Introduction 15 1 Fig. 1 a b  Oropharyngeal and tracheo-bronchial deposition of GAGs leads to severe airway obstruction due to macroglossia, supraglottic narrowing, and tracheomalacia. This obstructive anatomy and physiology leads to sleep apnoea and airway obstruction. As the disease progresses, the respiratory system is further compromised by pulmonary restriction secondary to the effects of the disease on the thoracic skeleton. Deposition of GAGs in the heart, liver and spleen leads to cardiomyopathy, cardiac valve dysplasia and hepatosplenomegaly. Bone and joint involvement results in severe skeletal deformities and limitations of joint mobility. In patients with CNS involvement, severe learning difficulties and progressive neurological decline occur. The clinical manifestations of MPS II generally lead to death in the first or second decade of life, although in the more attenuated form of MPS II, death may occur in early adulthood, and some patients have survived into their fifth and sixth decades of life. 36 This article gives an overview of the clinical manifestations, diagnosis and symptomatic management of patients with MPS II and provides, for the first time, recommendations for the use of ERT. Incidence and inheritance 1 23 38 35 35 Molecular basis of MPS II 34 3 FMR1 FMR2 33 General disease manifestations and diagnosis 1 Table 1 Presenting features of patients with mucopolysaccharidosis type II (Hunter syndrome) and the specialists likely to be involved in diagnosis and treatment Presenting feature Specialist Recurrent upper respiratory tract infections, recurrent otitis media, developmental delay, hepatosplenomegaly, joint restriction, coarse facies Paediatrician Paediatric neurologist Otolaryngologist Recurrent ear infections, abdominal distension, stiff joints Primary care physician Umbilical and inguinal hernias with recurrence Surgeon Hip dysplasia, arthropathy Orthopaedic specialist Upper airway obstruction, sleep apnoea, recurrent ear infections requiring tube placement Otolaryngologist Papilloedema in the absence of raised intracranial pressure Ophthalmologist Valvular thickening on echocardiography Cardiologist Joint pain and restriction Rheumatologist Papular pearly rash across the scapulae Dermatologist Restrictive joint range of motion Physiotherapist Carpal tunnel syndrome Hand surgeon Cervical myelopathy Neurosurgeon Clinical spectrum of MPS II 2 8 Fig. 2 Reported age at onset and prevalence of clinical features in 82 patients with mucopolysaccharidosis type II (Hunter syndrome) enrolled in HOS, the Hunter Outcome Survey  The traditional classification of patients into ‘mild’ or ‘severe’ subtypes, on the basis of length of survival and the presence or absence of CNS disease, is a gross simplification. The disorder should rather be regarded as a continuum between two extremes (severe and attenuated). It is important to note that individuals who are diagnosed with an attenuated form of the disease may still have symptoms and complications that lead to significant morbidity and disability, and may present with mild to moderate learning difficulties. Although the clinical course for the more severely affected patients is relatively predictable, there is considerable variability in the clinical phenotype and progression of the more attenuated form of the disease. 3 9 Fig. 3 Mortality by age of patients with mucopolysaccharidosis type II (Hunter syndrome) in the UK. Data are from the Society for Mucopolysaccharide Diseases (MPS Society) and are based on patients registered with the MPS Society between 1950 and October 2006  25 6 Physical appearance The typical patient with attenuated MPS II is short with some change of facial features. Significant arthropathy and connective tissue involvement lead to joint contractures. A combination of hepatomegaly and lax abdominal muscles leads to abdominal prominence. 32 Development 40 27 Patients with more severe MPS II also appear normal at birth, and early developmental milestones may be normal. Some patients fail hearing screening tests in the first year, and speech delay is not unusual in more severely affected patients. By 18–24 months, developmental delay is usually apparent. Most patients make very slow progress after this stage, with a developmental plateau beginning between 3 and 5 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. By the time of death in their second decade, most patients with CNS involvement are severely mentally handicapped and dependant on care providers for all their needs. Biochemical diagnosis Assessing urinary GAGs (heparan and dermatan sulphates) is the usual first screening test for MPS II, and can be quantitative (measurement of total urinary uronic acid) or qualitative (GAG electrophoresis). Although neither test can offer a definitive diagnosis, abnormal measurements indicate the likely presence of an MPS disorder. The sensitivity of these tests, however, is not perfect, particularly when measurements are made on samples of dilute urine. Definitive diagnosis is established by enzyme assay in leukocytes, fibroblasts or plasma, using substrates specific for I2S. Another sulphatase should be measured in conjunction, in order to exclude multiple sulphatase deficiency. This is a much rarer disorder than MPS II and is