Multidisciplinary Management of Hunter Syndrome

Hunter syndrome, or mucopolysaccharidosis II, is an X-linked, progressive lysosomal storage disease in which patients are deficient in the lysosomal enzyme iduronate-2-sulfatase (I2S),1,2 which results in cellular accumulation of the glycoaminoglycans dermatan and heparan sulfate. Hunter syndrome occurs almost exclusively in males, with a reported incidence of ∼1 in 170000 male births.3 The accumulation of glycoaminoglycans within tissues and organs contributes to the Hunter phenotype, which was recently reviewed in detail by Martin et al.3 Hunter syndrome is a heterogeneous disorder, both in age at onset of symptoms and severity. Patients typically have a normal appearance at birth, with the initial signs and symptoms emerging between 18 months and 4 years of age in the severe form and ∼2 years later for those with an attenuated phenotype form.1,3,4 All patients experience somatic involvement, which can include facial dysmorphism, enlarged liver and spleen, stiff joints and contractures, cardiac valve disease, and upper-airway obstruction. The most severely affected patients, who are estimated to include ∼75% of all patients with Hunter syndrome,4 have profound neurologic involvement leading to cognitive impairment and developmental regression; death usually occurs in the second decade of life.1,3 Patients with an attenuated phenotype may have normal intelligence and typically survive into adulthood.In 2006, Shire Human Genetic Therapies, Inc (Cambridge, MA) invited an international panel of physicians experienced in the management of patients with Hunter syndrome to discuss aspects of this metabolic disorder. The initial work of that group of experts resulted in a article that discussed the recognition and diagnosis of Hunter syndrome.3 The reader is directed to that review for a detailed presentation of the signs and symptoms of mucopolysaccharidosis II. In a subsequent meeting held in Rome, Italy, in April 2007, the panel of experts invited a group of subspecialists highly experienced in caring for patients with Hunter syndrome to present detailed discussions of specific management issues. In this review, developed from this conference, we discuss the primary clinical issues of which a physician needs to be aware in managing Hunter syndrome.The manifestations of Hunter syndrome are multisystemic, involving the nervous, respiratory, and musculoskeletal systems, among others.1,3 Some of the involvement is clearly life-threatening (eg, respiratory problems, complications related to general anesthesia), whereas other issues might be considered to primarily affect quality of life (eg, limited mobility and manual dexterity caused by progressive joint stiffness). In all cases, the management of the disease demands that the physician be aware of the special issues surrounding the patient with Hunter syndrome and that a multidisciplinary approach should be taken. In the following sections, the organ involvement of Hunter syndrome is briefly described, and special management concerns are discussed. The expert panel has drawn on both the medical literature and its clinical experience in creating this document.The neurologic impact of Hunter syndrome varies considerably. By definition, patients with a severe phenotype have profound central nervous system (CNS) involvement that severely impairs cognitive ability and results in developmental delay and, ultimately, developmental regression. Behavioral problems, including obstinacy, aggression, and hyperactivity, are common in the early years of life in patients with severe Hunter syndrome.4 At the other end of the spectrum, patients with an attenuated phenotype exhibit little neurologic involvement yet still can experience progressive somatic deterioration.Clinical methods of evaluating CNS morphology and physiology in Hunter syndrome may not always correlate well with functional cognitive status. For example, in an MRI study of 19 patients, the prevalence of brain atrophy, hydrocephalus, and severe white-matter lesions was significantly higher in patients with cognitive impairment than in those without cognitive impairment.5 However, the presence of these brain lesions was not diagnostic of impaired cognitive ability, because white-matter lesions, enlarged ventricles, and evidence of brain atrophy were sometimes present in patients without cognitive impairment.5Assessment of neurodevelopment in Hunter syndrome may be used to determine cognitive abilities and to follow the progression of neural involvement. However, standard neurobehavioral instruments were not designed for neurodegenerative conditions that affect multiple body systems or for longitudinal evaluation.6,7 In addition, the patient needs to be cooperative and be able to hear, understand, and perform the physical tasks requested. Because many patients develop moderate-to-profound hearing loss, it is important to realize that sensory abnormalities may interfere with performance of a test. To make an accurate assessment of the neurodevelopmental impact in Hunter syndrome, it is necessary to assess multiple domains of function by using age-appropriate instruments and to perform repeat testing over time, at yearly intervals if possible.6 The results of neurodevelopmental testing should be used to determine educational capabilities of the patient. In addition, parents and caregivers can be counseled to treat the affected children at their functional age rather than their chronological age.Behavioral problems in Hunter syndrome, including hyperactivity, obstinacy, and aggression, seem to be confined to patients with a severe phenotype.8,9 These behavioral problems are reported to begin in the second year of life and continue until age 8 or 9, when neurodegeneration limits this behavior.8 These behavioral problems have been described as serious and severely affecting home life.8 Severe hearing