ARTICLE

Mucopolysaccharidosis I: Management and Treatment Guidelines

Joseph Muenzer, MD, PhDa, James E. Wraith, MB, ChBb, Lorne A. Clarke, MDc, and the International Consensus Panel on the Management and Treatment of Mucopolysaccharidosis I
aDivision of Genetics and Metabolism, Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina; bWillink Biochemical Genetics Unit, Royal Manchester Childrens Hospital, Manchester, United Kingdom; cDepartment of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada

Financial Disclosure: Dr Muenzer received honoraria from Genzyme for presentations and advisory board meetings and travel expenses for meetings and was a principal investigator for the phase 1/2 and phase 3 trials of laronidase. Dr Wraith received honoraria for presentations and board meetings, travel expenses for meetings, and paid and unpaid consultancy work and was a principal investigator in the phase 3 trial and the 5 years of age trial of laronidase. Dr Clarke received honoraria from Genzyme for presentations and advisory board meetings and travel expenses for meetings and was a principal investigator in the phase 3 trial of laronidase. The initial consensus meeting to discuss these guidelines was sponsored by BioMarin/Genyzme.

Whats Known on This Subject

MPS is a rare lysosomal storage disorder caused by deciency of the enzyme -L-iduronidase, leading to multisystemic, life-threatening clinical manifestations. Disease management has been suboptimal because of poor disease recognition, diagnostic delays, phenotypic heterogeneity, and limited therapeutic options.

What This Study Adds

This article provides much-needed, system-specic treatment guidelines for MPS I, in light of the recent availability of ERT and improved protocols for HSCT.

ABSTRACT
OBJECTIVE. Disease management for mucopolysaccharidosis type I has been inconsistent because of disease rarity ( 1 case per 100 000 live births), phenotypic heterogeneity, and limited therapeutic options. The availability of hematopoietic stem cell transplantation and the recent introduction of enzyme replacement therapy for mucopolysaccharidosis I necessitate the establishment of system-specic management guidelines for this condition. METHODS. Twelve international experts on mucopolysaccharidosis I met in January 2003 to draft management and treatment guidelines for mucopolysaccharidosis I. Initial guidelines were revised and updated in 2008, on the basis of additional clinical data and therapeutic advances. Recommendations are based on our extensive clinical experience and a review of the literature. RESULTS. All patients with mucopolysaccharidosis I should receive a comprehensive

www.pediatrics.org/cgi/doi/10.1542/ peds.2008-0416 doi:10.1542/peds.2008-0416

Key Words -L-iduronidase, biochemical genetics, enzyme replacement therapy, guidelines, hematopoietic stem cell transplantation, lysosomal storage disorder, mucopolysaccharidosis Abbreviations MPSmucopolysaccharidosis CSF cerebrospinal uid ERT enzyme replacement therapy HSCT hematopoietic stem cell transplantation DQ developmental quotient
Accepted for publication Apr 4, 2008 Address correspondence to Joseph Muenzer, MD, PhD, Department of Pediatrics, CB 7487, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514. E-mail: muenzer@med. unc.edu PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright 2009 by the American Academy of Pediatrics

baseline evaluation, including neurologic, ophthalmologic, auditory, cardiac, respiratory, gastrointestinal, and musculoskeletal assessments, and should be monitored every 6 to 12 months with individualized specialty assessments, to monitor disease progression and effects of intervention. Patients are best treated by a multidisciplinary team. Treatments consist of palliative/supportive care, hematopoietic stem cell transplantation, and enzyme replacement therapy. The patients age ( 2 years or 2 years), predicted phenotype, and developmental quotient help dene the risk/ benet prole for hematopoietic stem cell transplantation (higher risk but can preserve central nervous system function) versus enzyme replacement therapy (low risk but cannot cross the blood-brain barrier).
CONCLUSION. We anticipate that provision of a standard of care for the treatment of

patients with mucopolysaccharidosis I will optimize clinical outcomes and patients quality of life. Pediatrics 2009;123: 1929

lysosomal enzyme l-iduronidase and is inherited as an autosomal recessive disorder. Patients with MPS I are unable to degrade the glycosaminoglycans dermatan sulfate and heparan sulfate. These components of proteoglycans provide structural support to the extracellular matrix and cartilaginous structures such as joints and heart valves, in addition to being involved in cellular regulation and communication. l-Iduronidase deciency results in the progressive accumulation of glycosaminoglycan within lysosomes, with subsequent multiorgan dysfunction and damage. MPS I encompasses a spectrum of phenotypes; however, all forms of the disease are biochemically indistinguishable, and all are characterized by progressive multisystemic deterioration.1,2 Historically, MPS I has been delineated into 3 separate diseases on the basis of clinical presentation, that is, Hurler syndrome (severe), Hurler-Scheie syndrome (intermediate), and Scheie syndrome (mild). However, it is increasingly
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UCOPOLYSACCHARIDOSIS TYPE I (MPS I) is a lysosomal storage disorder that is caused by a deciency of the

