18

The Mucopolysaccharidoses
J. Edward Wraith, Joe T.R. Clarke
18.1 Introduction
The disorders described in this chapter are associated with a progressive ac-
cumulation of glycosaminoglycans (GAG) within the cells of various organs,
ultimately compromising their function. The major sites of disease differ de-
pending on the specic enzyme deciency, and therefore the clinical presenta-
tion and approach to therapy is different for the various disease subtypes.
Patients with the severe form of mucopolysaccharidosis (MPS I; Hurler dis-
ease, MPS IH), MPS II (Hunter disease), andMPS VI (Maroteaux-Lamy disease)
generally present with facial dysmorphism and persistent respiratory disease
in the early years of life. Many patients will have undergone surgical procedures
for recurrent otitis media and hernia repair before the diagnosis is established.
Infants with MPS III (Sanlippo A, B, C, or D disease) present with learning
difculties and then develop a profound behavioral disturbance. The behavior
disorder is characteristic and often leads to the diagnosis. Somatic features
are mild in these patients. Children with MPS IVA (Morquio disease, type A)
have normal cognitive functions, but are affected by severe spondoepiphyseal
dysplasia, which in most patients leads to extreme short stature, deformity of
the chest, marked shortening and instability of the neck, and joint laxity. MPS
IVB (Morquio disease, type B) is much more variable in its effects. It has some
features of the skeletal dysplasia of MPS IVA; however, most patients also have
learning difculties. MPS VII (Sly disease) often presents as nonimmune hy-
drops fetalis. Those patients who survive or who present later resemble patients
with MPS IH with respect to clinical phenotype and supportive management.
So far only one patient with MPS IX (Natowicz disease) has been reported.
The phenotype of patients with more attenuated forms of MPS, e. g., MPS
IH/S or MPS IS (Hurler-Scheie or Scheie disease, respectively) is much more
difcult to predict, and treatment needs in this group of patients may be very
variable. The MPS disorders in general present as a continuum of clinical
involvement, and even patients with the most attenuated forms of Scheie syn-
drome may have severe disabilities, requiring major medical and surgical in-
terventions.
Because of the multisystem involvement in these patients, treatment is mul-
tidisciplinary and encompasses both the curative and palliative elements.
196 The Mucopolysaccharidoses
Those patients with severe central nervous system involvement (MPS III, San-
lippo disease) or severe bone dysplasia (MPS IVA, Morquio disease) present
particular challenges to management, as current therapies are poor in correct-
ing the effects of the genetic lesion in brain and bone, respectively. Table 18.1
summarizes the types of problems experienced by patients with MPS disorders
and strategies for their management.
Table 18.1. Supportive or nonspecic symptomatic treatment of MPS
System Problem Intervention
Eyes Corneal clouding Avoid direct sunlight; corneal transplantation
Glaucoma Topical -blockers; trabecular surgery
Retinal dystrophy None
Ears Recurrent otitis media Antibiotic therapy; ENT surgery
a
Sensorineural deafness Hearing aids
Dental Caries, dental abscess Oral hygiene; dental extractions
Respiratory Upper-airway obstruction ENT surgery
a
Obstructive sleep apnoea Oxygen therapy; CPAP
Restrictive lung disease Oxygen therapy; CPAP
Cardiac Cardiomyopathy Antifailure medication
Valve lesions Antifailure medication; valve replacement
Coronary artery disease None
Gastrointestinal Hepatosplenomegaly None
Umbilical and inguinal hernia Surgical repair
Swallowing problems Pureed diet, small, frequent meals; gastrostomy
Diarrhea antimotility medication
Drooling Hyoscine; surgical rerouting of salivary ducts
Central nervous
system
Hydrocephalus Ventriculo-atrial or ventriculo-peritoneal shunt
surgery
Atlantoaxial instability resulting
from odontoid dysplasia
Surgical decompression and fusion of cervical spine
Cervical compression myelopathy Surgical decompression and fusion
Seizures Anticonvulsant medication
Severe behavior problems Behavior management, medication
Sleep disturbance Medication
Mental retardation Appropriate educational support and interventions
Peripheral
nervous system
Peripheral nerve entrapment, e. g.,
carpal tunnel syndrome
Surgical decompression
Skeleton Degenerative hip dysplasia Analgesics; orthopedic surgical correction
Kyphosis or kyphoscoliosis Bracing or orthopedic surgical correction
Joint contractures Physiotherapy and orthoses
Genu valgum deformities Osteotomies
a
Including various combinations of tonsillectomy, adenoidectomy, myringotomy, the insertion of ventilation tubes, and
tracheostomy
ENT ears, nose, and throat; CPAP continuous positive airways pressure
Attempts at curative therapy have previously centered on the use of
hematopoetic stem cell transplant (HSCT), using either bone marrow or um-
bilical cord blood cells. Although all MPS disorders have been treated by HSCT,
Nomenclature 197
evidence for efcacy is strong in only MPS IH (Hurler disease) (Peters et al.
1996, 1998; Fleming et al. 1998) or MPS VI (Krivit et al. 1984; Lee et al. 2000).
The procedure is ineffective in MPS III (Sanlippo disease) (Sivakumar and
Wraith 1999), in MPS II (McKinnis et al. 1996), and in MPS IV (Morquio dis-
ease); too few patients with MPS VII (Sly syndrome) have received transplants
to make a reasonable assessment. The only patient with MPS IXto be described
did not undergo HSCT.
The introductionof recombinant humanenzyme replacement therapy(ERT)
is likely to make a major impact in the area of treatment in the years to come.
Laronidase (Aldurazyme) is available for the treatment of MPS I (Kakkis et al.
2001; Wraith 2004; Brooks 2002), and other enzyme strategies are in advanced
stages of clinical evaluation, with phase III launched presently for both MPS II
(Muenzer et al. 2002) and MPS VI.
Despite these advances in specic therapy, supportive and palliative care
are all that can be offered for most patients with various MPS disorders. Man-
agement should encompass a holistic approach, with symptom control and
enhanced quality of life the main goal of treatment. Many different specialties,
