Mucopolysaccharidosis type II: European recommendations for the diagnosis and multidisciplinary management of a rare disease

Literature searches for topics relating to the management of patients with MPS II were carried out in PubMed and EMBASE between 13 July and 16 September 2010, using Medical Subject Heading Terms and relevant keywords. To ensure relevance to the modern day clinical setting, literature searches were limited to articles published since 1 January 1990. Older articles identified by the authors were also included. Only articles from the peer-reviewed literature were included in the literature search. Articles in a non-English language with an abstract, and articles in the English language without an abstract were included if they were considered relevant to the search being carried out. Abstracts from industry-sponsored meetings were not included.

Idursulfase is a purified form of I2S, produced by recombinant DNA technology in a continuous human cell line. Intravenous ERT with idursulfase provides exogenous enzyme for selective uptake into cells via mannose-6-phosphate receptors on the cell surface [33]. Upon internalisation, the enzyme is transferred and localised within lysosomes, where it catabolises accumulated GAGs [3].

Idursulfase is indicated for the long-term treatment of patients with MPS II. In a randomised, placebo-controlled clinical trial, intravenous administration of idursulfase (0.5 mg/kg body weight weekly for up to 53 weeks) to 32 patients was associated with significant improvements in a composite endpoint comprising change in distance walked in 6 minutes and percentage of predicted forced vital capacity (%FVC) compared with patients receiving placebo (p = 0.0049) [34]. When evaluated individually after 53 weeks, the increase from baseline in mean (± SEM) distance walked in the 6-minute walk test was significantly greater in patients receiving idursulfase compared with those given placebo (+44.3 ± 12.3 m versus +7.3 ± 9.5 m, respectively; p = 0.0131; Figure 3a). %FVC increased more from baseline in patients treated with idursulfase than in the placebo group, although this difference did not reach significance (p = 0.0650; Figure 3b) [34]. The mean increase in absolute FVC from baseline was significantly greater in patients treated weekly with idursulfase compared with placebo (+0.22 ± 0.05 L versus +0.06 ± 0.03 L; p = 0.0011; Figure 3c). The mean decrease in liver volume at 53 weeks was significantly greater in patients treated with idursulfase compared with placebo (-25.3 ± 1.6% versus -0.8 ± 1.6%, respectively; p < 0.0001) as was the change in spleen volume (-25.1 ± 2.4% versus +7.2 ± 4.2%, respectively; p < 0.0001) [34]. Urinary GAG levels were significantly reduced from baseline in patients receiving ERT compared with placebo (mean change, -189.2 ± 25.8 μg/mg creatinine vs. +18.2 ± 29.9 μg/mg creatinine, respectively; p < 0.0001; Figure 3d) [34]. Aside from an improvement in elbow mobility between the weekly idursulfase group compared with placebo (p = 0.0476), no other significant differences between treatment groups for any joint range of motion were found [34].

Following this trial, a 2-year open-label extension study of weekly idursulfase was undertaken in a population of all 94 patients that completed the Phase II/III study [35]. Although %FVC did not change significantly except at a single timepoint, there was a sustained improvement in mean absolute FVC compared with the initial study's baseline (mean change at 3-year timepoint, +0.31 ± 0.06 L, 25.1%; p < 0.05) [34, 35]. Increases in distance walked in 6 minutes compared with baseline were maintained, although variable from one assessment to another. The largest increase was seen at 20 months after the start of the initial study - a mean increase of 42 ± 10 m from baseline (p < 0.01) [35]. Effects on liver and spleen volume were also maintained, and a sustained reduction in urinary GAG levels was observed during 3 years of treatment, with a final mean value of 81.7 μg/mg creatinine (well below the upper limit of normal) [35]. Joint range of abduction and flexion-extension improved for the shoulder to a degree felt to be clinically important (approximately 12° and 15°, respectively, at 36 months; both p ≤ 0.005) and remained stable in the elbow, wrist, digits, hip, knee and ankle [35]. After 24 months, both parent- and child-assessed measures of quality of life showed significant improvements from baseline (change in parent-assessed Disability Index Score, -0.13 ± 0.06, p = 0.047; change in child-assessed Disability Index Score, -0.15 ± 0.65, p = 0.031) [35].