being recognized that MPS I represents a disease continuum, with considerable clinical variability in age of onset and rate of disease progression. We recommend classifying cases in the MPS I spectrum into 2 broader groups, that is, severe MPS I (Hurler syndrome) and attenuated MPS I (Hurler-Scheie and Scheie syndromes). We prefer the term attenuated rather than mild because patients with Hurler-Scheie and Scheie syndromes typically have signicant disabilities attributable to somatic involvement. The severe end of the MPS I spectrum, representing the majority of known cases, is well described and can be delineated accurately. Children with severe MPS I usually die within the rst decade of life, as a result of cardiorespiratory failure and progressive neurologic disease.1 However, cases of attenuated MPS I vary widely with respect to age of presentation, symptoms, comorbidities, and disease course.1,2 Many patients with attenuated MPS I survive into adulthood, albeit with signicant morbidity. Before the availability of disease-specic therapies, treatment for MPS I was palliative and symptom-based. The advent of hematopoietic stem cell transplantation (HSCT) and, more recently, enzyme replacement therapy (ERT) has heightened the need for better disease recognition, early diagnosis, and up-to-date comprehensive guidelines for disease management and treatment. Better disease recognition across specialties, more-rapid diagnosis (possibly requiring newborn screening), and availability of diagnostic and treatment guidelines should improve disease outcomes and quality of life for both patients and caregivers. METHODS An international, multidisciplinary, working group of experts on MPS I met in 2003, with the goal of formulating diagnosis and management recommendations. The natural history of the disease was discussed, as was the role of supportive care, ERT, and HSCT. The meeting was supported by BioMarin Pharmaceutical (Novato, CA) and Genzyme (Cambridge, MA). The group included specialists in pediatrics, cardiology, ophthalmology, anesthesiology, transplantation, orthopedics, and genetics. The initial guidelines were revised and updated in 2008, on the basis of additional clinical data and therapeutic advances. Recommendations are based on our extensive clinical experience and review of the literature. INCIDENCE MPS I is a panethnic disorder with an estimated incidence of 1 case per 100 000 live births.1,3 Approximately 50% to 80% of patients have severe MPS I; one population study found that attenuated phenotypes represented 26% of the total MPS I population.4 However, these estimates may reect ascertainment bias, because severe cases may be easier to diagnose than attenuated cases. MOLECULAR BASIS AND PHENOTYPE DETERMINATION How glycosaminoglycan accumulation in lysosomes leads to clinical symptoms is incompletely understood. Both primary effects related to altered degradation of
20 MUENZER et al

heparan sulfate and dermatan sulfate and secondary effects related to alteration of cellular function probably underlie disease manifestations. All forms of MPS I have undetectable enzyme activity with currently available diagnostic assays.1,5 Therefore, residual enzyme activity cannot be used to predict disease phenotype. The extent of clinical manifestation is thought to be related to the rate of turnover and the distribution of stored glycosaminoglycan in the body; however, urinary glycosaminoglycan levels, although often higher in more severely affected patients, are not a reliable indicator of severity.6 It is widely accepted that mutational heterogeneity underlies the clinical heterogeneity of MPS I and that phenotype is largely determined by mutation. However, the large number of private (single-occurrence) mutations underlying MPS I has limited the predictive value of genotype for many patients.79 Currently, the Human Gene Mutation Database (professional release 7.3)10 lists 110 mutations in -L-iduronidase associated with MPS I, of which the majority are nonsense mutations, missense mutations, or small deletions. The frequency of MPS I alleles varies among ethnic populations. Among Caucasian patients, the p.W402X and p.Q70X alleles are found in 50% of patients with MPS I; these alleles are rare among Japanese, Korean, or Moroccan patients.8 Patients who are homozygous for a nonsense allele or have 2 different nonsense alleles have the severe form of MPS I. Most patients with attenuated disease have 1 missense mutation. Patients who have a p.R89Q or c.6787g3a (IVS 5-7g3a) allele in association with a null mutation typically have an attenuated phenotype. More than 30 polymorphisms or nonpathogenic sequence variants in the iduronidase gene have been detected. These sequence variants may modify the severity of the clinical disease if they are present with a pathogenic MPS I allele.11 DIAGNOSIS The combination of symptom variability in MPS I and lack of disease awareness confounds both parents and physicians and often results in diagnostic delays. Patients with attenuated MPS I may remain undiagnosed for years.12,13 Even those with severe MPS I may not be diagnosed for up to 12 to 18 months after the onset of symptoms. Most parents are prompted to seek treatment for their child with severe MPS I because of a change in facial features, restricted joint movement, skeletal deformity, a large head circumference, or frequent respiratory infections. Although pediatricians and primary care physicians usually are the rst clinicians consulted, other manifestations, such as cardiomyopathy, recurrent ear infections, hernias, and lumbar kyphosis or gibbus, may result in specialist referral. As effective treatment options become available, accurate early diagnosis is imperative, to prevent or to delay irreversible organ damage and to optimize treatment outcomes. Measurement of urinary glycosaminoglycan levels is a sensitive but nonspecic screening test for MPS I. False-negative results may occur, especially if the urine is too dilute (specic gravity of 1.015 g/mL). A den-

