The Journal of Pediatrics
Volume 155, Issue 4, Supplement , Pages S32-S46, October 2009

Guidelines for the Management of Mucopolysaccharidosis Type I

  • Ana Maria Martins, MD, PhD

      Affiliations

    • Centro de Referência em Erros Inatos do Metabolismo, Universidade Federal de São Paulo, São Paulo, Brazil
    • Corresponding Author InformationReprint requests: Ana Maria Martins, Rua Joaquim Antunes, 620/72 CEP 05415-010–São Paulo, SP, Brazil.
    • ,
  • Ana Paula Dualibi, MD, PhD

      Affiliations

    • Disciplina de Otorrinolaringologia Pediátrica da Universidade Federal de São Paulo, São Paulo, Brazil
    • ,
  • Denise Norato, MD, PhD

      Affiliations

    • Pontifícia Universidade Católica de Campinas, São Paulo, Brazil
    • ,
  • Edna Tiemi Takata, MD

      Affiliations

    • Centro de Referência em Erros Inatos do Metabolismo, Universidade Federal de São Paulo, São Paulo, Brazil
    • ,
  • Emerson S. Santos, MD

      Affiliations

    • Universidade de Ciências da Saúde de Alagoas, Maceio, Brazil
    • ,
  • Eugênia Ribeiro Valadares, MD, PhD

      Affiliations

    • Departamento de Propedêutica Complementar da Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
    • ,
  • Gilda Porta, MD, PhD

      Affiliations

    • Departamento de Pediatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
    • ,
  • Gisele de Luca, MD

      Affiliations

    • Universidade Estácio de Sá, Florianópolis, Disciplina Medicina e Biologia do Sono, Departamento de Psicobiologia, São Paulo, Brazil
    • ,
  • Gustavo Moreira, MD, PhD

      Affiliations

    • Universidade Federal de São Paulo, São Paulo, Brazil
    • ,
  • Helena Pimentel, MD

      Affiliations

    • Triagem Neonatal, Associação de Pais e Amigos do Excepcionais/APAE, Salvador, Bahia, Brazil
    • ,
  • Janice Coelho, PhD

      Affiliations

    • Departamento de Bioquímica-ICBS, Universidade Federal do Rio Grande do Sul e Serviço de Genética Médica do Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
    • ,
  • Jaime Moritz Brum, MD, PhD

      Affiliations

    • Medicina Laboratorial da Rede Sarah de Hospitais de Reabilitação, Belo Horizonte, Brazil
    • ,
  • José Semionato Filho, MD

      Affiliations

    • Centro Geral de Pediatria, Fundação Hospitalar do Estado de Minas Gerais, Belo Horizonte, Brazil
    • ,
  • Marcelo Soares Kerstenetzky, MD

      Affiliations

    • Serviço de Hepatologia Infantil do Hospital da Restauração – Pernambuco, Recife, Brazil
    • ,
  • Márcia R. Guimarães, MD

      Affiliations

    • Departamento de Oftalmologia da Faculdade de Medicine de Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
    • ,
  • Maria Verónica Muñoz Rojas, MD

      Affiliations

    • Setor de Mucopolissacaridose do Serviço de Genética Médica do Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
    • ,
  • Paulo Cesar Aranda, MD

      Affiliations

    • Serviço de Hematologia do Hospital Evangélico de Londrina – Paraná, Londrina, Brazil
    • ,
  • Ricardo Flores Pires, MD

      Affiliations

    • Clínica de Doenças Metabólicas Dr Ricardo Pires, Porto Alegre, Brazil
    • ,
  • Rodrigo G.C. Faria, MD

      Affiliations

    • Serviço de Ortopedia Pediátrica do Hospital Socor, Belo Horizonte, Brazil
    • ,
  • Ronald Moura Vale Mota, MD

      Affiliations

    • Serviço de Ortopedia Pediátrica do Hospital Socor, Belo Horizonte, Brazil
    • ,
  • Ursula Matte, PhD

      Affiliations

    • Laboratório de Terapia Gênica, Centro de Pesquisas do Hospital de Clínicas de Porto Alegre/Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
    • ,
  • Zelita Caldeira Ferreira Guedes, PhD

      Affiliations

    • Disciplina de Distúrbios da Comunicação Humana, Departamento de Fonoaudiologia da Universidade Federal de São Paulo, São Paulo, Brazil

