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 specific enzyme deficiency, 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), and MPS 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 (Sanfilippo A, B, C, or D disease) present with learning difficulties 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 difficulties. 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 difficult 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- filippo 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 nonspecific symptomatic treatment of MPS
System Problem Intervention
Eyes Corneal clouding Avoid direct sunlight; corneal transplantation Glaucoma Topicalβ-blockers; trabecular surgery
Retinal dystrophy None
Ears Recurrent otitis media Antibiotic therapy; ENT surgerya Sensorineural deafness Hearing aids
Dental Caries, dental abscess Oral hygiene; dental extractions Respiratory Upper-airway obstruction ENT surgerya
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
aIncluding 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,
evidence for efficacy 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 (Sanfilippo 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 IX to be described did not undergo HSCT.
The introduction of recombinant human enzyme 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 specific 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 deficiency Gene
symbol
OMIM No.
18.1 MPS IH Hurler α-l-Iduronidase IDUA 252800
MPS IH/S Hurler-Scheie α-l-Iduronidase IDUA 252800
MPS IS Scheie α-l-Iduronidase IDUA 252800
18.2 MPS II Hunter Iduronate-2-sulfatase IDS 309900
18.3 MPS IIIA Sanfilippo A Heparin N-sulfatase (sulfamidase) SGSH 252900
18.4 MPS IIIB Sanfilippo B α-N-Acetylglucosaminidase NAGU 252920
18.5 MPS IIIC Sanfilippo C Acetyl-CoA:α-glucosaminide N-acetyltransferase
MPS3C 252930 18.6 MPS IIID Sanfilippo 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 β-Galactosidase GLB1 253010
18.9 MPS VI Maroteaux-Lamy N-Acetylgalactosamine-4-sulfatase (arylsulfatase B)
ARSB 253200
18.10 MPS VII Sly β-Glucuronidase GUSB 253220
18.11 MPS IXa Natowicz Hyaluronidase HYAL1 601492
aOnly one good description of a patient with hyaluronidase deficiency (MPS IX, Natowicz syndrome) has been reported MPS, mucopolysaccharidosis
198 The Mucopolysaccharidoses
18.3 Treatment
I General Considerations
The MPS are all complex multisystem diseases. Irrespective of the type, manage- ment of of all of them requires supportive care and multidisciplinary treatment of a variety of systemic complications. Regular evaluation at 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 with MPS is unique; therefore, treatment options need to be 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 Specific Therapies
Specific therapy is available for MPS I, and clinical trials are currently in progress to evaluate specific treatment of MPS II and MPS VI. For the other MPS, no specific 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 marrow or 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 clouding usually 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 in joint mobility are routinely experienced, and growth may approach normal rates for children the same age. However, some skeletal abnormalities, especially abnormalities of the spine, do not respond to HSCT, and most severely affected children still require major orthopedic interventions (Peters et al. 1996, 1998).
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 ofα-l-iduronidase deficiency (MPS IH, -IH/S, -IS). (HSCT hematopoietic stem cell transplant by bone marrow or 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 specific therapies, such as HSCT and ERT, to assess their effec- tiveness and, in the case of ERT, to adjust enzyme dosage
Table18.3.SummaryofcomplicationsofMPSdisorders SystemProblemMPS IHMPS IH/ISMPS ISMPS IIMPS IIIMPS IVMPS VIMPS VIIaMPS IXb EyesCornealclouding++++++++++++++++++++? Glaucoma++++++++?? Retinaldystrophy+++++++?? EarsRecurrentotitismedia++++++++++++++++++++++? Sensorineuraldeafness+++++++++?? DentalCaries,dentalabscess++++++++++++?? RespiratoryUpperairwayobstruction++++++++++++++++?? Obstructivesleepapnoea+++++++++++++++?? Restrictivelungdisease++++++++++++? CardiacCardiomyopathy++c++++++++?? Valvelesions++++++++++++++++?? Coronaryarterydisease++++++++++?? GastrointestinalHepatoplenomegaly+++++++++++? Umbilicalandinguinalher- nias++++++++++++++? Swallowingproblems+++++++++++++?? Diarrhea+++++++++?? Drooling+++++++++?? CNSHydrocephalus++++++++?? Atlanto-axialinstability++++++++? Cervicalmyelopathy++++d++++d+++++++?? Seizures+++++++++? Behaviorproblems++++++++++? Sleepdisturbancee+++++++++?? Mentalretardation++++++++++++++++? Peripheral nerveCarpaltunnelsyndrome++++++++++++++++?? SkeletonDegenerativehipdysplasia++++++++++++++++++++++++++++ Kyphosisorkypho-scoliosis++++++++++++++++ Jointcontractures+++++++++++++f+++++++ Genuvalgumdeformities+++++++? aMPSVIIisrareandclinicallyheterogeneous.Itmaypresentasnonimmunefetalhydrops bOnlyonegooddescriptionofapatientwithhyaluronidasedeficiency(MPSIX,Natowiczsyndrome)hasbeenreported cMaybethepresentingproblemprogressingrapidlytodeathinearlyinfancy dAlatecomplicationinalmostallpatientswithseveredisease eNotcausedbyupper-airwayobstruction fJointlaxityandtheresultinginstability,ratherthanjointcontractures,isamajorprobleminMPSIV
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 examinationa
• •
Neurological • •
Developmental assessment • •
MRI of brain • •
MRI of spine • •
Ophthalmologic •
Visual acuity • •
Retinal examination • •
Corneal examinationb • •
Auditory •
ENT consultation • •
Audiometry • •
Cardiac • •
Chest radiograph (for heart size)
ECG • •
Echocardiogram • • •
Respiratory •
Pulmonary function testsc • •
Sleep study • •
Gastrointestinal
Spleen & liver volumesd • •
Musculoskeletal
Skeletal radiographse • •
Laboratory studies
Leukocyteα-l-iduronidasef •
Urinary GAG levelg • •
Urine analysis • •
aIncluding measurement of height, weight, head circumference, and blood pressure
bIncluding measurement of intraocular pressures
cForced vital capacity (FVC) and1-s forced expiratory volume (FEV1)
dBest measured by MRI or CT scan
eAP 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 flexion 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), leukocyteα-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
gFor assessment of the response to enzyme replacement therapy or HSCT
References
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