itive diagnosis of MPS I is based on decient -L-iduronidase activity in broblasts, leukocytes, serum, or blood spots.14,15 Pseudodeciency of -L-iduronidase has been described but is rare and is not associated with increases in urinary glycosaminoglycan levels.16 Prenatal diagnosis is available, based on either enzyme testing or DNA testing (for family members of a patient whose mutations are known). CLINICAL MANAGEMENT General Considerations The care of patients with MPS I requires regular assessments, supportive care, and treatment of a variety of systemic complications. Because of the complexity and rarity of this disease, patients are best monitored by a multidisciplinary team at a facility with MPS I experience. The primary care provider is an essential part of the multidisciplinary team, especially for patients who do not live near a major medical center. An involved primary care provider should be on hand to manage day-to-day problems, to refer the patient to appropriate specialists, and to facilitate communication between team members and the patients family. Table 1 presents the core assessments required at diagnosis for all patients with MPS I and the minimal recommended intervals for follow-up assessments. A comprehensive baseline evaluation provides important benchmarks with which to gauge disease progression and responses to therapy. All patients should be evaluated at least annually. Baseline and annual evaluations may be facilitated by a short hospital stay or coordinated outpatient clinic visits over 1 to 3 days to allow for efcient multispecialty review. Patients schedule of follow-up assessments should be individually tailored according to their age, disease manifestations, rate of disease progression, types of treatment, and specialized needs. Monitoring of substrate clearance through urinary glycosaminoglycan levels and spleen and liver volumes is necessary only for HSCT- or ERT-treated patients. Below, we review major disease manifestations and their management according to organ system. Cognitive Development Progressive cognitive impairment is a hallmark of severe MPS I, whereas cognition is normal or only slightly impaired in attenuated MPS I. Children with severe MPS I have progressive neurodegenerative disease. Although early development may seem normal, delay is usually obvious by 12 to 24 months of age.1 Most patients reach a developmental plateau before beginning a decline, which usually leaves them severely mentally disabled at the time of death. Because of a combination of enlarged tongue, hearing loss, and developmental delay, children with severe MPS I develop minimal language skills, but most develop some social skills.1,17 Behavior in severely affected children with MPS I tends toward placidity, rather than the hyperactive and aggressive behavior seen in MPS II and MPS III.1 Children with severe MPS I should receive as much developmental stimulation as possible during the early

TABLE 1 Recommended Minimal Schedule of Assessments for All Patients With MPS I
Initial Assessments General Demographic characteristics Patient diagnosis Medical history Physical examination General appearance Clinical assessments Neurologic/central nervous system Computed tomographic or MRI scans of brain MRI scans of spine Median nerve conduction velocity Cognitive testing (DQ/IQ) Auditory Audiometry Ophthalmologic Visual acuity Retinal examination Corneal examination Respiratory Forced vital capacity/forced expiratory volume Sleep study Cardiac Echocardiography Electrocardiography Musculoskeletal Skeletal survey with radiographsa Gastrointestinal Spleen volumeb Liver volumeb Vital signs and laboratory tests Height and weight Head circumferencea Blood pressure Enzyme activity level Urinary glycosaminoglycan level Urinalysis Functional outcome measurements Mucopolysaccharidosis Health Assessment Questionnaire or other tools exploring functional ability and quality of lifed Every 6 mo Every 12 mo Every Other Year

X X X X X

X X X

X X X X X X X X X X X X X X X X X X X X

X X X

X X X

X X X X X X X X X X X X Xc Xc X

Xc Xc

This schedule of assessments addresses the core MPS I-related disease manifestations that are assessed to stage disease progression over the lifelong course of the disease. The schedule was adapted from the report by Pastores et al,13 with permission. Physicians should determine the actual frequency of necessary assessments according to each patients need for medical care and routine follow-up monitoring. See text for additional guidance on individualization of routine follow-up assessments. All tests requiring sedation are recommended only if sedation is considered to be safe for the patient. a Studies are only for pediatric patients, unless determined otherwise by the treating physician. b The recommended method for determining organ volumes is MRI or computed tomography, to enable quantitative analysis. If it is unsafe to sedate the patient, in the opinion of the clinician, then ultrasonography may be substituted. c Studies are only for patients treated with ERT, unless determined otherwise by the treating physician. d Assessment may not be possible for uncooperative patients or patients younger than 5 to 6 years of age.

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stages of the disease. Adapting the environment to the childs needs (eg, keyboards with oversized characters) may support development. Skills developed early may be retained throughout later stages of deterioration. Neurocognitive function testing at diagnosis and then every year is recommended for individuals with severe MPS I. Children with attenuated MPS I who have learning disabilities or behavioral problems benet from standard interventions. Neurocognitive testing is recommended to facilitate development of interventions and educational plans to enhance academic performance. Neurologic Manifestations Communicating hydrocephalus is common in severe MPS I and is less common in attenuated MPS I; typically, it progresses slowly over months to years. Papilledema and vomiting are unusual, even if opening cerebrospinal uid (CSF) pressure is markedly elevated ( 40 cm H2O). For some patients, abnormal eye movements and acute loss of vision are the presenting features. Chronic increases in intracranial pressure may contribute to delayed neuromotor development and visual/eye problems in severe MPS I. Head circumference should be measured regularly. Noncontrast computed tomography or MRI of the head can determine ventricular size and should be performed at diagnosis and then every 1 to 2 years for patients with severe MPS I, as well as when there is an acceleration in head growth. Imaging studies alone may not distinguish between brain atrophy and increased CSF pressure. If communicating hydrocephalus is suspected, then measurement of CSF pressure through lumbar puncture with sedation should be considered. Ventriculoperitoneal shunting may successfully reduce CSF pressure but typically does not reverse clinical disease signicantly, although it may ameliorate symptoms such as headache or sleep behavior. In patients with attenuated MPS I, CSF pressure may slowly increase over years without signicant changes in brain imaging results, including ventricular size. Chronic recurrent headaches and mild optic nerve compression may be the only signs of elevated intracranial pressure. Spinal cord compression resulting in cervical myelopathy is not typical in patients with severe MPS I, although cervical subluxation can cause spinal cord injury. In contrast, patients with attenuated MPS I frequently develop spinal cord compression and cervical instability.18 Diagnosis usually is not made until signicant cord involvement, such as weakness in the lower extremities or abnormal gait, occurs. Flexion and extension radiographic views of the neck, for evaluation of cervical spine stability, should be obtained at baseline for patients with severe MPS I. For patients with evidence of odontoid dysplasia, radiographs should be repeated every 1 to 2 years and/or before any surgical procedure requiring general anesthesia. Patients with attenuated MPS I should undergo MRI studies of the spinal cord and brain at least every 2 years. Any patient with MPS I with abnormal gait, sensory changes, or weakness in the lower extremities should be evaluated by a neurologist for possible spinal
22 MUENZER et al

