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 Children’s 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.

What’s Known on This Subject What This Study Adds

MPS is a rare lysosomal storage disorder caused by deficiency of the enzyme ␣-L-idu- This article provides much-needed, system-specific treatment guidelines for MPS I, in
ronidase, leading to multisystemic, life-threatening clinical manifestations. Disease light of the recent availability of ERT and improved protocols for HSCT.
management has been suboptimal because of poor disease recognition, diagnostic
delays, phenotypic heterogeneity, and limited therapeutic options.

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 trans- www.pediatrics.org/cgi/doi/10.1542/
peds.2008-0416
plantation and the recent introduction of enzyme replacement therapy for mucopo-
lysaccharidosis I necessitate the establishment of system-specific management guide- doi:10.1542/peds.2008-0416
lines for this condition. Key Words
␣-L-iduronidase, biochemical genetics,
METHODS. Twelve international experts on mucopolysaccharidosis I met in January enzyme replacement therapy, guidelines,
hematopoietic stem cell transplantation,
2003 to draft management and treatment guidelines for mucopolysaccharidosis I. lysosomal storage disorder,
Initial guidelines were revised and updated in 2008, on the basis of additional clinical mucopolysaccharidosis
data and therapeutic advances. Recommendations are based on our extensive clinical Abbreviations
experience and a review of the literature. MPS—mucopolysaccharidosis
CSF— cerebrospinal fluid
RESULTS. All patients with mucopolysaccharidosis I should receive a comprehensive ERT— enzyme replacement therapy
baseline evaluation, including neurologic, ophthalmologic, auditory, cardiac, respi- HSCT— hematopoietic stem cell
transplantation
ratory, gastrointestinal, and musculoskeletal assessments, and should be monitored DQ— developmental quotient
every 6 to 12 months with individualized specialty assessments, to monitor disease Accepted for publication Apr 4, 2008
progression and effects of intervention. Patients are best treated by a multidisci- Address correspondence to Joseph Muenzer,
plinary team. Treatments consist of palliative/supportive care, hematopoietic stem MD, PhD, Department of Pediatrics, CB 7487,
cell transplantation, and enzyme replacement therapy. The patient’s age (⬎2 years or University of North Carolina at Chapel Hill,
Chapel Hill, NC 27514. E-mail: muenzer@med.
ⱕ2 years), predicted phenotype, and developmental quotient help define the risk/ unc.edu
benefit profile for hematopoietic stem cell transplantation (higher risk but can PEDIATRICS (ISSN Numbers: Print, 0031-4005;
preserve central nervous system function) versus enzyme replacement therapy (low Online, 1098-4275). Copyright © 2009 by the
risk but cannot cross the blood-brain barrier). American Academy of Pediatrics

