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Mucopolysaccharidosis Type II (Hunter Syndrome): a Clinical Review and Recommendations for Treatment in the Era of Enzyme Replacement Therapy

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Mucopolysaccharidosis Type II (Hunter Syndrome): a Clinical Review and Recommendations for Treatment in the Era of Enzyme Replacement Therapy Eur J Pediatr (2008) 167:267–277 DOI 10.1007/s00431-007-0635-4 REVIEW Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy J. Edmond Wraith & Maurizio Scarpa & Michael Beck & Olaf A. Bodamer & Linda De Meirleir & Nathalie Guffon & Allan Meldgaard Lund & Gunilla Malm & Ans T. Van der Ploeg & Jiri Zeman Received: 22 June 2007 /Revised: 29 October 2007 /Accepted: 29 October 2007 / Published online: 23 November 2007 # The Author(s) 2007 Abstract Mucopolysaccharidosis type II (MPS II; Hunter treating very young patients and those with CNS involvement syndrome) is a rare X-linked recessive disease caused by is also discussed. ERT with idursulfase has the potential to deficiency of the lysosomal enzyme iduronate-2-sulphatase, benefit many patients with MPS II, especially if started early leading to progressive accumulation of glycosaminoglycans in the course of the disease. in nearly all cell types, tissues and organs. Clinical manifes- tations include severe airway obstruction, skeletal deformities, cardiomyopathy and, in most patients, neurological decline. Keywords Mucopolysaccharidosis type II . Death usually occurs in the second decade of life, although Hunter syndrome . Enzyme replacement therapy. some patients with less severe disease have survived into their Idursulfase . Treatment recommendations fifth or sixth decade. Until recently, there has been no effective therapy for MPS II, and care has been palliative. Enzyme Abbreviations replacement therapy (ERT) with recombinant human iduro- CNS Central nervous system nate-2-sulphatase (idursulfase), however, has now been ERT Enzyme replacement therapy introduced. Weekly intravenous infusions of idursulfase have GAGs Glycosaminoglycans been shown to improve many of the signs and symptoms and HOS Hunter Outcome Survey overall wellbeing in patients with MPS II. This paper provides HSCT Haematopoietic stem cell transplantation an overview of the clinical manifestations, diagnosis and I2S Iduronate-2-sulphatase symptomatic management of patients with MPS II and M6P Mannose-6-phosphate provides recommendations for the use of ERT. The issue of MPS Mucopolysaccharidosis J. E. Wraith (*) L. De Meirleir Willink Biochemical Genetics Unit, University Hospital VUB, Brussels, Belgium Royal Manchester Children’s Hospital, Hospital Road, Manchester M27 4HA, UK N. Guffon e-mail: [email protected] Edouard Herriott Hospital, Lyon, France M. Scarpa A. Meldgaard Lund Centre for Rare Diseases, University of Padua, Rigshospitalet, Copenhagen, Denmark Padua, Italy G. Malm M. Beck Karolinska Hospital, Huddinge, Sweden Universitäts Kinderklinik, Mainz, Germany A. T. Van der Ploeg Erasmus Medical Centre, Rotterdam, The Netherlands O. A. Bodamer Universitäts Klinik für Kinder- und Jugendheilkunde, J. Zeman Vienna, Austria Charles University, Prague, Czech Republic 268 Eur J Pediatr (2008) 167:267–277 Introduction associated with MPS II can be slowed or even prevented. The availability of ERT thus requires a greater awareness First described by Major Charles Hunter in 1917 [15], and understanding of the disease amongst a range of mucopolysaccharidosis type II (MPS II or Hunter syndrome; medical specialists and primary care physicians, so that OMIM +309900) is an X-linked recessive disease caused by early diagnosis can be made and treatment started before deficiency of the lysosomal enzyme iduronate-2-sulphatase organ damage becomes irreversible. (I2S). This enzyme cleaves O-linked sulphate moieties from This article gives an overview of the clinical manifes- the glycosaminoglycans (GAGs) dermatan sulphate and tations, diagnosis and symptomatic management of patients heparan sulphate as the first step in their degradative with MPS II and provides, for the first time, recommenda- pathway. The clinical phenotype of MPS II (Fig. 1)is tions for the use of ERT. characterised by progressive pathological lysosomal storage of GAGs in nearly all cell types, tissues and organs. Oropharyngeal and tracheo-bronchial deposition of GAGs Incidence and inheritance leads to severe airway obstruction due to macroglossia, supraglottic narrowing, and tracheomalacia. This obstructive Data from The Netherlands and Germany indicate that the anatomy and physiology leads to sleep apnoea and airway incidence of MPS II is 1.3 per 100,000 male live births [1, 23]. obstruction. As the disease progresses, the respiratory system Two-thirds of patients present with CNS involvement, is further compromised by pulmonary restriction secondary to representing the more severe end of the disease phenotype. the effects of