cord compression. The evaluation should include neck exion and extension radiographic studies, as well as a MRI study of the full spine. Importantly, although spinal cord compression may be evident on MRI scans, spinal instability is not. Somatosensory evoked potentials can be used to detect early cord compression and to guide the timing of surgical intervention.19 Anecdotal experience suggests that patients with MPS I who undergo spinal surgery have increased risk of major complications, including spinal cord infarction and spinal instability. Carpal tunnel syndrome develops in most patients with attenuated MPS I, although the majority do not develop classic symptoms of nerve compression, even with severe nerve entrapment and damage. For many patients, nighttime pain, numbness, or tingling may be the rst signs, but these typically occur only after severe reduction in nerve conduction velocity.20,21 Some patients have experienced recurrence of carpal tunnel syndrome after repair. Nerve conduction studies should be considered at the time of diagnosis of attenuated MPS I and every 1 to 2 years thereafter. For most patients, electromyography usually is not necessary. Ear, Nose, and Throat Manifestations Even in the absence of infection, children with severe MPS I commonly are plagued by chronic recurrent rhinitis accompanied by persistent nasal discharge and frequent ear infections. Patients with attenuated MPS I have increased frequency of chronic sinus infections. Tonsillectomy and adenoidectomy should be considered for all patients who develop airway compromise, including snoring and coarse breathing. Severely affected children who require recurrent placement of ventilation tubes may benet from a T-tube as an alternative, because such patients are less likely to outgrow the need for ventilation tubes. Routine ear, nose, and throat examinations performed at least annually are recommended. Auditory Manifestations Patients with severe MPS I commonly experience conductive and neurosensory deafness. Hearing loss may be attributable to frequent ear infections, defective ossication in the middle ear, scarring of the tympanic membrane, or nerve damage. Most patients with attenuated MPS I develop some degree of hearing loss, usually in the high-frequency range, as adults. Annual audiologic examinations are warranted for all patients with MPS I and are particularly important for patients with attenuated MPS I. Hearing aids are benecial and are typically underutilized in severe MPS I. Ophthalmologic Manifestations All patients with MPS I have some degree of corneal clouding, although the extent varies greatly.22,23 Both patients with severe MPS I and those with attenuated MPS I may experience profound loss of vision as a result of corneal clouding. Patients with both phenotypes commonly experience loss of peripheral vision as a result of

retinal degeneration and night blindness as a result of rod dysfunction. In severe MPS I, acute blindness may occur in the presence of untreated communicating hydrocephalus. Open-angle glaucoma occasionally may develop; however, it should be noted that high intraocular pressure measurements in patients with corneal involvement may be attributable to corneal thickening rather than glaucoma.23 Patients with severe MPS I should have at least yearly pediatric ophthalmologic evaluations, including intraocular pressure measurements to detect glaucoma. Corneal transplantation has not been performed routinely for patients with severe MPS I. Corrective lenses should be prescribed to correct refractive errors. Corneal transplantation has been performed in attenuated MPS I and can markedly improve vision, although corneal clouding may develop in the transplanted cornea. Glaucoma has not been screened for routinely in patients with attenuated MPS I but may occur. Eye examinations (acuity and pressure assessments and ophthalmoscopy) should be performed at the time of diagnosis of attenuated MPS I and every year thereafter. Corrective lenses should be prescribed as necessary to correct refractive errors. Respiratory and Pulmonary Manifestations All patients with MPS I, particularly those with severe MPS I, are at risk of severe respiratory insufciency as a result of restrictive lung disease, obstructive sleep apnea, and/or asthma.24,25 Upper airway disease may result from enlarged tongue, tonsils, and adenoids; narrowed trachea; redundant airway tissue; and thickened vocal cords. Most patients with severe MPS I develop snoring and obstructive upper airway disease by 2 or 3 years of age. The obstructive sleep apnea typically occurs rst during rapid eye movement sleep and can be diagnosed only through sleep studies. Pulmonary function testing for some patients with attenuated MPS I may reveal severe restrictive lung disease, which usually is not appreciated through clinical history or physical examination. The cause of the restriction is predominantly extrinsic to the lung and involves a combination of skeletal abnormalities of the chest and spine and hepatosplenomegaly, limiting diaphragmatic excursion. Severe restrictive lung disease may aggravate developing obstructive sleep apnea. Patients with severe obstructive airway disease may benet from positive airway pressure treatment (continuous positive airway pressure or bilevel positive airway pressure therapy), with or without supplemental oxygen treatment. Asthma medications should be administered as the clinical condition dictates. Although tonsillectomy and adenoidectomy can be helpful, progressive storage elsewhere in the upper airway or pharynx may lead to respiratory symptoms. Such patients should be referred to an otolaryngologic surgeon experienced in the management of difcult airways. Tracheostomy may be lifesaving for patients with severe sleep apnea and/or valvular heart disease. All patients with MPS I should be monitored routinely by a pulmonologist, who can help assess respira-