generally associated with a very poor prognosis. It should be noted that the amount of enzyme activity measured in vitro from cellular extracts does not indicate where an individual falls within the MPS II spectrum of disease severity. Prenatal diagnosis 7 Carrier testing Previous methods of carrier detection based on an I2S assay in either plasma or hair roots are now known to be unreliable, as there is considerable overlap between the normal and heterozygous ranges. The only definitive test for determining carrier status is based on DNA analysis. In a small number of families, however, the mutation remains elusive, despite full sequencing of the I2S locus. Symptomatic treatment Even with the introduction of ERT, patients with MPS II still require supportive symptomatic treatment from a wide range of specialists. A comprehensive initial assessment of each patient at diagnosis should therefore be undertaken, and should be followed by regular reviews. Supportive management and the anticipation of possible complications can greatly improve the quality of life of affected individuals and their families. Family members should be offered genetic counselling, and contact with other affected families, patients and support groups can be helpful. Skeletal abnormalities Orthopaedic complications, caused by a combination of direct bone involvement and severe arthropathy, can lead to significant disability. The destructive arthropathy, which especially affects the hip joints, is a feature of the skeletal disease in some patients and may be due to secondary events occurring within chondrocytes and/or osteoblasts as a result of storage. Progressive arthropathy may affect all joints and leads to severe restriction of motion. The hip joints appear to be particularly vulnerable and severe erosive hip dysplasia can be especially disabling. Poor hand function, due to the characteristic claw-hand deformity, carpal tunnel syndrome and interphalangeal joint stiffness, is also common. Abnormal joint function is largely a result of both metaphyseal deformities and thickened joint capsules. Secondary erosive joint disease is particularly disabling and is extremely difficult to manage medically and/or surgically. The deformed acetabulum and pelvis makes prosthetic surgery a challenge, and many patients become wheelchair-bound because of hip pain. The role of physical therapy in MPS II is not well studied, but range-of-motion exercises appear to offer some benefit in preserving joint function and should be started at an early age. If significant restriction of joint movement has already occurred, range-of-motion exercises may slow further progression. Cardiovascular system 24 14 2 Table 2 Prevalence and reported age at onset (median and 10th–90th percentiles) of the main cardiovascular manifestations of mucopolysaccharidosis type II (Hunter syndrome) in a cohort of 82 patients in HOS, the Hunter Outcome Survey Cardiac manifestation n Prevalence (%) Age at onset (years) Valvular disease 34 53 6.2 (2.9–13.8) Murmur 32 52 6.4 (3.7–12.3) Cardiomyopathy 4 9 7.6 (5.2–27.3) Any cardiovascular sign/symptom 49 72 6.0 (2.9–13.7) Respiratory disease and upper airway manifestations 4 26 39 16 17 In patients with attenuated MPS II, rhinorrhoea tends to improve with age, but upper airway obstruction and sleep apnoea become more troublesome with increasing age. A progressive restrictive respiratory defect also becomes apparent with increasing age, mainly due to progressive changes in the thoracic skeleton. Sleep studies should form part of the regular assessment schedule, and significant episodes of hypoxia should be managed by continuous or bilevel positive airway pressure devices. Severely affected patients often find such treatment difficult to tolerate. In these patients, supplemental oxygen alone may be an acceptable alternative, but should be used with caution in patients with documented hypercapnia. Tonsillectomy and adenoidectomy are frequently performed to correct Eustachian tube dysfunction and to decrease airway obstruction. Severely affected patients also tend to have frequent ear infections and constant rhinorrhoea. Early placement of ventilating tubes is recommended in severely affected individuals. Gastrointestinal system 10 Abdominal hernias should be repaired surgically, though recurrence can occur. Diarrhoea can be controlled by diet and the use of antimotility drugs. Central nervous system Communicating high pressure hydrocephalus, which is common in MPS I, is rare in MPS II. Other CNS complications, such as seizures, are more common. They are usually tonic–clonic in nature and respond to standard anticonvulsant treatment. 