loss and lack of sleep (caused by obstructive sleep apnea [OSA]) as well as regression of cognitive abilities as neurodegeneration progresses may also contribute to the behavior. When cognitive abilities have regressed substantially, withdrawal typically occurs. Medical therapy to control disruptive behavior is not generally effective.8 Behavior-modification programs can be tried, but they also are typically not very successful. No evidence has been reported to support use of the newer “atypical” antipsychotic medications to control behavior in patients with Hunter syndrome, and it is our opinion that, in general, they are not effective.Communicating hydrocephalus, a disturbance in the reabsorption of cerebrospinal fluid (CSF),10,11 is a common finding in Hunter syndrome and may contribute to neurologic deterioration. Signs of hydrocephalus may include behavioral changes, headache, and vision disturbances and are typically slow and subtle in their onset. Ventriculoperitoneal shunting is the standard treatment for managing communicating hydrocephalus, and it has been reported to improve vision disturbances and reduce headaches.10,12 In 1 case, motor function was reported to improve after ventriculoperitoneal shunting.11 Little other experience has been reported in the medical literature; thus, the issue about when to shunt remains unresolved. It is our opinion that shunting might be considered for patients with MRI evidence of progressive ventricular enlargement and/or a confirmed CSF pressure of >25 to 30 cmH2O (18–22 mmHg).Spinal cord compression caused by dural thickening or by instability of the atlantoaxial joint has been reported13–15 (Fig 1). Symptoms may include abnormal gait, muscle weakness, clumsiness with fine motor skills, and bladder dysfunction.13–16 Patients with Hunter syndrome should be screened for clinical and radiologic evidence of spinal cord compression. Atlantoaxial instability can be identified by flexion-extension radiography, but MRI is required to confirm cord compression secondary to dural thickening.13,14 Care should be taken during general anesthesia to prevent cord compression resulting from atlantoaxial instability. Because cord compression is often associated with irreversible neurologic dysfunction, decompression surgery should be considered at the onset of symptoms before significant impairment has occurred.13Seizures are common in patients with a severe phenotype,17 and their incidence parallels the cognitive deterioration. In contrast, seizures are much less common in patients with an attenuated phenotype. In 1 recent study, seizures were reported in 27.7% of patients with a severe phenotype and in only 5.9% of those with an attenuated phenotype.17 The initial onset of seizures may not be readily recognized by parents, because they may take the form of absence seizures that are characterized by “staring” episodes and may not require treatment. The incidence of these subtle seizures should be considered as a trigger for further neurologic assessment. No studies have been reported that evaluated the association of behavioral problems and seizures, and it is our opinion that these problems are not related. Generalized tonic-clonic seizures are common as disease progresses and usually can be controlled by anticonvulsant monotherapy.Carpal tunnel syndrome is the most common entrapment neuropathy in adults, but it is rarely seen in children. However, carpal tunnel syndrome is commonly seen in patients aged 5 to 10 years with Hunter syndrome and, if untreated, may result in irreversible contracture of distal interphalangeal joints as well as dysesthesia, sensibility loss of the first 3 fingers, and paresis of the thenar muscles.18 Importantly, patients rarely report pain until loss of function occurs. Standard electrophysiologic testing will identify median nerve compression even before symptoms appear, and it should be initiated by the ages of 4 to 5 years and repeated at 1- or 2-year intervals. For some patients, sedation or general anesthesia might be necessary to obtain high-quality results. (Please note that both sedation and general anesthesia are high-risk procedures for patients with Hunter syndrome, as described in the “General Anesthesia” section below.) Electromyography testing is not typically tolerated by the unsedated child. Decompression surgery is recommended for patients with demonstrated loss of hand function or abnormal nerve-conduction studies and results in rapid and sustained improvement of function.18–22 The rate of reoccurrence of carpal tunnel syndrome after surgery in patients with Hunter syndrome is not known, and patients have remained symptom-free for up to 11 years.18 However, because reoccurrence of median nerve compression caused by scarring or continued glycoaminoglycan deposition is a possibility, ongoing monitoring is necessary.Hearing loss is nearly universal in Hunter syndrome,23,24 and it is characterized by both conductive and sensorineural involvement.25 Chronic otitis media is common and contributes to the conductive hearing loss.25,26 The mucosa of the middle ear has been described as thick and edematous, with large, foamy cells that stain positive with periodic acid Schiff, indicative of glycoaminoglycan storage.27 Otosclerosis has been described and also contributes to conductive hearing loss.27–30 The etiology of neurosensory loss of hearing is less well established. In 1 case, compression of the cochlear nerve caused by arachnoid hyperplasia was described.25 Reduction in spiral ganglion cells and degeneration of hair cells also may contribute to neurosensory loss.31 Because hearing loss can contribute to behavioral problems and learning difficulties, it is important to perform routine otologic and audiologic evaluations for patients with Hunter syndrome at least every 6 to 12 months. Myringotomy with placement of ventilating tubes may improve hearing.26 The