tory status and guide treatment. Sleep studies should be performed routinely for patients with severe MPS I after the age of 2 to 3 years and for patients with attenuated MPS I at diagnosis and every year thereafter, if respiratory insufciency is detected. Pulmonary function testing and sleep studies may be required before anesthesia. Bronchoscopy during anesthesia can be helpful in pulmonary evaluation. Cardiac Manifestations Cardiac manifestations are common across the MPS I spectrum and worsen with age. In patients with severe MPS I, valvular disease, arrhythmia, cardiomyopathy, congestive heart failure, coronary artery disease, pulmonary and systemic hypertension, and cor pulmonale may occur.26 Patients with severe MPS I may die suddenly after developing an upper respiratory infection, because of myocardial infarction secondary to severe coronary artery disease.27 Patients with attenuated MPS I typically develop left-sided valvular disease with primary mitral and aortic valve dysplasia, causing regurgitation or stenosis; patients with obstructive airway disease also may develop pulmonary hypertension and/or cor pulmonale. Progression of pulmonary hypertension and congestive heart failure may be insidious. Coronary artery disease in MPS I is atypical, in that it may be characterized by insidious narrowing of entire vessels and is not easily identied through routine cardiac testing. All patients with MPS I should undergo a cardiology evaluation, including electrocardiography and echocardiography, at diagnosis and every 1 to 2 years thereafter. Medical treatment of hypertension and congestive heart failure is determined by the situation. Replacement of severely damaged valves has been performed for patients with attenuated MPS I,28,29 and the morbidity and mortality rates associated with such procedures seem to be increased in those patients. It should be noted that, according to new American Heart Association guidelines, bacterial endocarditis prophylaxis is recommended only for patients with a history of endocarditis, a prosthetic valve, or foreign material in the heart.30 Skeletal Manifestations and Joint Diseases Skeletal complications may dominate the clinical course of patients with MPS I. All patients with severe MPS I develop progressive skeletal and joint disease, which ultimately leads to signicant disability.1 In severe MPS I, skeletal involvement may not be evident until the characteristic gibbus deformity of the lumbar spine is apparent at 6 to 14 months of age. Eventually, most bones are involved in defective ossication, a condition known as dysostosis multiplex. As vertebrae become progressively attened and beaked, spinal deformities, including kyphosis, scoliosis, and kyphoscoliosis, may develop. Hips may be affected, resulting in dysplasia or subluxation. Long-bone irregularities produce valgus and varus deformities, and genu valgum may occur in the knees. Phalangeal dysostosis and synovial thickening produce the characteristic claw deformity and trigger digits. Carpal tunnel syndrome and phalangeal inPEDIATRICS Volume 123, Number 1, January 2009 23

volvement diminish hand function. By the time severely affected children are 2 years of age, joint stiffening and progressive arthropathy affect all joints. Radiographs obtained at birth can detect dysostosis in some patients with MPS I. Patients with attenuated MPS I have progressive arthropathy, which ultimately leads to loss of joint range of motion. Patients present with mild to severe skeletal involvement and tend to have short stature. Kyphosis and/or scoliosis are frequent presenting symptoms, with attendant hip and back pain. Patients also may experience generalized pain and malaise, which may be attributable to osteopenia and microfractures. Patients with moderate/severe skeletal disease should be monitored by an orthopedic surgeon, preferably one who is familiar with MPS disorders. Early detection of skeletal abnormalities, such as kyphoscoliosis, before irreversible changes occur may provide more surgical options. Spine deformities may require fusion; acetabular hip dysplasia can be addressed with osteotomy and genu valgum with epiphyseal stapling. Flexor tendon or carpal tunnel release can provide relief and the return of some hand function. Premature cessation of skeletal growth may occur in MPS I and should be taken into account when surgical procedures are being planned. Physical therapists can assess the degree of joint restriction and develop interventions to maintain joint function and muscle strength. In patients with attenuated MPS I, joint stiffness and pain may be lessened through passive and active range-of-motion exercises and hydrotherapy. In severe MPS I, these interventions may stabilize but not improve joint function and stiffness. The benet of physical therapy in patients with severe orthopedic compromise is controversial, with some anecdotal parental experience suggesting that it may be harmful. Splints often are used to maintain joint position and to prevent xed exion deformities, but the long-term benets have not been studied in MPS. Occupational therapists can improve quality of life and functional independence; the most-effective occupational therapies are those that patients can perform on their own. Anesthesia Many patients with MPS I present major anesthetic risks because of upper airway obstruction. Difculty with intubation may prove fatal.31 We recommend that patients undergo procedures requiring general anesthesia only at centers with access to anesthesiologists who are experienced with MPS disorders and their complications. Anesthetic risk increases with age. Spinal instability, specically of the atlantoaxial joint, requires careful positioning to avoid hyperextension of the neck. Radiography should be performed for all patients, to evaluate individual risks. The accumulation of glycosaminoglycan in the airway severely limits the anesthesiologists ability to observe the larynx with the laryngoscope. The limited jaw movement, short neck, enlarged tongue, and thick secretion compound the difculty of observing the larynx for even very skilled anesthesiologists. Intubation may be very difcult for
24 MUENZER et al

