Clinical and Genetic Characteristics of Romanian Patients with Mucopolysaccharidosis Type II

  • Camelia Alkhzouz
  • Cecilia Lazea
  • Simona Bucerzan
  • Ioana Nascu
  • Eva Kiss
  • Carmencita Lucia Denes
  • Paula Grigorescu-Sido
Research Report
Part of the JIMD Reports book series (JIMD, volume 33)

Abstract

Background: Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a rare X-linked disorder caused by deficiency of iduronate-2-sulfatase (I2S) enzyme, which leads to the accumulation of partially digested glycosaminoglycans (GAGs) in the lysosomes and induces multisystemic alteration (coarse facial features; skeletal dysplasia; hepatosplenomegaly; joint stiffness and contractures; heart, lung, vision, and hearing disability; profound neurological decline).

The purpose of this study is to present the clinical and genetic characteristics of Romanian patients with Hunter syndrome and the genotype–phenotype correlation.

Material and Methods: 15 unrelated patients, with MPS II ranging from mild (4 subjects) to severe phenotype (11 subjects) aged 2 to 20 years, were evaluated clinically, cognitive development, enzyme assay and molecular analysis.

Results: The molecular analysis of the 15 unrelated Romanian MPS II patients has identified 15 different mutations (2 major genetic defects (13%) and 13 minor genetic defects (87%)): microdeletions and point mutations (missense, nonsense), seven of them described for the first time—deletion encompassing 3 to exon 7; c823G>T, pD275Y; c.1600A>C (pN534H); c.102_10delAG (p.D5Cfs*11); c.448_471del (p.P150_P157del); c.421delA (p.I141Yfs*72); and c.419-1G>C. The major genetic defects were correlated with a severe course of disease.

Conclusion: This is the first study on the clinical and molecular characterization of the MPS II Romanian patients. This study supports the evidence of the mutational heterogeneity of the I2S gene as well as the difficulty to correlate genotype and phenotype in the patients with MPS II.