21 Hypertrophic pachymeningitis cervicalis and cervical compression secondary to hyperplasia of the transverse ligaments should be quickly and aggressively treated in patients with attenuated disease. Early and careful cervical decompression performed by an experienced team may prevent severe and devastating consequences. Peripheral nervous system 13 Visual problems 31 2 20 37 2 Regular, annual, ophthalmological assessment is required and should include a measure of intraocular pressure. Spectacles should be prescribed as appropriate. Hearing 29 22 Education and behaviour Given the intellectual involvement in the more severely affected patients, it is important that infants with MPS II are provided with a stimulating environment to encourage as much learning as possible during the early stages, as some skills may be retained during the later period of general deterioration. For patients with more attenuated forms of the disease, deafness and physical limitations may impact on education. Educational assessments of special needs should be undertaken to ensure that an appropriate educational environment is provided. This may be in a mainstream school with additional help or within a special school system. Many patients with severe MPS II exhibit hyperactivity and aggression. Psychological assessment, behaviour management and the use of medication should be considered in these patients. The hyperactivity generally responds poorly to methylphenidate, and over-sedation is a risk with other forms of medication. Anaesthetic complications 12 Dysostosis multiplex leading to rigidity of the neck and spine. Although instability of the spine is rare, significant cervical compression may be present in patients with attenuated disease. This can result in sudden neurological deterioration if excessive neck manipulation is performed during attempts to intubate the patient. Induction may be difficult because of an inability to maintain an adequate airway. Intubation may require smaller-than-anticipated endotracheal tubes and a narrow trachea and thickened vocal cords will impede view. It is recommended that a paediatric pulmonologist or ear, nose and throat specialist should be present during intubation. Fibre-optic laryngotracheoscopy is usually essential. Extubation can also be hazardous for these patients, and there is an increased incidence of post-obstructive pulmonary oedema. Recovery from anaesthesia may be slow, and post-operative airway obstruction is always a risk. Enzyme replacement therapy Recombinant I2S (idursulfase; Elaprase, Shire Human Genetic Therapies, Cambridge, MA, USA) has recently been licensed for treatment of patients with MPS II in the United States, European Union and Switzerland. 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 allow specific binding of idursulfatase to M6P receptors on the cell surface, leading to cellular internalisation and targeting of the enzyme to lysosomes, and subsequent catabolism of accumulated GAGs. Phase I/II trial Twelve patients were enrolled in a randomized, double-blind, placebo-controlled trial of idursulfase for 24 weeks, followed by an open-label extension study. P P P P 18 Phase II/III trial A multinational, randomized, double-blind, placebo-controlled trial was performed to evaluate the safety and efficacy of idursulfase, 0.5 mg/kg administered weekly, compared with placebo. Additionally, the trial evaluated idursulfase, 0.5 mg/kg every other week, compared with placebo. Ninety-six patients were randomized to one of three groups with each patient receiving a total of 52 infusions of either idursulfase, idursulfase alternating weekly with placebo, or placebo. The primary efficacy endpoint of the trial was a composite of two clinical measures – forced vital capacity and the 6-min walk test. P P 19 19 Current treatment with idursulfase Idursulfase is given by weekly intravenous infusion over 3 h at a dose of 0.5 mg/kg diluted in an appropriate volume of saline (according to weight). Patients may receive premedication with antipyretics and/or antihistamines at the discretion of the prescribing physician. Patients who have experienced infusion-related reactions should be premedicated for subsequent infusions. Consideration should be given to the possibility of sodium overload in small infants, and, if necessary, the total volume of the infusion can be decreased to 50 ml. Although the treatment is generally safe and infusion-related reactions are no more frequent than with other protein-based therapies, anaphylactoid reactions have been reported. Early response to ERT The response to ERT appears to depend on the severity of the individual’s condition and the age at which the treatment begins. In our experience, the first sign of efficacy in most young (prepubertal) patients is usually an enhanced feeling of wellbeing and greater energy, manifesting as an increased ability to take part in normal daily activities. By 2 months, most patients have urinary GAG levels approaching the normal range and there is usually evidence of a reduction in size of the liver and spleen. After a further month of therapy there is often an improvement in soft-tissues joint contractures and the beginning of a growth spurt. By 6 months of treatment, most patients have improved the distance that they can achieve in the 6-min walk test and most show stabilisation (if not improvement) in pulmonary function tests. Most of the improvement occurs in the first 12–18 months of treatment. After this period of time, gains are very slow and the condition of most patients will generally have stabilised, although physicians still need to be vigilant and look actively for possible disease-related complications. ERT for particular patient groups Treating very young patients Experience of treating children under the age of 5 years with idursulfase is limited, as the clinical trials enrolled patients above this age so that the