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:
19–29

M UCOPOLYSACCHARIDOSIS TYPE I (MPS I) is a lysosomal storage disorder that is caused by a deficiency of the
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 deficiency 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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being recognized that MPS I represents a disease contin-
uum, with considerable clinical variability in age of onset
and rate of disease progression. We recommend classi-
fying 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 pa-
tients with Hurler-Scheie and Scheie syndromes typi-
cally have significant disabilities attributable to somatic
involvement. The severe end of the MPS I spectrum,
representing the majority of known cases, is well de-
scribed and can be delineated accurately. Children with
severe MPS I usually die within the first decade of life, as
a result of cardiorespiratory failure and progressive neu-
rologic disease.1 However, cases of attenuated MPS I
vary widely with respect to age of presentation, symp-
toms, comorbidities, and disease course.1,2 Many patients
with attenuated MPS I survive into adulthood, albeit
with significant morbidity.
Before the availability of disease-specific therapies,
treatment for MPS I was palliative and symptom-based.
The advent of hematopoietic stem cell transplantation
(HSCT) and, more recently, enzyme replacement ther-
apy (ERT) has heightened the need for better disease
recognition, early diagnosis, and up-to-date comprehen-
sive 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 formu-
lating 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 in-
cluded specialists in pediatrics, cardiology, ophthalmol-
ogy, anesthesiology, transplantation, orthopedics, and
genetics. The initial guidelines were revised and updated
in 2008, on the basis of additional clinical data and thera-
peutic advances. Recommendations are based on our ex-
tensive 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 reflect 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
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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 dis-
ease 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) muta-
tions underlying MPS I has limited the predictive value
of genotype for many patients.7–9 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 Cauca-
sian 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 Pa-
tients 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 ⱖ1 mis-
sense mutation. Patients who have a p.R89Q or c.678-
7g3a (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 defor-
mity, a large head circumference, or frequent respiratory
infections. Although pediatricians and primary care phy-
sicians usually are the first 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 nonspecific screening test for MPS I.
False-negative results may occur, especially if the urine
is too dilute (specific gravity of ⬍1.015 g/mL). A defin-
itive diagnosis of MPS I is based on deficient ␣-L-iduroni- TABLE 1 Recommended Minimal Schedule of Assessments for All
dase activity in fibroblasts, leukocytes, serum, or blood Patients With MPS I
spots.14,15 Pseudodeficiency of ␣-L-iduronidase has been
Initial Every Every Every
described but is rare and is not associated with increases Assessments 6 mo 12 mo Other
in urinary glycosaminoglycan levels.16 Prenatal diagnosis Year
is available, based on either enzyme testing or DNA
General
testing (for family members of a patient whose muta- Demographic characteristics X
tions are known). Patient diagnosis X
Medical history X X
CLINICAL MANAGEMENT Physical examination X X
General appearance X X
General Considerations Clinical assessments
The care of patients with MPS I requires regular assess- Neurologic/central nervous
ments, supportive care, and treatment of a variety of system
systemic complications. Because of the complexity and Computed tomographic or X X
rarity of this disease, patients are best monitored by a MRI scans of brain
multidisciplinary team at a facility with MPS I experi- MRI scans of spine X X
Median nerve conduction X X
ence. The primary care provider is an essential part of
velocity
the multidisciplinary team, especially for patients who Cognitive testing (DQ/IQ) X X
do not live near a major medical center. An involved Auditory
primary care provider should be on hand to manage Audiometry X X
day-to-day problems, to refer the patient to appropriate Ophthalmologic
specialists, and to facilitate communication between Visual acuity X X
team members and the patient’s family. Retinal examination X X
Table 1 presents the core assessments required at Corneal examination X X
diagnosis for all patients with MPS I and the minimal Respiratory
recommended intervals for follow-up assessments. A Forced vital capacity/forced X X
expiratory volume
comprehensive baseline evaluation provides important
Sleep study X X
benchmarks with which to gauge disease progression Cardiac
and responses to therapy. All patients should be evalu- Echocardiography X X
ated at least annually. Baseline and annual evaluations Electrocardiography X X
may be facilitated by a short hospital stay or coordinated Musculoskeletal
outpatient clinic visits over 1 to 3 days to allow for Skeletal survey with X X
efficient multispecialty review. Patients’ schedule of fol- radiographsa
low-up assessments should be individually tailored ac- Gastrointestinal
cording to their age, disease manifestations, rate of dis- Spleen volumeb X Xc
ease progression, types of treatment, and specialized Liver volumeb X Xc
Vital signs and laboratory tests
needs. Monitoring of substrate clearance through uri-
Height and weight X X
nary glycosaminoglycan levels and spleen and liver vol- Head circumferencea X X
umes is necessary only for HSCT- or ERT-treated pa- Blood pressure X X
tients. Below, we review major disease manifestations Enzyme activity level X
and their management according to organ system. Urinary glycosaminoglycan level X Xc
Urinalysis X Xc
Cognitive Development Functional outcome measurements
Mucopolysaccharidosis Health X X
Progressive cognitive impairment is a hallmark of severe
Assessment Questionnaire
MPS I, whereas cognition is normal or only slightly
or other tools exploring
impaired in attenuated MPS I. Children with severe MPS functional ability and
I have progressive neurodegenerative disease. Although quality of lifed
early development may seem normal, delay is usually This schedule of assessments addresses the core MPS I-related disease manifestations that are
obvious by 12 to 24 months of age.1 Most patients reach assessed to stage disease progression over the lifelong course of the disease. The schedule was
a developmental plateau before beginning a decline, adapted from the report by Pastores et al,13 with permission. Physicians should determine the
which usually leaves them severely mentally disabled at actual frequency of necessary assessments according to each patient’s need for medical care
and routine follow-up monitoring. See text for additional guidance on individualization of
the time of death. Because of a combination of enlarged
routine follow-up assessments. All tests requiring sedation are recommended only if sedation is
tongue, hearing loss, and developmental delay, children considered to be safe for the patient.
with severe MPS I develop minimal language skills, but a Studies are only for pediatric patients, unless determined otherwise by the treating physician.

most develop some social skills.1,17 Behavior in severely b The recommended method for determining organ volumes is MRI or computed tomography,

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
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

developmental stimulation as possible during the early years of age.