Keywords

Hunter disease Mucopolysaccharidosis type II Romania 

References

  1. Beck M (2011) Mucopolysaccharidosis type II (Hunter syndrome): clinical picture and treatment. Curr Pharm Biotechnol 12:861–866CrossRefPubMedGoogle Scholar
  2. Bonuccelli G, Regis S, Filocamo M et al (1998) A deletion involving exons 2–4 in the iduronate-2-sulfatase gene of a patient with intermediate Hunter syndrome. Clin Genet 53:474–477CrossRefPubMedGoogle Scholar
  3. Brusius-Facchin AC, Schwartz IVD, Zimmer C et al (2014) Mucopolysaccharidosis type II: Identification of 30 novel mutations among Latin American patients. Mol Genet Metab 111:133–138CrossRefPubMedGoogle Scholar
  4. Bunge S, Steglich C, Beck M et al (1992) Mutation analysis of the iduronate-2-sulfatase gene in patients with mucopolysaccharidosis type II (Hunter syndrome). Hum Mol Genet 1:335–339CrossRefPubMedGoogle Scholar
  5. Bunge S, Steglich C, Zuther C et al (1993) Iduronate-2-sulfatase gene mutations in 16 patients with mucopolysaccharidosis type II (Hunter syndrome). Hum Mol Genet 2:1871–1875CrossRefPubMedGoogle Scholar
  6. Crotty PL, Braun SE, Anderson RA et al (1992) Mutation R468W of the iduronate-2-sulfatase gene in mild Hunter syndrome (mucopolysaccharidosis type II) confirmed by in vitro mutagenesis and expression. Hum Mol Genet 1(9):755–757CrossRefPubMedGoogle Scholar
  7. Flomen RH, Green PM, Bentley DR et al (1992) Detection of point mutations and a gross deletion in six Hunter syndrome patients. Genomics 13:543–550CrossRefPubMedGoogle Scholar
  8. Froissart R, Blond JL, Maire I et al (1993) Hunter syndrome: gene deletions and rearrangements. Hum Mutat 2:138–140CrossRefPubMedGoogle Scholar
  9. Froissart R, Maire I, Millat G et al (1998) Identification of iduronate sulfatase gene alterations in 70 unrelated Hunter patients. Clin Genet 53:362–368CrossRefPubMedGoogle Scholar
  10. Giugliani R, Villarreal ML, Valdez CA et al (2014) Guidelines for diagnosis and treatment of Hunter syndrome for clinicians in Latin America. Genet Mol Biol 37:315–329CrossRefPubMedPubMedCentralGoogle Scholar
  11. Goldenfum SL, Young E, Michelakakis H et al (1996) Mutation analysis in 20 patients with Hunter disease. Hum Mutat 7:76–78CrossRefPubMedGoogle Scholar
  12. Gort L, Chabás A, Coll MJ (1998) Hunter disease in the Spanish population: molecular analysis in 31 families. J Inherit Metab Dis 21(6):655–661CrossRefPubMedGoogle Scholar
  13. Hartog C, Fryer A, Upadhyaya M (1999) Mutation analysis of iduronate-2-sulphatase gene in 24 patients with Hunter syndrome: characterisation of 6 novel mutations. Hum Mutat 14(1):87CrossRefPubMedGoogle Scholar
  14. Karsten SL, Voskoboeva E, Tishkanina S et al (1998) Mutational spectrum of the iduronate-2-sulfatase (IDS) gene in 36 unrelated Russian MPS II patients. Hum Genet 103(6):732–735CrossRefPubMedGoogle Scholar
  15. Lissens W, Seneca S, Liebaers I (1997) Molecular analysis in 23 Hunter disease families. J Inherit Metab Dis 20(3):453–456CrossRefPubMedGoogle Scholar
  16. Lualdi S, Di Rocco M, Corsolini F et al (2006) Identification of nine new IDS alleles in mucopolysaccharidosis II. Quantitative evaluation by real-time RT-PCR of mRNAs sensitive to nonsense-mediated and nonstop decay mechanisms. Biochim Biophys Acta 1762(4):478–484CrossRefPubMedGoogle Scholar
  17. Martin R, Beck M, Eng C et al (2008) Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics 121(2):377–386CrossRefGoogle Scholar
  18. Patel P, Suzuki Y, Maeda M et al (2014) Growth charts for patients with Hunter syndrome. Mol Genet Metab Rep 1:5–18CrossRefPubMedPubMedCentralGoogle Scholar
  19. Patlas M, Hadas-Halpern I, Abrahamov A, Zimran A, Elstein D (2002) Repeat abdominal ultrasound evaluation of 100 patients with type I Gaucher disease treated with enzyme replacement therapy for up to 7 years. Hematol J 3:17–20CrossRefPubMedGoogle Scholar
  20. Rathmann M, Bunge S, Beck M, Kresse H, Tylki-Szymanska A, Gal A (1996) Mucopolysaccharidosis type II (Hunter syndrome): mutation “hot spots” in the iduronate-2-sulfatase gene. Am J Hum Genet 59(6):1202–1209PubMedPubMedCentralGoogle Scholar
  21. Scarpa M, Almássy Z, Beck M et al (2011) Mucopolysaccharidosis type II: European recommendations for the diagnosis and multidisciplinary management of a rare disease. Orphanet J Rare Dis 6(1):72CrossRefPubMedPubMedCentralGoogle Scholar
  22. Timms KM, Lu F, Shen Y et al (1995) 130 kb of DNA sequence reveals two new genes and a regional duplication distal to the human iduronate-2-sulfate sulfatase locus. Genome Res 5(1):71–78CrossRefPubMedGoogle Scholar
  23. Vafiadaki E, Cooper A, Heptinstall LE et al (1998) Mutation analysis in 57 unrelated patients with MPS II (Hunter’s disease). Arch Dis Child 79(3):237–241CrossRefPubMedPubMedCentralGoogle Scholar
  24. Weinreb NJ, Charrow J, Andersson HC et al (2002) Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry. Am J Med 113:112–119CrossRefPubMedGoogle Scholar
  25. Wraith JE, Scarpa M, Beck M et al (2008) Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr 167(3):267–277CrossRefPubMedGoogle Scholar
  26. Zhang H, Li J, Zhang X et al (2011) Analysis of the IDS gene in 38 patients with Hunter syndrome: The c.879G > A (p.Gln293Gln) synonymous variation in a female create exonic splicing. PLoS One 6(8), e22951. doi:10.1371/journal.pone.0022951CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Camelia Alkhzouz
    • 1
  • Cecilia Lazea
    • 1
  • Simona Bucerzan
    • 1
  • Ioana Nascu
    • 1
  • Eva Kiss
    • 1
  • Carmencita Lucia Denes
    • 1
  • Paula Grigorescu-Sido
    • 1
  1. 1.1st Department of PediatricsIuliu Haţieganu University of Medicine and PharmacyCluj-NapocaRomania

Personalised recommendations