patients with MPS I. Fiber-optic bronchoscopy can be used to evaluate the degree of airway disease and also can be used to intubate patients with difcult airways. Laryngeal mask airways can be used for airway management for short periods or to facilitate ber-optic intubation.31,32 Endotracheal tubes may need to be smaller than anticipated for the age and size of a patient with MPS I. Patients commonly experience postoperative airway obstruction, and overnight hospital observations are not uncommon. Awareness of the possibility of postoperative tracheostomy is important for all parties involved. When possible, procedures requiring general anesthesia should be avoided, to minimize risk; for example, computed tomographic scans may be an alternative to brain MRI scans for very young patients, because the latter typically require general anesthesia and airway management. Dental Manifestations Patients with MPS I may develop gum, tooth, and enamel abnormalities, frequent caries, dentigerous cysts, and abscesses. Gingival cysts in particular may be a source of pain, which can be managed with analgesics, antibiotics, and gum massage. Patients or caregivers should be taught to perform regular at-home dental care. Routine dental ofce care should be performed regularly. For some patients, anesthesia may be required for dental procedures. Because these patients present major anesthetic risks that may prove fatal, dental work requiring anesthesia should be performed in hospitals with anesthesiologists who are experienced with MPS disorders and their complications. For patients with severe MPS I, the dentist ideally should be based in a childrens hospital and have experience in pediatric dentistry. Dental examinations and radiographic studies should be performed routinely. All patients should be seen by a dentist at least every 6 months. Hernias Inguinal and umbilical hernias are common among patients with MPS I. For patients with severe MPS I, inguinal hernias are commonly repaired before disease diagnosis. Umbilical hernias frequently recur after initial repair, perhaps as a result of impaired elastogenesis.33 The abdominal protuberance caused by progressive hepatosplenomegaly may enlarge umbilical hernias. Gastrointestinal Manifestations Periodic episodes of diarrhea may alternate with constipation. Dietary modications and the conservative use of laxatives can help to control diarrhea and constipation. Abdominal pain also may be common in patients with attenuated MPS I. Other Essential Support Services for Patients and Their Families or Caregivers The diagnosis of MPS I may have a profound psychosocial impact on patients and their families, who must cope with the reality of a progressive debilitating disease.

Resources such as social services, family therapy, and local and national MPS resource groups should be made available to assist patients and their families with emotional, nancial, and social issues related to coping with MPS I. Genetic counseling also is important for patients and families, so that they have an understanding of the autosomal recessive inheritance of MPS I and the likelihood that future offspring will be affected. TREATMENT OF MPS I Hematopoietic Stem Cell Transplantation When successful, hematopoietic stem cell transplantation (HSCT) using either bone marrow or umbilical cord stem cells can prevent and/or reverse many but not all of the clinical features of severe MPS I. However, it must be performed early in the disease course, before developmental deterioration begins,3441 and it carries signicant risk of morbidity and death. HSCT should be undertaken only after extensive pretransplantation assessment, for carefully selected children for whom long-term monitoring will be possible. The rst successful allogeneic HSCT procedure for MPS I involved a 1-year-old boy with severe MPS I, in 1980. Thirteen months after HSCT, the patients plasma -L-iduronidase activity was similar to that seen in heterozygotes, his hepatosplenomegaly and corneal clouding had reversed, and his developmental deterioration had been arrested.42 At the age of 20 years, the patient demonstrated full engraftment and, with intelligence in the low reference range, was self-reliant and able to operate a computer.43 To date, 400 patients with severe MPS I have received transplants, primarily using bone marrow but increasingly using umbilical cord blood.38,40 In both related and unrelated donor transplantations, failure to achieve complete engraftment has been a signicant contributor to morbidity and death. Pretransplantation preparation must be sufciently immunosuppressive and myeloablative to optimize successful engraftment.44 Although success rates for HSCT have improved in recent years, the risks are still signicant; the reported mortality rate in a recent, large, retrospective analysis was 15%, with a rate of survival with engraftment of 56%.45 The clinical success of HSCT depends on the age of the child at transplantation, the degree of clinical involvement, the childs cardiopulmonary status and neurologic development, the type of donor, and the ability to achieve stable engraftment without the development of graft-versus-host disease.38,46 Access to developmental services, such as speech, behavioral, and physical therapy, also contributes to the overall outcome.46 The best developmental and clinical outcomes have been observed in children with developmental quotients (DQs) of 70 and ages of 2 years at the time of transplantation.36 One of the most important benets of HSCT is the preservation of intellectual development in children who, on the basis of mutational analysis, would have been predicted to develop severe mental impairment. Improvements in hearing, joint mobility, respiratory