the disease on the thoracic skeleton. Deposition There have been very few reports of recurrent or common of GAGs in the heart, liver and spleen leads to cardiomyop- mutations within the gene encoding I2S. As a consequence, athy, cardiac valve dysplasia and hepatosplenomegaly. Bone genotype–phenotype correlations have been difficult to and joint involvement results in severe skeletal deformities establish, with the exception of those patients who present and limitations of joint mobility. In patients with CNS with large deletions, which are most often associated with involvement, severe learning difficulties and progressive more severe disease [38]. neurological decline occur. The clinical manifestations of As MPS II is an X-linked recessive condition, it would MPS II generally lead to death in the first or second decade of not be expected to affect females. Despite this, a few girls life, although in the more attenuated form of MPS II, death have been reported with MPS II [35]. Affected females may occur in early adulthood, and some patients have generally have low levels of I2S activity and an attenuated survived into their fifth and sixth decades of life. clinical phenotype, although the somatic abnormalities can Until recently, there has been no effective therapy for be severe in some individuals. In affected heterozygous MPS II. Care has been palliative, focusing on management females, skewed inactivation of the X-chromosome pre- of the multiple clinical symptoms. Haematopoietic stem cell vents expression of the normal allele [35]. therapy (HSCT) has been attempted in some patients [36], but the long-term results have been unsatisfactory. The recent introduction of enzyme replacement therapy (ERT) Molecular basis of MPS II with recombinant human I2S (idursulfase), however, has raised the possibility that the burden of GAG storage can be MPS II is the only known X-linked MPS disorder. The reduced and that the progressive tissue and organ damage human gene encoding I2S has been mapped to Xq28. It Fig. 1 Appearance of a ab child with mucopolysac- charidosis type II (Hunter syndrome) at (a) 6 years of age and (b) 12 years of age, illustrating the ‘typi- cal’ clinical phenotype at the more severe end of the disease spectrum. The manifestations of the syn- drome and the rate of progression, however, may vary widely among individual patients Eur J Pediatr (2008) 167:267–277 269 contains nine exons spread over 24 kb. Individuals with Clinical spectrum of MPS II major deletions or rearrangements in the gene usually have severe MPS II. An I2S-like pseudogene, comprising copies MPS II is a variable, progressive, multisystem disorder. In of exons 2 and 3 and intron 7, is located about 20 kb from most patients, symptoms are severe and death occurs at an the active gene [34]. A recurring rearrangement is due to early age. In other patients the disease has a more chronic recombination between the intron region of the gene and a and protracted course. The age of presentation of MPS II is homologous region near exon 3 of the pseudogene, with also variable, as are the presenting signs and disease inversion of the intervening DNA [3]. Very large deletions complications. Figure 2 shows the age at onset of the main of the I2S locus may extend to adjoining genes, as the signs and symptoms of the disease in a cohort of 82 patients neighbouring DNA is gene rich. A contiguous gene enrolled in HOS, the Hunter Outcome Survey. This is a syndrome involving fragile X mental retardation (FMR1 multinational long-term outcomes survey to investigate the and FMR2) genes could possibly explain the unusual natural history of MPS II and the safety and efficacy of phenotypes seen in some severely affected patients [33]. ERT with idursulfase [8]. Over 150 different mutations, resulting in a spectrum of The traditional classification of patients into ‘mild’ or disease phenotypes, have been described. ‘severe’ subtypes, on the basis of length of survival and the presence or absence of CNS disease, is a gross simplifica- tion. The disorder should rather be regarded as a continuum General disease manifestations and diagnosis between two extremes (severe and attenuated). It is important to note that individuals who are diagnosed with Treatment of possible disease complications can greatly an attenuated form of the disease may still have symptoms improve quality of life. Early diagnosis is therefore and complications that lead to significant morbidity and essential, particularly with the recent introduction of ERT. disability, and may present with mild to moderate learning Table 1 shows the common presenting features of patients difficulties. Although the clinical course for the more with MPS II, together with the range of specialists who are severely affected patients is relatively predictable, there is likely to be involved in diagnosis and care. considerable variability
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