both within and allied to clinical medicine, as well as lay members of voluntary
organizations, have roles to play. Adequate respite care is important for those
families who have children with profound behavioral disturbance.
18.2 Nomenclature
No. Disorder Eponym Enzyme deciency Gene
symbol
OMIM
No.
18.1 MPS IH Hurler -l-Iduronidase IDUA 252800
MPS IH/S Hurler-Scheie -l-Iduronidase IDUA 252800
MPS IS Scheie -l-Iduronidase IDUA 252800
18.2 MPS II Hunter Iduronate-2-sulfatase IDS 309900
18.3 MPS IIIA Sanlippo A Heparin N-sulfatase (sulfamidase) SGSH 252900
18.4 MPS IIIB Sanlippo B -N-Acetylglucosaminidase NAGU 252920
18.5 MPS IIIC Sanlippo C Acetyl-CoA:-glucosaminide
N-acetyltransferase
MPS3C 252930
18.6 MPS IIID Sanlippo D N-Acetylglucosamine-6-sulfatase GNS 252940
18.7 MPS IVA Morquio A N-Acetylgalactosamine-6-sulfatase GALNS 253000
18.8 MPS IVB Morquio B -Galactosidase GLB1 253010
18.9 MPS VI Maroteaux-Lamy N-Acetylgalactosamine-4-sulfatase
(arylsulfatase B)
ARSB 253200
18.10 MPS VII Sly -Glucuronidase GUSB 253220
18.11 MPS IX
a
Natowicz Hyaluronidase HYAL1 601492
a
Only one good description of a patient with hyaluronidase deciency (MPS IX, Natowicz syndrome) has been reported
MPS, mucopolysaccharidosis
198 The Mucopolysaccharidoses
18.3 Treatment
I
General Considerations
The MPSare all complexmultisystemdiseases. Irrespective of the type, manage-
ment of of all of themrequires supportive care and multidisciplinary treatment
of a variety of systemic complications. Regular evaluationat a major center with
special interest and expertise in the management of the diseases is important
in the coordination of interdisciplinary input and to coordinate multispecialty
treatment strategies. Because of the progressive nature of the diseases, indi-
viduals with MPS need to be evaluated regularly in order to identify potential
problems early at a time when intervention would decrease morbidity, prevent
premature mortality, and enhance the quality of life of affected patients. Every
patient withMPS is unique; therefore, treatment options needtobe individually
based.
In addition to the neurological complications experienced by many, distor-
tion and narrowing of the upper airway and deformities of the chest present
potential fatal anesthetic risks for most patients with MPS. Even the most triv-
ial procedures requiring general anesthesia should be done at centers with
anesthetists who are experienced with MPS disorders.
I
Specic Therapies
Specictherapyis availablefor MPSI, andclinical trials arecurrentlyinprogress
to evaluate specic treatment of MPS II and MPS VI. For the other MPS, no
specic therapy exists at present.
G
Hematopoietic Stem Cell Transplantation
In patients under the age of 2 years who have normal or near-normal devel-
opmental scores (DQ >70), HSCT should be considered, using either HLA-
matched bone marrowor umbilical cord blood cells as the donor cells. The best
results are achieved with HLA-matched sibling donors. Successful engraftment
is associated with resolution of hepatosplenomegaly and upper airway obstruc-
tion. Corneal cloudingusually resolves slowly, but never completely. Intraocular
pressures may decrease. Cardiac manifestations attributable to muscle involve-
ment are corrected, but valvular abnormalities are resistant to HSCT and often
progress. Improvements injoint mobilityare routinelyexperienced, andgrowth
may approach normal rates for children the same age. However, some skeletal
abnormalities, especially abnormalities of the spine, do not respond to HSCT,
andmost severely affectedchildrenstill require major orthopedic interventions
(Peters et al. 1996, 1998).
Treatment 199
G
Enzyme Replacement Therapy
ERT has been demonstrated in randomized, double-blind, placebo-controlled
studies to produce improvements in joint mobility, pulmonary function, and
exercise tolerance in patients with MPS IH/S and MPS IS. However, the extent
and sustainability of improvement, whether other clinical features of the dis-
ease will also response to therapy, and the optimum dosage of laronidase, are
unknown. Laronidase (Aldurazyme), is licensed in the European Union and the
US to treat the nonneurological aspects of the disease; there is no evidence that
the recombinant protein crosses the blood-brain barrier. Dosages and treat-
ment intervals are summarized in Table 18.2). A role as an adjunct to HSCT
in patients with MPS IH is currently under investigation. ERT may have the
least impact in patients with the most attenuated forms of the disease (Scheie
disease). Treatment costs are greater in these patients than in patients with
more severe forms of the disease because the dosage of laronidase is based on
body weight, and patients with Scheie disease are relatively heavy, compared
with patients with Hurler-Scheie or Hurler disease. ERT for both MPS II and
MPS VI is currently undergoing clinical trial. Fig. 18.1 shows the approach to
the treatment of MPS I.
Table 18.2. Treatment of MPS I by enzyme replacement
Disorder Age Medication Dosage Route & frequency
MPS IH All Laronidase (Aldurazyme) 100 U/kg (0.58 mgs/kg) IV weekly
MPS IH/IS
MPS IS
200 The Mucopolysaccharidoses
Fig. 18.1. Flow chart for the management of -l-iduronidase deciency (MPS IH, -IH/S, -IS). (HSCT hematopoietic stem
cell transplant by bone marrowor umbilical cord blood cells, MPS mucopolysaccharidosis, HS heparan, DS dematan sulfate)
18.4 Follow-up and Monitoring
The objectives of monitoring patients with MPS disorders are:
1. To provide on-going support for the patient and family
2. To anticipate complications (Table 18.3), identify them early when they
occur, and treat them in order to decrease morbidity
3. To monitor specic therapies, such as HSCT and ERT, to assess their effec-
tiveness and, in the case of ERT, to adjust enzyme dosage
Follow-up and Monitoring 201
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202 The Mucopolysaccharidoses
A general schedule of assessment and reassessment is shown in Table 18.4.
What is shown represents a minimum follow-up schedule; adjustments are
always necessary in individual cases, as unanticipated problems arise.
Table 18.4. Recommended follow-up and monitoring of MPS disorders
Initial Every 6 months Every 12 months Every 2 years
General
Medical history and physical
examination
a