Similar findings have been reported in a separate 12-month, open-label, clinical study of 10 adult Japanese patients with attenuated forms of MPS II [36]. Idursulfase has also been found to have a positive influence on growth in 18 patients with MPS II, especially in children younger than 10 years of age (Figure 3e) [37]. In this group a mean height increase of 14.6 cm was seen over 3 years of ERT.

Transplantation of stem cells using bone marrow, peripheral blood haematopoietic cells or umbilical cord blood has been shown to be effective in slowing disease progression in selected lysosomal and peroxisomal inherited metabolic storage diseases, including MPS IH (Hurler syndrome), MPS VI (Maroteaux-Lamy syndrome), X-linked adrenoleukodystrophy, metachromatic leukodystrophy and globoid-cell leukodystrophy (Krabbe disease) [48‐54]. SCT relies on the progressive replacement throughout the body of endogenous haematopoietic lineage cells with exogenous cells transplanted from a healthy donor. Importantly, experiments in mice have shown that the transplanted cells can migrate across the blood-brain barrier, differentiate into microglia, and express lysosomal enzymes that can be taken up by cells in the CNS and delivered to the lysosome [55]. This, coupled with the apparent inability of enzymes administered intravenously to cross the blood-brain barrier, has stimulated interest in the therapeutic potential of STC for preventing or treating the neurological manifestations of metabolic storage diseases, including MPS II.

At the time of writing, no controlled clinical studies have been conducted to evaluate the effects of bone marrow transplantation (BMT), haematopoietic stem cell transplantation (HSCT) or umbilical cord blood transplantation (UCBT) in patients with MPS II; with experience limited to single published case studies or small case series. This is hardly surprising given the rarity of MPS II, and it is unlikely that formal randomised controlled trials will ever be conducted.

The use of STC for the treatment of MPS II is controversial because of the profound risk of morbidity and mortality associated with this treatment approach [31]. Many patients receive immunosuppressant and steroid medication following transplantation to protect against or alleviate graft-versus-host disease [56]. However, the use of immunosuppressants can leave the patient vulnerable to infection, and the chronic use of steroids may lead to orthopaedic complications (e.g. osteonecrosis of the hip) [47].

Owing to the dearth of therapeutic options for alleviating the neurological manifestations of LSDs, much research has focused on the development of well-tolerated therapies that can cross the blood-brain barrier. One approach that has been explored is the infusion of ERT into the cerebrospinal fluid, thereby enabling widespread distribution throughout the CNS. Experiments in animal models have yielded promising results [67], and a study into the feasibility and safety of intrathecally delivered idursulfase in patients with MPS II is underway.

Other areas of research include the use of pharmacological chaperones, gene therapy and substrate reduction therapy. Although a comprehensive overview of these therapeutic options is beyond the scope of this article, all have been found to cross the blood-brain barrier and promising findings have been reported in vitro and in animal models [68‐72]. It is hoped that in the near future these therapies may help to prevent or reverse the neurological manifestations observed in patients with severe forms of MPS II.

Cardiovascular manifestations develop at a young age in patients with MPS II, and most patients exhibit at least one cardiovascular sign or symptom by the second decade of life [3]. Typical changes include valve disease (e.g. changes in morphology and impaired function: affecting mitral, aortic, tricuspid and pulmonary valves in decreasing frequency), ventricular hypertrophy, hypertension, and arrhythmia (e.g. tachycardia, bradycardia, atrioventricular block) [3, 14, 73]. The progression of cardiac involvement must be monitored closely, and patients should undergo regular echocardiography, electrocardiography, and Holter monitoring, if indicated (Table 1).

Valve disease affects more than half of patients and can lead to ventricular hypertrophy or heart failure [3, 12]. In some countries, prophylactic antibiotic therapy may be given before any surgical or major dental procedure as a precaution. However, this practice is no longer recommended by the National Institute for Health and Clinical Excellence [74]. Valve replacement has been reported, but remains uncommon [75, 76]. Hypertension is typically under-diagnosed in patients with MPS II and should be treated using standard agents, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics and calcium-channel blockers (CO). Arrhythmias should be treated with ablation, antiarrhythmic drugs, anticoagulants and, if necessary, placement of an implantable cardioverter defibrillator (CO).