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stages of the disease. Adapting the environment to the
child’s 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 benefit from standard
interventions. Neurocognitive testing is recommended
to facilitate development of interventions and educa-
tional 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
fluid (CSF) pressure is markedly elevated (⬎40 cm H2O).
For some patients, abnormal eye movements and acute
loss of vision are the presenting features. Chronic in-
creases in intracranial pressure may contribute to de-
layed neuromotor development and visual/eye problems
in severe MPS I. Head circumference should be mea-
sured 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 hydrocepha-
lus is suspected, then measurement of CSF pressure
through lumbar puncture with sedation should be con-
sidered. Ventriculoperitoneal shunting may successfully
reduce CSF pressure but typically does not reverse
clinical disease significantly, although it may amelio-
rate symptoms such as headache or sleep behavior.
In patients with attenuated MPS I, CSF pressure may
slowly increase over years without significant 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 myelop-
athy is not typical in patients with severe MPS I, al-
though cervical subluxation can cause spinal cord injury.
In contrast, patients with attenuated MPS I frequently
develop spinal cord compression and cervical instabili-
ty.18 Diagnosis usually is not made until significant 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 ob-
tained at baseline for patients with severe MPS I. For
patients with evidence of odontoid dysplasia, radio-
graphs should be repeated every 1 to 2 years and/or
before any surgical procedure requiring general anesthe-
sia. 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
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cord compression. The evaluation should include neck
flexion 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 experi-
ence suggests that patients with MPS I who undergo
spinal surgery have increased risk of major complica-
tions, including spinal cord infarction and spinal insta-
bility.
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 first signs, but these typically occur only after severe
reduction in nerve conduction velocity.20,21 Some pa-
tients have experienced recurrence of carpal tunnel syn-
drome 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 rhi-
nitis accompanied by persistent nasal discharge and fre-
quent ear infections. Patients with attenuated MPS I
have increased frequency of chronic sinus infections.
Tonsillectomy and adenoidectomy should be consid-
ered for all patients who develop airway compromise,
including snoring and coarse breathing. Severely af-
fected children who require recurrent placement of ven-
tilation tubes may benefit from a T-tube as an alterna-
tive, because such patients are less likely to outgrow the
need for ventilation tubes. Routine ear, nose, and throat
examinations performed at least annually are recom-
mended.
Auditory Manifestations
Patients with severe MPS I commonly experience con-
ductive and neurosensory deafness. Hearing loss may be
attributable to frequent ear infections, defective ossifica-
tion in the middle ear, scarring of the tympanic mem-
brane, 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 attenu-
ated MPS I. Hearing aids are beneficial 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 com-
monly 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; how-
ever, 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, includ-
ing 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 atten-
uated MPS I and can markedly improve vision, although
corneal clouding may develop in the transplanted cor-
nea. 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 there-
after. 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 insufficiency 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 tra-
chea; 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 first
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 dis-
ease, which usually is not appreciated through clinical
history or physical examination. The cause of the restric-
tion 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 aggra-
vate developing obstructive sleep apnea.
Patients with severe obstructive airway disease may
benefit from positive airway pressure treatment (contin-
uous 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 man-
agement of difficult airways. Tracheostomy may be life-
saving for patients with severe sleep apnea and/or val-
vular heart disease.
All patients with MPS I should be monitored rou-
tinely by a pulmonologist, who can help assess respira-
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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 respira-
tory insufficiency is detected. Pulmonary function test-
ing and sleep studies may be required before anesthesia.
Bronchoscopy during anesthesia can be helpful in pul-
monary 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, pulmo-
nary 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 ste-
nosis; 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
identified through routine cardiac testing.
All patients with MPS I should undergo a cardiology
evaluation, including electrocardiography and echocar-
diography, 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 pa-
tients 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 guide-
lines, bacterial endocarditis prophylaxis is recommended
only for patients with a history of endocarditis, a pros-
thetic 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 significant 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 ossifi-
cation, a condition known as dysostosis multiplex. As
vertebrae become progressively flattened and beaked,