function, and cardiac function and the resolution of communicating hydrocephalus after successful HSCT may contribute to improvement in intellectual functioning, even in the absence of central nervous system correction.1 Although HSCT may improve hearing for 30% to 40% of children, it does not reverse profound conductive and sensorineural hearing abnormalities.47 Hepatosplenomegaly and upper airway obstruction, including sleep apnea, may resolve within several months after HSCT.48 In addition, facial features may become less coarse, growth may improve, and urinary glycosaminoglycan levels may return to normal or nearly normal levels. Although retinal abnormalities often persist, corneal clouding stabilizes or slowly resolves, and ocular pressures may normalize.46 Cardiac manifestations, including heart failure and tachyarrhythmia, may be corrected within 1 year after successful HSCT, and improvements in myocardial muscle function and coronary artery patency have been documented up to 14 years after HSCT.49,50 Cardiac valvular deformities, however, seem to be resistant to HSCT treatment and frequently progress.44,46,50 Skeletal abnormalities do not respond to HSCT, and most patients with severe MPS I with good engraftment still require multiple orthopedic interventions.38,51 However, patients with severe MPS I with good engraftment may experience progressive improvement in the grade of odontoid dysplasia.52 Enzyme Replacement Therapy Laronidase (recombinant human -L-iduronidase; Aldurazyme [Genzyme Corporation, Cambridge, MA]) is approved for the treatment of patients with MPS I in the United States, Europe, and many other countries. To date, 100 patients have been treated with laronidase in clinical trials.5356 In addition to phase 1/253 and phase 355 studies, a study in children 5 years of age56 and a dose-ranging study have been completed.57 An open-label phase I/2 clinical study initiated in 1997 demonstrated that laronidase was biologically active and that the selected dose regimen, based on treatment studies in the MPS I canine animal model,58,59 cleared accumulated glycosaminoglycan. Ten patients with MPS I received weekly intravenous administration of laronidase (100 U/kg, 0.58 mg/kg body weight). Patients demonstrated decreased urinary glycosaminoglycan excretion and reductions in liver and spleen volumes. All patients had improved New York Heart Association scores after 1 year of treatment, and some patients had improved shoulder exion range of motion, sleep apnea/hypopnea index, and visual acuity. These improvements were sustained with continued treatment.26,54 Functional status and endurance generally improved in laronidase-treated patients, as indicated by improvements in self-care, increased range of mobility, and the ability to run or to play sports, depending on the severity of baseline disease.26,54 A 26-week, double-blind, placebo-controlled, phase 3 study of weekly laronidase treatment (0.58 mg/kg body weight) for 45 patients showed substantial decreases in urinary glycosaminoglycan levels and hepatomegaly.55 Urinary glycosaminoglycan levels decreased within 4
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weeks after initiation of treatment, and values were reduced by 54% with sustained treatment. Liver volumes normalized for most patients. After 26 weeks, patients who received laronidase showed a mean 5.6% increase in the percentage of predicted normal forced vital capacity and a mean 38.1-m improvement in the 6-minute walk test, compared with patients who received placebo. Because of patient heterogeneity, overall changes in shoulder exion and sleep study apnea/hypopnea index values were not signicant, but there were trends toward improvement for patients with more-severe symptoms at baseline. Adverse event proles for the phase 3 trial were similar for the laronidase and placebo groups. Although most patients developed IgG antibodies to laronidase, infusion-related reactions (such as ushing, fever, headache, or rash) were generally manageable with slowing of the infusion rate and/or administration of medication (antipyretic agents or antihistamines). Laronidase therapy had a positive safety and tolerability prole, with low associated risks. During the phase 3 extension study, 1 patient experienced 2 treatment-related serious adverse events (respiratory difculty and anaphylaxis), which might have been exacerbated by preexisting severe upper airway obstruction and restrictive lung disease. An emergency tracheostomy was required during the second event, to maintain the patients airway. Acute illness at the time of infusion and the extent of MPS I-related respiratory disease seem to contribute to the severity of some reactions and may complicate the management of serious infusion-associated reactions. A 6-year follow-up study of 5 of the original 10 patients in the phase I/II trial who were treated with laronidase found clinical improvement or stabilization, in contrast to the natural history of the disease, as well as some additional decrease in urinary glycosaminoglycan excretion and liver size.54 In those patients, shoulder range of motion stabilized or improved. Patients who were treated before puberty grew substantially. Overall, the evaluated patients with MPS I who were treated with laronidase for 6 years reported improved ability to perform normal activities of daily living.54 Up to 7 years of laronidase treatment resolved left ventricular hypertrophy in those 5 patients, but mitral and aortic valves remained thickened and, in some cases, developed progressive thickening and regurgitation.60 Effects of laronidase on the eye were evaluated in a subgroup of 8 patients in the phase 3 extension trial; after 4 years of laronidase treatment, ocular manifestations (including visual acuity) remained stable in 5 patients and worsened in 3 patients.61 Because laronidase does not cross the blood-brain barrier in any appreciable amount at the labeled dose, it is unlikely to improve cognitive or central nervous system function in patients with MPS I. Like HSCT, laronidase may not correct preexisting cardiac valvular disease or skeletal abnormalities, although it can improve or preserve joint mobility. Early initiation of therapy, before irreversible damage, may be more effective in slowing disease progression.
26 MUENZER et al