Article Outline

ADLs, Activities of daily living, ATR, Abdominal thorax rebalance, BAEP, Brain stem auditory evoked potential, BHM, Bronchial hygiene maneuvers, BMT, Bone marrow transplant, CFP, Federal Psychology Council, CH, Communicating hydrocephalus, CHF, Congestive heart failure, CNS, Central nervous system, CPAP, Continuous positive airway pressure, CT, Computerized cranial tomography, CTMA, Cetyltrimethylammonium, EFA, Expiratory flow acceleration maneuver, EMEA, Evaluation of medicinal products, ERT, Enzymatic replacement therapy, GAG, Glycosaminoglycans, GVHD, Graft versus host disease, HR, Heart rate, HSCT, Hematopoietic stem cell transplant, IDUA, Alpha iduronidase, LSD, Lysosomal storage disorders, MNR, Magnetic resonance, MPS, Mucopolysaccharidoses, MPS I, Mucopolysaccharidoses type I, OSAHS, Obstructive sleep apnea-hypopnea syndrome, RFLP, Restriction fragment length polymorphism, ROM, Range of movement, RR, Respiratory rate, ST-s, ST segment, UARS, Upper airway resistance syndrome

 

Mucopolysaccharidosis type I (MPS I) is the prototype of the MPS disorders, a subgroup of lysosomal storage diseases. The incidence of MPS I in Brazil is unknown, but a retrospective population study in Australia conducted between 1980 and 1996 yielded an overall prevalence of 1 in 22 500 for all MPS types.1 In British Columbia, cases ascertained between 1952 and 1986 determined that the frequency of MPS type I Hurler, the most severe form of the disease, was approximately 1 in 144 000 newborns,2 a result similar to that found in The Netherlands.3 A recent analysis of data collected by the Society for Mucopolysaccharides in the United Kingdom in patients with MPS I found a prevalence of 1.07 per 100 000 births.4

MPS I is characterized by a deficiency in α-L-iduronidase enzyme activity, leading to buildup and urinary excretion of high levels of glycosaminoglycans (GAGs), specifically dermatan and heparan sulfates. The disease is genetically determined and shows autosomal recessive inheritance.5, 6 MPS types were initially named by using eponyms, but after the advent of biochemistry, specific enzymatic deficiencies were established for each MPS type. MPS I, first described by Hurler as a severe form of MPS and by Scheie as a mild form, were subsequently identified as the same disease. Although MPS I is classically referred to as Hurler, Hurler-Scheie (intermediate presentation between the Hurler and Scheie extremes), or Scheie syndromes, there is no biochemical or molecular basis for this classification, and the disease encompasses a continuum of severity, with varying degrees of skeletal, cardiac, digestive, respiratory, and central nervous system involvement, all resulting from the same underlying enzymatic deficiency.7 Common symptoms include atypical facies, progressive infiltration of tissues, normal intelligence or developmental delay and mental retardation, growth retardation, short stature, multiple dysostosis multiplex, joint stiffness, corneal clouding, cardiomyopathy, valvular compromise, respiratory insufficiency, hepatosplenomegaly, and recurrent respiratory infections.5, 6, 7 Patients with MPS I have a reduced life expectancy. Without treatment, patients with the most severe form of the disease have a median survival of 6.8 years.4 Patients with a more attenuated form of the diease (Hurler-Scheie and Scheie) survive to adolescence or adulthood, but with significant morbidity.5

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Clinical Manifestations of MPS I 

As a multi-systemic disease, MPS I requires early intervention and multi-disciplinary management for optimal patient quality of life, treatment response, and survival. Patient and family disease education are essential.8 Each patient's treatment and follow-up plan should be individualized according to the patient's unique situation and clinical status.7, 8, 9

Airway Manifestations 

Thoracic cage limited mobility and deformities in tracheal or bronchial cartilage cause the pulmonary problems in these patients. Nasal secretion and tracheal thickening are frequent. Other head and neck manifestations include craniofacial abnormalities, depressed nasal bridge, chronic rhinitis, shortened neck, enlarged tonsils and adenoids, protruding tongue, infiltration of glottis tissues, abnormal epiglottis, tracheal compression, and bronchial narrowing.10

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is characterized by partial or total obstruction of upper airways during sleep, accompanied by alterations in arterial blood gases and in sleep architecture, with characteristic clinical symptoms and long-term complications.11 Snoring and disturbed sleep are the most common symptoms of OSAHS in children. Night sweats and bedwetting may also be observed. Daytime symptoms include mouth breathing, morning headache, excessive drowsiness, and behavioral disorders such as hyperactivity and aggressiveness. The latter is often confounded with, or worsen, behavioral alterations already present.12 Possible complications are impaired learning, developmental delay, growth retardation, systemic arterial hypertension, pulmonary hypertension, or both,13 and sudden death. The gold-standard diagnosis of OSAHS is polysomnography or sleep study. Pediatric studies must be staged and interpreted according to the appropriate criteria for patient age.14, 15, 16, 17, 18 In addition to cyclic obstructive apnea, many children have partial and persistent upper airway obstruction associated with hypoxemia and hypercapnea. This is combination is known as obstructive hypoventilation and is especially common in children <3 years of age, the critical age at which symptoms appear in children with MPS I. Upper airway resistance syndrome (UARS) has also been described in both children and adults. Patients with UARS have snoring and excessive daytime drowsiness, but no apnea or alteration in arterial gases on polysomnography.19