spinal deformities, including kyphosis, scoliosis, and ky-
phoscoliosis, may develop. Hips may be affected, result-
ing 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 in-
PEDIATRICS 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 ob-
tained at birth can detect dysostosis in some patients with
MPS I.
Patients with attenuated MPS I have progressive ar-
thropathy, 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 experi-
ence generalized pain and malaise, which may be attrib-
utable 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 ir-
reversible changes occur may provide more surgical op-
tions. 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 re-
striction and develop interventions to maintain joint
function and muscle strength. In patients with attenu-
ated 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 stiff-
ness. The benefit 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 fixed flexion deformities, but the long-term
benefits 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. Difficulty with in-
tubation may prove fatal.31 We recommend that patients
undergo procedures requiring general anesthesia only at
centers with access to anesthesiologists who are experi-
enced with MPS disorders and their complications. An-
esthetic risk increases with age.
Spinal instability, specifically of the atlantoaxial joint,
requires careful positioning to avoid hyperextension of
the neck. Radiography should be performed for all pa-
tients, to evaluate individual risks. The accumulation of
glycosaminoglycan in the airway severely limits the an-
esthesiologist’s ability to observe the larynx with the
laryngoscope. The limited jaw movement, short neck,
enlarged tongue, and thick secretion compound the dif-
ficulty of observing the larynx for even very skilled
anesthesiologists. Intubation may be very difficult for
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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 difficult airways.
Laryngeal mask airways can be used for airway man-
agement for short periods or to facilitate fiber-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 hos-
pital observations are not uncommon. Awareness of
the possibility of postoperative tracheostomy is impor-
tant for all parties involved. When possible, proce-
dures 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 re-
quire 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 office care
should be performed regularly. For some patients, anes-
thesia 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 complica-
tions. For patients with severe MPS I, the dentist ideally
should be based in a children’s hospital and have expe-
rience 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 pa-
tients with MPS I. For patients with severe MPS I, in-
guinal 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 hep-
atosplenomegaly may enlarge umbilical hernias.
Gastrointestinal Manifestations
Periodic episodes of diarrhea may alternate with consti-
pation. Dietary modifications and the conservative use
of laxatives can help to control diarrhea and constipa-
tion. 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 psychoso-
cial 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 emo-
tional, financial, 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 likeli-
hood that future offspring will be affected.
TREATMENT OF MPS I
Hematopoietic Stem Cell Transplantation
When successful, hematopoietic stem cell transplanta-
tion (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 develop-
mental deterioration begins,34–41 and it carries significant
risk of morbidity and death. HSCT should be undertaken
only after extensive pretransplantation assessment, for
carefully selected children for whom long-term moni-
toring will be possible.
The first successful allogeneic HSCT procedure for
MPS I involved a 1-year-old boy with severe MPS I, in
1980. Thirteen months after HSCT, the patient’s plasma
␣-L-iduronidase activity was similar to that seen in het-
erozygotes, his hepatosplenomegaly and corneal cloud-
ing 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 sig-
nificant contributor to morbidity and death. Pretrans-
plantation preparation must be sufficiently immunosup-
pressive and myeloablative to optimize successful
engraftment.44 Although success rates for HSCT have
improved in recent years, the risks are still significant;
the reported mortality rate in a recent, large, retrospec-
tive 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 involve-
ment, the child’s 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 ther-
apy, also contributes to the overall outcome.46 The best
developmental and clinical outcomes have been ob-
served in children with developmental quotients (DQs)
of ⬎70 and ages of ⬍2 years at the time of transplanta-
tion.36
One of the most important benefits 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
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function, and cardiac function and the resolution of
communicating hydrocephalus after successful HSCT
may contribute to improvement in intellectual function-
ing, even in the absence of central nervous system cor-
rection.1 Although HSCT may improve hearing for 30%
to 40% of children, it does not reverse profound con-
ductive 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 of-
ten persist, corneal clouding stabilizes or slowly resolves,
and ocular pressures may normalize.46 Cardiac manifes-
tations, 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, how-
ever, seem to be resistant to HSCT treatment and fre-
quently 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 im-
provement in the grade of odontoid dysplasia.52
Enzyme Replacement Therapy
Laronidase (recombinant human ␣-L-iduronidase; Al-
