Description of the condition
Mucopolysaccharidosis II (MPS II or Hunter syndrome) belongs to a group of inherited diseases of glycosaminoglycan (GAG) catabolism called mucopolysaccharidoses. The GAGs are oligosaccharide components of the proteoglycans, macromolecules responsible for the integrity and function of connective tissue. Mucopolysaccharidoses are caused by a lysosomal enzyme deficiency for the stepwise degradation of the GAGs. All of the mucopolysaccharidoses are of recessive autosome inheritance, except MPS II, which is an X-linked recessive disease. The syndrome was described by Charles Hunter in 1917 and is the result of a deficiency of iduronate-2-sulfatase (I2S), with consequent increase of the urinary concentration of the GAGs dermatan sulphate and heparan sulphate. The clinical phenotype of MPS II is characterised by progressive pathological lysosomal storage of GAGs in nearly all cell types, tissues and organs. The iduronate 2-sulfatase gene is located on chromosome Xq28, and more than 350 mutations have been identified to date, including different deletions, splice-site and point mutations. This genetic heterogeneity may explain the high degree of clinical heterogeneity in MPS II (Martin 2008; Wraith 2008a).
This is a rare disease with an estimated incidence of approximately 1 in 162,000 live births. Although males are predominantly affected, a small number of affected females have been described (Meikle 1999; Tuschl 2005). This is a variable, progressive, multisystem disease and should be regarded as a continuum between two extremes (severe and attenuated). Two-thirds of patients present central nervous system (CNS) involvement, representing the more severe form, with clinical features appearing between two and four years of age. In these cases, the progressive neurologic involvement is prominent and leads to severe mental impairment; death usually occurs in the first or second decade of life, usually because of obstructive airway disease or cardiac failure (or both) associated with loss of neurologic function. At the opposite end of the spectrum, clinical signs and symptoms have a slightly later onset and the neurologic dysfunction may be minimal, but with obvious somatic involvement, and longer survival (Wraith 2008a). Data from the 'Hunter Outcome Survey' (HOS), the only large-scale, multinational observational study of patients with MPS II, showed that median age at death was significantly lower in patients with cognitive involvement compared with those without cognitive involvement (11.7 versus 14.1 years; P = 0.024) (Jones 2008).
The most common clinical signs and symptoms include dysostosis multiplex with decreased range of joint motion, coarse facial features, enlarged tongue, hearing loss, abnormal dentition, upper airway obstruction with or without sleep apnoea, restrictive lung disease, hepatosplenomegaly, cardiomyopathy, skeletal deformities, and severe short stature (Young 1983).
The development of children with MPS II seems normal in the first months of life, but the outcome is highly changeable. Even in individuals with attenuated disease, cranial magnetic resonance imaging (MRI) scans are often grossly abnormal, with extensive white matter changes as well as dilated perivascular spaces, despite apparently normal intellectual skills. Individuals with more severe MPS II also appear normal at birth, and early development may be normal. Some individuals fail hearing screening tests in the first year, and speech delay is not unusual in those more severely affected. By 18 to 24 months developmental delay is usually apparent. Most individuals make very slow progress after this stage, with a developmental plateau beginning between three and five years of age. Unlike children with severe MPS I, who are usually placid, more severely affected children with MPS II can be hyperactive and aggressive. One of the most important limitations beside the neurologic involvement in individuals suffering from MPS II, is the impact that the progressive physical abnormalities have on their quality of life. Due to a combination of the bone disease, decreased respiratory capacity and impaired cardiac function, they suffer from chronic, severely diminished endurance. With the disease progression their ability to walk even short distances may be lost and eventually many patients become wheelchair-bound. By the time of death in their second decade, most individuals with CNS involvement show severe learning difficulties and are dependant on care providers for all their needs (Wraith 2008a).
The measurement of urinary GAGs (heparan and dermatan sulphate) is the usual first screening test for MPS II. As in almost all cases of MPS, the total urinary GAG level is increased. However, this is not diagnostic of MPS II, so additional tests must be performed. Futhermore, a negative urine GAG test does not necessarily rule out a diagnosis of MPS II, because false-negative results can occur as a result of a lack of sensitivity of the testing method (de Jong 1992). Definitive diagnosis is established by enzyme assay in leukocytes, fibroblasts or plasma, using substrates specific for I2S. Absent or low I2S activity in males is diagnostic of MPS II, provided that multiple sulphatase deficiency is excluded by finding normal activity of another sulphatase. Absolute enzyme activity cannot be used to predict the severity of the phenotype. Mutation analysis may be used to confirm Hunter syndrome in males. However, it is difficult to establish a genotype-phenotype correlation to provide an indication of the likely prognosis, this is because patients carrying the same alterations may present different phenotypes, suggesting that others factors may modulate the clinical phenotype (Kresse 1982;Martin 2008; Neufeld 2001).
As the definition of effective treatment for MPS II is "an improvement in or a prevention of progression of disease activity as indicated by a stabilisation in clinical condition associated with an improvement in the abnormalities present at baseline" (Vellodi 2007), the primary endpoints for the evaluation of interventions for the treatment of this condition should reflect improvement in important signs and symptoms observed in the disease, such as a change in the speed of growth and in the impairment of cardiac and respiratory system.
The usual management of MPS II has been palliative and focused on the treatment of signs and symptoms. Care for the person with MPS II involves a multidisciplinary approach and includes paediatricians, neurologists, orthopedists, otolaryngologists, ophthalmologists, and occupational and physical therapists, as well as geneticists and counsellors (National Horizon Scanning Centre 2005). Hemapoietic stem cell transplantation (HSCT) by bone marrow transplantation, human amnion membrane implantation, fibroblast transplantation, serum or plasma infusion has been suggested as a means of providing donor cells capable of expressing I2S, but the results are disappointing and long-term outcomes are limited, therefore, HSCT is not currently recommended for individuals with MPS II (Martin 2008).
Description of the intervention
Recently idursulfase (Elaprase®, Shire Human Genetic Therapies, Inc, Cambridge, MA), a recombinant human I2S produced in a human cell line, was approved in the United States of America and the European Union for the treatment of MPS II.
How the intervention might work
The rationale for therapy is that exogenous I2S would replace the I2S that is deficient in patients and either stop or reverse disease progression. Idursulfase is produced in a continuous human cell line and is a purified form of the natural lysosomal enzyme I2S. Mannose-6-phosphate (M6P) residues on the oligosaccharide chains of the glycoprotein enzyme and allows specific binding of idursulfase to M6P receptors on the cell surface, leading to cellular internalisation and targeting of the enzyme to lysosomes, and subsequent catabolism of accumulated GAGs (Wraith 2008b).
Why it is important to do this review
There is no definitive treatment for people diagnosed with MPS II. The appearance of a promising therapeutic strategy, idursulfase, makes it necessary to map the knowledge in this area based on the rigor inherent to systematic reviews by considering relevant aspects of the effectiveness and safety of this therapeutic strategy for relevant clinical issues.
The current publication is a minor update of a Cochrane review first published in 2011 (da Silva 2011).