The nasofibrolaryngoscopy allows visualization of the entire nasal cavity, nasopharynx, soft palate, tongue root, palatine tonsils (often not visible in oropharynx examination with macroglossia), epiglottis, and larynx. This allows dynamic evaluation of swallowing, phonation, and respiration. In addition to OSAHS, patients with MPS tend to have recurrent respiratory infections (otitis media, sinusitis, and tonsillitis).20, 21

Recurrent and excessive rhinorrhea is a frequent complaint in this patient group.10, 22, 23 Excessive build-up of mucus and increased viscosity common in MPS may lead to secretion stasis and alteration in paranasal sinus drainage, causing secondary infections and chronic alterations in nasal mucosa. Although an unusual finding, formation of nasal polyps may occur as a result of chronic inflammation of nasal mucus, associated to mucus stasis.24

Alternatives in diagnosing respiratory problems, besides polysomnography and nasolaryngoscopy, include full lung function tests, arterial blood gases, pulse oximetry, hemoglobin levels, and imaging examinations (computerized cranial tomography [CT], magnetic resonance [MNR]), which can contribute toward locating the obstruction site and assessing pulmonary structure.

Treatment 

The aim of clinical treatment is to control recurrent airway infections. Normally, nasal isotonic or hypertonic saline solution is used to eliminate crusts and secretions, improve cilia mobility, and reduce mucus edema. Nasal topical decongestants may be used for acute episodes in which nasal obstruction is very intense, bearing in mind the reduced effect of the medicine when used for periods longer than a week. Systemic decongestants must be used sparingly so secretions are not further thickened.25 Antibiotics (10- to 15-day courses) are used for treating purulent nasal secretion or acute bacterial infection such as acute otitis media or tonsillitis. Systemic corticosteroids for brief periods may help reduce the edema and facilitate drainage of secretions.

The most frequent surgical procedures include adenotonsillectomy, surgery of the nasal shells, tracheostomy, laser surgery of tracheal lesion, and uvulopalatopharyngoplasty. Because airway blockage in MPS is multi-factorial, the outcomes of adenotonsillectomy vary, but substantial short- to medium-term improvements in respiratory quality are seen in most cases. However, as the disease progresses, tracheostomy or nasal continuous positive airway pressure (CPAP) may become necessary.

Airway surgery can be complicated by macroglossia, limited mouth opening, a restricted operation margin, and instability of the cervical column, making it difficult to visualize the operative field. Neck hyperextension in these patients can cause an acute cord compression. An alternative option to performing adenoidectomy when access via the oral opening is impaired is endoscopic surgery through the nasal route.26 Definitive or temporary tracheotomy may be performed before other surgeries to facilitate airway control. Tracheostomy should be avoided whenever possible because of difficulties in surgical technique, stiffening of the trachea, significant anatomic alterations with a short neck, and the possibility of postoperative complications such as tracheitis, recurrent pneumonia, and blockage of the tracheostomy by thick excretions.10 Swallowing, already impaired by the anatomic alterations and neurological compromise tends to worsen, increasing aspiration risk.27 The challenges of managing a tracheostomy in these patients, with the difficulty in acceptance by the patient and family, should also be taken into account, and whenever feasible, nasal CPAP should be used instead.28, 29

Anesthesia 

Patients with MPS are particularly prone to anesthetic complications during surgery or invasive diagnostic procedures. Whenever possible, local anesthesia should be used. Children with MPS have been described as the “worst airway problem in pediatric anesthesia,” but airway access is also an issue in adult patients.30, 31 Upper airway problems, a narrowed tracheal lumen, the presence of granular tissue in the lower airways, and cardiac alterations contribute to the high anesthetic risk.30, 31 Of all the MPS types, the greatest frequency of peroperative complications is seen in patients with MPS I; 54% of patients with MPS I have tracheal intubation difficulties and 23% have intubation failure, compared with 25% and 8%, respectively, reported for all MPS . The key to good anesthesia planning is a complete initial evaluation that should include size laryngoscopy and bronchoscopy to measure airways, radiography to evaluate spine curvature and unstable atlantoaxial joint, and full evaluation for obstructive sleep apnea and hepatic, pulmonary, or cardiac disfunction. Pre-surgery preparation involves patients taking antibiotics and corticosteroids to reduce secretion and edema in the upper airway. Induction with inhaled anesthetics allows a controlled situation while maintaining spontaneous breathing.30, 31, 32

Use of muscle relaxants is only advised when the airway is safe. Tracheal intubation options include an oral or nasal route with direct laryngoscopy, angled-video laryngoscopy, bronchoscopy, and retrograde intubation. A laryngeal mask may also be used, or a tracheotomy may be performed. Proper treatment of these patients requires special attention to trachea conditions, and for each case, options ranging from intubation to tracheotomy should be considered.30

