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18 the Mucopolysaccharidoses J 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 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(Morquiodisease,typeB)ismuchmorevariableinitseffects.Ithassome 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 Topical β-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 Hydrocephalus Ventriculo-atrial or ventriculo-peritoneal shunt system surgery Atlantoaxial instability resulting Surgical decompression and fusion of cervical spine from odontoid dysplasia 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 Peripheral nerve entrapment, e. g., Surgical decompression nervous system carpal tunnel syndrome 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- bilicalcordbloodcells.AlthoughallMPSdisordershavebeentreatedbyHSCT, Nomenclature 197 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 OMIM symbol 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 MPS3C 252930 N-acetyltransferase 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 ARSB 253200 (arylsulfatase B) 18.10 MPS VII Sly β-Glucuronidase GUSB 253220 18.11 MPS IXa Natowicz Hyaluronidase HYAL1 601492 a Only 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 Specifictherapy is availableforMPSI,andclinical trials arecurrently inprogress 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
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