Use of ERT With HSCT Short-term laronidase administration in combination with HSCT in severe MPS I has been shown to be feasible and safe6267 and may improve mortality and engraftment rates, especially for patients in poor clinical condition, because it can decrease disease-related complications.6567 After full engraftment is achieved, the benet derived from additional enzyme supplied by laronidase is unclear. Laronidase may be benecial for patients with only partial posttransplantation engraftment; however, experience with this group is limited. Treatment Algorithm The risk/benet ratio for HSCT versus ERT must be determined individually for each patient with MPS I. Important considerations are patient age, disease phenotype, DQ, severity of clinical disease, and potential for growth (Fig 1). In the case of a newly diagnosed patient 2 years of age who is cognitively intact (ie, DQ of 70), it is important to preserve cognitive abilities. If deterioration is anticipated on the basis of clinical ndings, neurodevelopmental testing results, and genotype information (eg, identication of 2 nonsense mutations), then HSCT is expected to have more long-term clinical impact than laronidase in stabilizing neurocognitive function. If an attenuated phenotype is suspected, then the preferred option is laronidase. For children with severe physical disease who are cognitively intact, laronidase administered before HSCT may help to improve their health status and physical condition and to increase their chances for a successful HSCT outcome. For children 2 years of age who have DQs of 70, less cognitive benet is expected from HSCT. In such cases, laronidase, which has lower associated risks than HSCT, may improve the physical manifestations of the disease and improve quality of life like HSCT. HSCT should be considered if neurocognitive function improves with interventions for individuals whose neurodevelopmental function has been adversely affected by multiple medical problems, as well as limited access to educational services and therapies (eg, occupational, physical, and speech therapies). For older patients in whom developmental decline already has occurred, laronidase is the more reasonable option for palliative therapy. For children who have no neurologic or cognitive damage, laronidase is recommended. HSCT is discouraged for such children because it offers no therapeutic advantage over laronidase and places the patient at increased risk from the procedure. Role of MPS I Registry Long-term clinical outcome data are needed for better understanding of how different treatment options affect clinical disease and for provision of an evidence-based rationale for management recommendations. A MPS I registry (www.mpsiregistry.com) was established by BioMarin Pharmaceutical (Novato, CA) and Genzyme (Cambridge, MA), as part of a postmarketing regulatory commitment after the approval of laronidase. This on-

FIGURE 1 Treatment algorithm for patients with a diagnosis of MPS I. This algorithm is meant as a general guideline only. Specic patient circumstances, such as treatment availability and the patients unique clinical situation, must always be factored into treatment decisions. For example, a child 2 years of age with a DQ of 70 could still be a good candidate for HSCT if his or her DQ was decreased by very poor motor skills resulting from somatic manifestations of severe MPS I. aPrediction of disease severity based on clinical picture, neurodevelopmental testing, genotype and other relevant information.

going observational database tracks natural history ndings and outcomes for patients with MPS I.13 Participation is open to all physicians treating patients with MPS I, and clinical data are collected (with written consent) and submitted condentially from around the world. Health care professionals have access to aggregate data on MPS I and can query the database for specic information to facilitate the care of their patients with MPS I. All patients, regardless of treatment status or geographic location, should be encouraged to participate in the MPS I registry. The MPS I registry, if used, should be able to capture treatment and outcome data that ultimately can guide clinicians to develop the most-effective therapeutic strategies for the full spectrum of cases of MPS I. CONCLUSIONS With the advent of HSCT and ERT, effective treatments now exist for MPS I; they are likely to be most benecial early in the disease, before irreversible changes occur. Early recognition of the constellation of symptoms of MPS I and prompt referral to a multidisciplinary care center experienced in lysosomal storage disorders are essential. Each patient with MPS I is unique and may exhibit a distinct clinical course. Consequently, there is no one-size-ts-all intervention or management strategy. Treatment options and disease management strategies must be developed within the parameters of each individual case, including the age at diagnosis, the severity of the disease, and the degree and type of clinical involvement. Systematic evaluations should improve the quality of life for both children with MPS I and their families. ACKNOWLEDGMENTS The International Consensus Panel on the Management and Treatment of Mucopolysaccharidosis I included Charles Barnett, MD (Dallas, TX); Lorne A. Clarke, MD

(Vancouver, Canada); Nathalie Guffon, MD (Lyon, France); Ronald V. Lacro, MD (Boston, MA); Joseph Muenzer, MD, PhD (Chapel Hill, NC); James Ogilvie, MD (Salt Lake City, UT); Charles Peters, MD (Kansas, MO); Maurizio Scarpa, MD, PhD (Padova, Italy); Ida V. D. Schwartz, MD, PhD (Porto Alegre, Brazil); David H. Viskochil, MD, PhD (Salt Lake City, UT); Robert Walker, MD (Manchester, United Kingdom); and James E. Wraith, FRCPCH (Manchester, United Kingdom). We thank Lisa Underhill, MS (Global Medical Affairs, Genzyme) for writing assistance. REFERENCES
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