Depending on disease severity, neurological manifestations of MPS II may include a delay in achieving developmental milestones, cognitive impairment and seizures [11, 12]. In addition, communicating hydrocephalus, spinal cord compression, and carpal tunnel syndrome (CTS) typically require surgical intervention [47]. Impaired cognition or delayed speech in children of preschool age should provoke further investigation with cognitive tests, and behavioural therapy and/or the use of behaviour-modifying medication may be necessary (CO). Seizures can usually be controlled by anticonvulsant therapy [47]. To avoid unwanted adverse events, low-dose monotherapy is preferred (CO). For patients with communicating hydrocephalus or evidence of progressive ventricular enlargement, a ventriculoperitoneal shunt can be placed to relieve intracranial pressure [77, 78]. Motor function has been reported to improve after shunt placement [79].

A common feature of MPS II is progressive compression of the spinal cord with resulting cervical myelopathy [47, 80]. This can lead to reduced activity, difficulty in rising from a sitting position, paresis and spasticity, pain or loss of sensation in the upper and lower body, as well as bladder and bowel dysfunction. Irreversible cord damage can occur if this is left untreated, so surgical decompression should be considered as soon as symptoms occur [81‐83]. Similarly, decompression of the median nerve is recommended for patients with demonstrated loss of hand sensation and/or function or abnormal nerve conduction studies (CTS). Both decompression procedures have been associated with rapid and sustained improvement in sensation and function, as well as providing pain relief [47, 84‐87].

Ocular involvement in MPS II generally consists of loss of vision, optic disc swelling, papilloedema, optic atrophy and retinal pigmentary degeneration [2, 88]. Corneal clouding is almost never encountered [2]. Treatment of ocular complications in patients with MPS II does not differ substantially from approaches used for otherwise healthy individuals (see Table 1). If glaucoma occurs, most patients respond well to intraocular pressure-lowering eye drops (CO). If optic nerve involvement occurs due to raised intracranial pressure, this should be addressed using standard methods. Unfortunately, optic involvement associated with GAG accumulation or retinal degradation cannot be treated, although patients do benefit from magnifying devices when reading (CO).

Typical musculoskeletal manifestations of MPS II include short stature, spine deformities, joint stiffness, contractures, and claw-like hands [89]. Orthopaedic therapy should be considered for patients with musculoskeletal manifestations, as this can help to address psychosocial aspects of the disease, such as loss of mobility and independence, as well as relieving the symptoms themselves. Non-surgical approaches include physiotherapy and the use of orthopaedic devices, such as orthotic footwear, braces, corsets and walking aids, to assist with daily living activities. These approaches can also help maximise muscle strength and range of movement [89]. Surgical procedures include decompression of the spinal cord or median nerve, instrumented fusion (to stabilise and strengthen the spine), arthroscopy, hip or knee replacement, and correction of the lower limb axis [89, 90].

It has been suggested that recombinant human growth hormone (GH) may help overcome short stature in patients with MPS II [91]. GH therapy has been shown to be well tolerated and effective in improving linear growth in patients with GH deficiency, Turner syndrome and other growth disorders [92‐94]; however, experience in patients with MPS II is very limited. The only published report of GH therapy in patients with MPS II is provided by Polgreen & Miller, who observed transient increases in growth velocity in two patients treated for up to 1 year [91]. Although GH therapy was well tolerated in these patients, there are currently insufficient data on the safety and efficacy of this approach in children with MPS II to recommend it as a standard of care (CO). Furthermore, rapid growth carries the theoretical risk of worsening of orthopaedic complications typically observed in patients with MPS II [95]. With this in mind, patients with MPS II who are prescribed GH therapy must be followed closely by orthopaedic physicians who are familiar with MPS diseases [96].

