Mucopolysaccharidosis type II: an update on mutation spectrum

Area of Science:

• Genetics
• Biochemistry
• Rare Diseases

Background:

• Mucopolysaccharidosis type II (MPS II), or Hunter disease, results from iduronate-2-sulphatase (IDS) deficiency.
• Clinical presentation of MPS II is highly variable, and IDS enzyme activity levels do not reliably predict phenotype.
• Genetic analysis is essential for diagnosing MPS II, as all affected individuals exhibit alterations in the IDS gene.

Purpose of the Study:

• To investigate the spectrum of IDS gene alterations in patients with MPS II.
• To explore the relationship between genotype and phenotype in MPS II to aid in prognosis and treatment evaluation.
• To identify the frequency and patterns of de novo mutations and mosaicism in MPS II.

Main Methods:

• Genetic analysis of the IDS gene in 155 unrelated individuals with MPS II.
• Identification and characterization of both large and small gene alterations.
• Investigation of familial cases to detect mosaicism and de novo mutations, particularly in male meiosis.

Main Results:

• All 155 MPS II patients studied had identifiable alterations in the IDS gene.
• A total of 155 gene alterations were identified, including 27 large and 128 small (96 unique) alterations, confirming extreme genetic heterogeneity.
• De novo mutations were frequent, especially during male meiosis, and maternal mosaicism was observed in a subset of sporadic cases.

Conclusions:

• The extensive genetic heterogeneity of the IDS gene likely contributes to the wide clinical variability observed in MPS II.
• Establishing genotype-phenotype correlations is challenging but increasingly important for guiding therapeutic strategies tailored to individual patient phenotypes.
• Factors beyond the IDS gene may modulate the clinical phenotype, indicating a complex interplay of genetic and environmental influences in MPS II progression.