Neurological
Developmental assessment
MRI of brain
MRI of spine
Ophthalmologic
Visual acuity
Retinal examination
Corneal examination
b

Auditory
ENT consultation
Audiometry
Cardiac
Chest radiograph (for heart size)
ECG
Echocardiogram
Respiratory
Pulmonary function tests
c

Sleep study
Gastrointestinal
Spleen & liver volumes
d

Musculoskeletal
Skeletal radiographs
e

Laboratory studies
Leukocyte -l-iduronidase
f

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g

Urine analysis
a
Including measurement of height, weight, head circumference, and blood pressure
b
Including measurement of intraocular pressures
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1
)
d
Best measured by MRI or CT scan
e
AP and lateral views of the skull, PA view of the chest, lateral views of the spine (including the cervical spine), AP view
of the hips and pelvis, single AP view of both hands together. In the case of MPS IV, include lateral views of the neck in
exion and extension to assess stability of the atlanto-axial joint, and a single AP view of the upper cervical spine through
the open mouth to assess the integrity of the odontoid process. These studies are primarily for the asssessment of disease in
children; the menu and schedule for radiographic studies in adults would be more limited, emphasizing the assessment of
osteoarthritis
f
In patients who have undergone hematopoietic stem cell transplantation (HSCT), leukocyte -l-iduronidase assays and
VNTR analyses on DNA extracted from peripheral blood should be done monthly from the time of transplantation, then
every 6 months, to assess engraftment
g
For assessment of the response to enzyme replacement therapy or HSCT
References 203
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