patients would be able to comply with and be able to cooperate with repeated pulmonary function and endurance testing. The following is therefore based on our personal clinical experience. Treating patients at a very young age leads to practical problems with the infusions. These may be resolved with indwelling vascular access devices. Outcomes are likely to be better in patients treated from a very young age, but there are currently no recommendations on how to monitor the response to treatment, especially in patients either too young to cooperate with the tests used in the clinical trials (pulmonary function tests and 6-min walk test) or in patients who are not yet showing symptoms of the disease. This situation would be improved by identifying a suitable biomarker that would reflect the disease burden and that would respond promptly to therapy. We believe that these challenges should not prevent the introduction of treatment in patients under the age of 5 years after discussion with parents. Careful clinical follow-up, however, will be necessary in these patients, accompanied by regular (annual) developmental assessments. As of October 2006, there were 12 patients below 5 years of age in HOS. Treating patients with severe CNS involvement Idursulfase is not expected to cross the blood–brain barrier and therefore would not be expected to lead to any improvement in CNS dysfunction in patients with severe MPS II. In most patients there is likely to be some initial benefit in terms of enhanced respiratory function due to airway improvement and reduction in size of the liver and spleen. In addition, joint mobility may improve as a result of ERT on peri-articular soft tissue. The burden of weekly intravenous therapy may be significant in some patients with very severe CNS disease. The authors believe that patients with severe CNS involvement may be offered the possibility of treatment for a ‘trial’ period of 12–18 months, after which time a decision should be made as to whether to continue. Decisions on whether to start and continue treatment should be made only after detailed discussion with the parents. Home therapy More than 90% of patients treated with idursulfase have had no infusion-related reactions and, in those who do, the reactions are mostly minor and respond promptly to reducing the rate of infusion and using antipyretics and antihistamines for future treatments. Under these circumstances, it would appear that idursulfase is a therapy that could be administered safely in the patient’s home after a minimum of 12 infusions in hospital. Depending on the labelling and clinical practices in particular countries, a logical approach would appear to be to consider home therapy for those patients with minimal or no obstructive airway disease (as judged by sleep study and pulmonary function tests). It should be stressed, however, that ERT during respiratory infections or other intercurrent illnesses are contraindicated. Treatment should be postponed under such circumstances, regardless of whether treatment is given in the hospital or home setting. Management of infusion reactions Infusion-related reactions appear to be of two types: those occurring during the infusion and ‘late’ reactions occurring 12 h or more after the infusion. The classic reactions occurring during the infusion, with fever, chills and urticaria, respond to temporarily stopping the infusion, administering paracetamol (acetominophen) and antihistamines, and restarting the infusion after at least 30 min but at a slower rate. Before subsequent infusions, patients should be premedicated with acetominophen and antihistamines 1 h before the infusion. If the reactions continue despite this premedication, consideration should be given to pretreatment with corticosteroids; for example, prednisolone, 1 mg/kg, 12 h and 1 h before infusion. Late reactions typically consist of a sunburn-type rash and mild wheezing. The rash can be managed as above, but the wheezing requires bronchodilator treatment and, possibly, oxygen supplementation. All patients who have significant infusion-associated reactions should have specific immune testing. Reducing the rate of infusion is mandatory in these patients. To assess the efficacy of ERT in individual patients and to ensure the appropriate management of possible infusion-related reactions, it is recommended that the treatment of patients receiving ERT is overseen by experienced physicians in centres with expertise in treating lysosomal storage diseases. Haematopoietic stem cell therapy 36 The future 28 5 30 11 Conclusion MPS II (Hunter syndrome) is a severe progressive multisystemic disorder that has the potential to cause disease in most body systems and is usually fatal in the second or third decade of life. Ideally, management should be centralised in major medical centres with access to all medical specialties. Management is multidisciplinary and a holistic approach to the patient is required, especially for those who have severe neurological involvement. ERT is an important new therapy that has the potential to help many patients, providing that it is started early in the course of the disease. CNS disease remains a major challenge and an innovative approach to treatment will be needed if this is to be addressed fully.