durazyme [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.53–56 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 ac-
tive and that the selected dose regimen, based on treat-
ment 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). Pa-
tients demonstrated decreased urinary glycosaminogly-
can excretion and reductions in liver and spleen vol-
umes. All patients had improved New York Heart
Association scores after 1 year of treatment, and some
patients had improved shoulder flexion range of motion,
sleep apnea/hypopnea index, and visual acuity. These
improvements were sustained with continued treat-
ment.26,54 Functional status and endurance generally im-
proved 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
PEDIATRICS Volume 123, Number 1, January 2009 25
weeks after initiation of treatment, and values were
reduced by 54% with sustained treatment. Liver vol-
umes 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 re-
ceived placebo. Because of patient heterogeneity, overall
changes in shoulder flexion and sleep study apnea/hy-
popnea index values were not significant, but there were
trends toward improvement for patients with more-se-
vere symptoms at baseline.
Adverse event profiles for the phase 3 trial were sim-
ilar for the laronidase and placebo groups. Although
most patients developed IgG antibodies to laronidase,
infusion-related reactions (such as flushing, fever, head-
ache, or rash) were generally manageable with slowing
of the infusion rate and/or administration of medication
(antipyretic agents or antihistamines). Laronidase ther-
apy had a positive safety and tolerability profile, with
low associated risks. During the phase 3 extension study,
1 patient experienced 2 treatment-related serious ad-
verse events (respiratory difficulty and anaphylaxis),
which might have been exacerbated by preexisting se-
vere upper airway obstruction and restrictive lung dis-
ease. An emergency tracheostomy was required during
the second event, to maintain the patient’s 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 hyper-
trophy in those 5 patients, but mitral and aortic valves
remained thickened and, in some cases, developed pro-
gressive thickening and regurgitation.60 Effects of laroni-
dase 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 wors-
ened 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 sys-
tem function in patients with MPS I. Like HSCT, laroni-
dase may not correct preexisting cardiac valvular disease
or skeletal abnormalities, although it can improve or
preserve joint mobility. Early initiation of therapy, be-
fore irreversible damage, may be more effective in slow-
ing disease progression.
26 MUENZER et al
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Use of ERT With HSCT
Short-term laronidase administration in combination
with HSCT in severe MPS I has been shown to be feasible
and safe62–67 and may improve mortality and engraft-
ment rates, especially for patients in poor clinical condi-
tion, because it can decrease disease-related complica-
tions.65–67 After full engraftment is achieved, the benefit
derived from additional enzyme supplied by laronidase is
unclear. Laronidase may be beneficial for patients with
only partial posttransplantation engraftment; however,
experience with this group is limited.
Treatment Algorithm
The risk/benefit ratio for HSCT versus ERT must be
determined individually for each patient with MPS I.
Important considerations are patient age, disease pheno-
type, 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 ⱖ70), it is im-
portant to preserve cognitive abilities. If deterioration is
anticipated on the basis of clinical findings, neurodevel-
opmental testing results, and genotype information (eg,
identification 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 adminis-
tered 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 benefit 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 im-
proves with interventions for individuals whose neuro-
developmental 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 recom-
mended. 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. Specific patient
circumstances, such as treatment availability and the patient’s
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 mani-
festations 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 find-
ings and outcomes for patients with MPS I.13 Participa-
tion is open to all physicians treating patients with MPS
I, and clinical data are collected (with written consent)
and submitted confidentially from around the world.
Health care professionals have access to aggregate data
on MPS I and can query the database for specific infor-
mation 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 therapeu-
tic 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 beneficial
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-fits-all” intervention or management strat-
egy. Treatment options and disease management strate-
gies must be developed within the parameters of each
individual case, including the age at diagnosis, the se-
verity 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
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(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.
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PEDIATRICS Volume 123, Number 1, January 2009 29
 Mucopolysaccharidosis I: Management and Treatment Guidelines
Joseph Muenzer, James E. Wraith and Lorne A. Clarke
Pediatrics 2009;123;19
DOI: 10.1542/peds.2008-0416

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 Mucopolysaccharidosis I: Management and Treatment Guidelines
Joseph Muenzer, James E. Wraith and Lorne A. Clarke
Pediatrics 2009;123;19
DOI: 10.1542/peds.2008-0416

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/123/1/19

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
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