use of hearing aids should be encouraged.Obvious corneal clouding is not prominent in Hunter syndrome.1 In the largest study of the eye in Hunter syndrome (N = 33 patients), optic nerve head swelling was seen in ∼20%, and optic atrophy was found in ∼11% of the patients.32 Retinopathy has been reported also.32–37 has been by and may result in and loss of eye is for patients with Hunter swelling is the be CSF pressure is shunting may be It is important to note that may CSF pressure or hydrocephalus, but the absence of not confirm normal CSF is not a of pressure in Hunter syndrome.The of Hunter syndrome to which limits the ability to the and the ability to and/or may interfere with the of involvement and cognitive impairment may also the required for and patients exhibit some are reported to be and in some is associated with of involvement with first procedures may be in patients with Hunter syndrome because of the limited of the anesthesia may be required for some procedures in patients with severe disease (eg, for or but anesthesia special in Hunter syndrome are because of the and reported and of is a to the and of patients with Hunter syndrome.1 to tissues are for most respiratory problems associated with Hunter These include enlarged and and leading to have been reported in 1 The mucosa the is often and it when as during the disease may develop and leading to significant on caused by of the the during in which the normal of the be may to during In addition, a with and stiff and resulting from organ enlargement contribute to is commonly in Hunter and in which often patients from sleep 3 and 4 (Fig The lack of sleep may result in behavioral some patients, the respiratory also may be with deposition of glycoaminoglycan in the may be the mucosa the appearance of or it may be thickening may contribute to it rarely the of a of medical physical and function testing using may be for monitoring progressive in respiratory However, the of the patient and, thus, be on very patients or on patients with a severe phenotype. may be by the an sleep study in the during unsedated sleep should be used to its and to the of treatment include and to and and and However, because many children in the to be a study can be at home by using a with the results reviewed by a may be for a of respiratory involvement. will a high-quality but also may the and obstruction. may be for patients with limited mobility of the in case, this will accurate of the that occurs during It is important to that these of should be considered because may that the other is required for patient with Hunter syndrome who has respiratory of involvement with the of including and but because of the progressive of the changes, this approach may only positive pressure during sleep is often to the management at an pressure a that to during of this approach is positive pressure varies the of positive pressure that a positive pressure is during and require for both the and or caregivers and can be The for special also may make may be an of an in patients with severe but complications are the of the is often for or of the with of a has been reported in patients with Hunter but it can have significant to with and the of in and not with the normal of the child. These also may of are commonly associated with which may be and, at discussed including of the and of the by tissues of the and may general anesthesia in patients with Hunter Because of the is common with Hunter of anesthesia in Hunter syndrome reported or in 5 of 12 In some experienced it is common to perform and a by using a before surgery that the can be for the that is about to be a is often the most sometimes the only for It is important to have a for of an in the of including with the parents about the of or is some evidence that early after the may reduce the of For or in patients for a may control of the of complications not end at the of of the and other can make if not Patients may be to an after or may upper-airway and has been reported to as as after In that case, respiratory resulted in an and, ultimately, the death of the patient. also has been The of is not known, but the primary is an resulting in pressure that results in of fluid from to the The use of a at the of may the and improve because the of this with the work of and anesthesia a high-risk and, should be only by who have experience in patients with and only in medical In to an experienced in some it is common for an or to be during the of anesthesia and of the patient. approach is to over a in all cases, because this also of and and contributes to the management of the patient. Because of the associated with general it is to to perform multiple procedures during a anesthesia It is our experience that the associated with general anesthesia are for a patient who has general anesthesia without that the between the procedures is However, a patient should be considered at if a has because of the progressive of Hunter patients require sedation or anesthesia for the of diagnostic it can be to use sedation by of an or rather than this can be for patients with Hunter syndrome because of the incidence of upper-airway the other of the has its In our sedation in patients with Hunter syndrome should be only in a for general with and monitoring and for and by an experienced involvement is nearly universal in Hunter syndrome and is characterized by stiff joints and joint of These problems mobility and affect quality of abnormal of all and of many of the joints has been described and is associated with in the often prevent patients with Hunter syndrome from and may therapy is designed to and improve physical function and an initial approach to the management of joint involvement of Hunter The first should be to neurologic (eg, spinal cord compression or and a directed at the may and of fine motor for the and for It is important that the patient be able to perform the on or because (eg, 