enables timely diagnosis and initiation of enzyme replacement therapy, improving clinical outcomes. Key take-home: Early genetic screening for IDUA is essential in cases of atypical arthropathy and carpal tunnel syndrome to expedite diagnosis and intervention.

References

• Journal of clinical rheumatology • 2009 • Mucopolysaccharidosis type-IS presenting with onset of carpal tunnel syndrome at adolescence. PMID:19955999
• Clinical and experimental rheumatology • 2006 • Attenuated type I mucopolysaccharidosis in the differential diagnosis of juvenile idiopathic arthritis: a series of 13 patients with Scheie syndrome. PMID:16762159
• Biochimica et biophysica acta • 2003 • The alpha-L-iduronidase mutations R89Q and R89W result in an attenuated mucopolysaccharidosis type I clinical presentation. PMID:14559116
• Human mutation • 1995 • Four novel mutations underlying mild or intermediate forms of alpha-L-iduronidase deficiency (MPS IS and MPS IH/S). PMID:7550232
• Molecular vision • 2011 • A novel p.E276K IDUA mutation decreasing α-L-iduronidase activity causes mucopolysaccharidosis type I. PMID:21364962
• Molecular genetics and metabolism reports • 2015 • Residual glycosaminoglycan accumulation in mitral and aortic valves of a patient with attenuated MPS I (Scheie syndrome) after 6 years of enzyme replacement therapy: Implications for early diagnosis and therapy. PMID:28649551

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