Ear, nose and throat features of MPS II include hearing loss, recurrent otitis media, an enlarged tongue, hypertrophic adenoids and tonsils and progressive airway obstruction [97, 98]. Chronic and recurrent (more than six episodes per year) upper-respiratory tract infections are common, and affected patients may benefit from analysis of functional antibodies to Streptococcus pneumoniae and Haemophilus influenzae, with booster vaccinations being provided when appropriate (CO). In the absence of a correctable immune deficiency, adenotonsillectomy or ventilation tube insertion may be appropriate for patients with severe signs and symptoms (CO). If hearing loss occurs secondary to persistent middle ear effusion, the possibility of providing hearing aids or inserting ventilation tubes should be discussed with the patient and their parents. Both treatments are effective, but hearing aids are preferred for children with significant comorbidity (CO). Macroglossia secondary to GAG storage is very difficult to manage. Operations on the tongue are not indicated in patients with MPS II, as the risk of postoperative respiratory obstructions is high (CO).

Upper airway obstruction is a major contributor to the premature mortality seen in MPS II [13]. It is thought to result from progressive deposition of GAGs in the soft tissues of the throat and trachea, and may lead to obstructive sleep apnoea [98]. Initial treatments for obstructive sleep apnoea include nocturnal supplemental oxygen. Tonsillectomy and adenoidectomy may be performed when these are enlarged [90, 97], but, because of the progressive involvement of the throat and trachea, improvements may only be partial and/or temporary. Continuous positive airway pressure (CPAP) can be used to splint the airway open during sleep, and has been associated with marked improvements in sleep quality [98, 99], leading to reduced fatigue during the following day and fewer complaints of headache [98]. For patients for whom CPAP is not well tolerated, tracheostomy may be used to bypass the upper airway obstruction or to support the trachea when there is significant collapse due to tracheobronchomalacia. However, complications following this procedure are common and can be life-threatening [100], so caution is advised (CO).

Patients with MPS II should undergo regular examination of the upper airway for signs and symptoms of developing airway obstruction, and an overnight sleep study should be conducted in patients with obstructive sleep apnoea (Table 1) [47, 98]. For a more thorough evaluation of the airway, bronchoscopy may be performed [47]. Routine monitoring of pulmonary function is challenging, as spirometry requires the full cooperation of the patient and is effort dependent. It cannot be used reliably for children younger than 6-7 years of age and may be impossible for patients with significant CNS involvement [98].

Surgical intervention is often required at a young age to address the clinical manifestations of MPS II [75, 76, 90]. The most common procedures are insertion of ventilation tubes, hernia repair, adenoidectomy, tonsillectomy, and median nerve decompression [90]. Surgery may sometimes precede diagnosis, so it is important to evaluate a patient's surgical history when a diagnosis of MPS II is suspected [90].

The short neck, immobile jaw, and pathological changes in the upper airways make general anaesthesia for patients with MPS II a difficult and high-risk procedure [98]. For this reason, it is good practice to consider local or regional anaesthesia where possible. Combining minor surgical procedures may be appropriate in some instances; however, extending the operation time increases the risks of respiratory complications dramatically, so caution is advised (CO).

Before surgery, the patient should be assessed by a multidisciplinary team that includes a cardiologist, otorhinolaryngologist and anaesthetist. A full cardiac assessment is necessary (CO). The severity of obstructive sleep apnoea can be assessed with a sleep study or more formal polysomnography. If possible, flexible nasendoscopy and a computed tomography scan of the airway should be carried out preoperatively to evaluate the anatomy of the airway [101, 102]. Tracheomalacia of the airway makes visualisation and subsequent endotracheal intubation problematic (Figure 1e) [103, 104]. Extubation presents another major risk, as postobstruction pulmonary oedema may exacerbate upper-airway obstruction and has been reported to occur as late as 27 hours after surgery [97, 105, 106]. Some patients may be unable to maintain the airway after extubation, resulting in the need for urgent reintubation or tracheostomy. Early extubation can reduce this risk substantially [98]. As a rule, it is recommended that patients with MPS II should only undergo surgery at centres with experience of the perioperative management of individuals with this disease, and on-site intensive care facilities [98, 106].