10 may be than a with a physical studies evidence of of physical therapy in Hunter syndrome have been it is important to by and periodic The should be for the joints that are For example, joint of testing is often but joint of joints in whereas of require the of The patient also be able to in the or may be for improvement during surgery has a in the management of Hunter In the of the the is very and of the head has been (Fig These are of and In an surgery be to for a patient with Hunter syndrome with surgery should be of the is often secondary to carpal tunnel syndrome but it also may However, glycoaminoglycan deposition in may their of their distal interphalangeal recognition and surgery to the is for contracture of the involvement is common in Hunter studies have that nearly all patients of phenotype exhibit cardiac abnormalities on For example, et patients and reported that the patients with a severe phenotype and the 11 patients with an attenuated phenotype abnormal results. the patients who were to be as the severe or attenuated phenotype, only 5 patients normal is with and affected in have thickening of the and and has storage in the and in cells in the abnormalities (eg, also contribute to cardiac in patients with Hunter of the cardiac involvement of Hunter syndrome should include and/or if The of these should be by the but every 1 to 3 years is typically has been but this remains Because of the dysfunction, therapy is required before surgery or in this has been and should be as with Hunter syndrome, both severe and can have normal up to years of age but to issues in some and many parents have therapy to However, the and of for Hunter syndrome are not yet known, and evidence to support its use in patients with Hunter The of in Hunter syndrome is not known, but it is to be at least the result of have function in a patient was found to be normal in the only reported in the the patient with severe disease, the progression of neurologic involvement results in a general in and The patient will the ability to and The ability to control and bladder function will be and the patient will the of death on the death is often but severe neurologic impairment and a as a result of an to are the a should be considered when results in All other should be and directed at the of the including the use of pain if at of in Hunter syndrome have been including or and These have been in patients or in of patients, and evidence of clinical has been methods include and therapy with has been in clinical has the treatment of for the severe form of mucopolysaccharidosis in which it is reported to reduce somatic involvement and prevent it is before months of No controlled clinical studies have been the of in Hunter syndrome, and the of the medical literature only or some evidence of improvement in the somatic signs and symptoms of Hunter syndrome has been reported with the results of these studies have evidence of cord has been as a readily of cells for report of the use of cord in Hunter syndrome has been et a with cord and reported that and was use of for treatment of Hunter syndrome remains because of the significant and that may be associated with this For patients disease, the use of may to complications (eg, of the and the presence of disease most It remains even when very early in life or with cord as the of will the of cognitive involvement in patients with the severe Patients and their parents these and the in the quality of life that may Human Genetic Therapies, is for for patients with Hunter in the and was primarily on the results of a clinical study demonstrated that of as an at a of significantly the primary a of in in 6 and in with those who were a in liver and and in glycoaminoglycan also were experienced by patients with clinical continued as an study in which all patients were with of at for at least of this study have not yet been clinical was well and most of the reported were with those in an with Hunter The most common were related to the headache, and/or These were by or the and by with and/or have been in some patients during of as have in which a secondary after treatment and of the initial Patients who have experienced these may require after an of have and issue when to remains for many patients with Hunter The clinical demonstrated clinical of treatment for patients with Hunter syndrome years of age were able to with and the testing as experience that should be initiated before the onset of irreversible and, before significant disease patients with the severe form of Hunter syndrome were not in the clinical is to that the somatic manifestations of their disease not be by treatment. clinical support this In contrast, is not to the and patients with a severe phenotype are not to have cognitive improvement or with treatment of a patient with a severe phenotype may significantly improve or quality of but the of in patients with severe neurologic impairment to be the between and phenotype in Hunter syndrome identify patients with the severe phenotype and, thus, the of management and treatment of this approach has been of limited for most are and in a for the of the phenotype. it be that other may the of even of the always result in a severe phenotype, as of have been associated with a severe phenotype and has been reported in patients with an or attenuated the an with the loss of is primarily associated with the attenuated syndrome is a that multiple organs and its management a multidisciplinary will all a as will as and procedures that require general anesthesia should be in a medical that has experience in children with Hunter the to treat patients with mucopolysaccharidosis II, CNS disease is not to be affected by The impact of initiated early in life on and abnormalities is not monitoring of the clinical of patients with mucopolysaccharidosis is to determine Human Genetic Therapies, Inc for the by and reviewed the to the of all with