Auditory Manifestations 

Hearing loss occurs in 70% to 100% of the patients with MPS I. Several factors lead to sound conduction alterations: middle ear mucus and tympanic membrane thickened by GAG deposits, tubal obstruction, ossicular malformation, alteration in the temporal bone, thick and copious mucus, and secretory otitis media.23, 33, 34, 35, 36, 37, 38 Neurosensorial hearing loss caused by an unknown mechanism may be progressive. Lack of data on auditory loss is explained by the difficulty in assessing hearing in patients with severe MPS I who have cognitive impairment. Audiometry can often be performed with techniques indicated for children. Middle ear condition is assessed with tympanometry. In uncooperative patients, brain stem auditory evoked potential (BAEP) through bone and airway can be used, although this requires patient sedation. An alternative option is otoacoustic emissions, which identify hearing loss above 25 dB, but cannot establish the type and extent of the loss. Treatment of conduction hearing loss requires insertion of definitive, short- or long-stay ventilation tubes, although the conduction component may persist.38

Neuropsychological Manifestations 

Neuropsychological manifestations in patients with MPS I may arise from primary GAG accumulation in the central nervous system (CNS) or be caused by deposits in adjacent structures such as the meninges and bone structures. In general, patients with MPS I develop normally or have only mild developmental delay in the first year of life. In severe MPS I, developmental delay is observed between 12 and 24 months of life, chiefly in the speech realm, with subsequent progressive cognitive and sensorial deterioration, most markedly in visual and auditory areas.5, 39, 40 The mental, motor, and behavioral status of patients can be monitored with developmental scales and IQ tests. Mental level can be determined with a battery of instruments that measure aspects of intellectual function. The combination of these assessments can furnish relevant information on intellectual deterioration and clinical evolution in patients. Choice of assessment instruments (psychometric tests) should be based on chronological age and the patient's visual, auditory, and motor abilities. A Federal Psychology Council (CFP) resolution (# 002/2003) recommends using recognized instruments validated for the Brazilian population to minimize the effects of cultural and social influences.40, 41

MPS I may evolve with neurological complications, such as communicating hydrocephalus (CH) and spinal cord compression. The defect in spinal fluid reabsortion caused by GAG deposits in the meninges leads to CH.5 In MPS I, classic signs of intracranial hypertension are usually absent; CH evolves insidiously, and symptoms are difficult to distinguish from primary disease brain damage. Behavioral alterations such as agitation or hypoactivity may be signs of intracranial hypertension.5, 7, 41, 42, 43, 44 CT is used to diagnose CH. Spinal cord compression may occur because of GAG deposits in the cervical meninges with narrowing of the medullar channel by atlanto-axial subluxation caused by loose ligament, odontoid process hypoplasia, or both.44, 45, 46, 47 Although less common, low cord compression can also occur because of thoraco-lumbar kyphosis. Most cases present with spastic tetraparesis, but spastic paraparesis or hemiparesis may also occur.48 Clinical manifestations of compression can be detected early with imaging examinations and electrophysiological studies.49

Cardiac Manifestations 

Cardiac involvement is common in all the MPS types, occuring in 70% to 80% of cases. Cardiovascular abnormalities may result from progressive GAG infiltration in the valvular tissues, myocardium, coronary artery, and conduction system. Significant cardiac alterations are also caused by chronic hypoxemia. The most prominent cardiac manifestation in MPS I is valvular abnormality with stenosis, regurgitation, or both. The tricuspid and mitral valves are most commonly affected, but the aortic valve and, more rarely, the pulmonary valve may also be involved. Coronary lesions have been described, with medial segmental thickening causing ischemic heart disease, but clinical or electrocardiographic evidence of ischemia is rare, whereby patients often evolve with dilated myocardiopathy because of myocardial dysfunction. The endocardium, particularly of the left atrium and ventricle, may be thickened and show alterations compatible with endocardial fibroelastosis. Pericardial thickening has also been described, as has conduction system involvement. Narrowing of the abdominal aorta and visceral and renal veins most likely contributes to the development of arterial hypertension.5, 22, 32, 50, 51

Early death in patients with MPS may be caused in part by cardiomyopathy. Approximately half of all patients with severe MPS I die from cardiac causes, congestive heart failure (CHF) or sudden arrhythmia. Myocardiopathy can occur early, and MPS I diagnosis should be considered in infants with inexplicable cardiomyopathy, especially when there are associated skeletal abnormalities.52 Electrocardiogram results may be normal and show no signs of ischemia, arrhythmia, or hypertrophy. This may occur because GAGs have low electrical conductivity and therefore result in low voltage. Patients with CHF may manifest sinusal tachycardia, diffuse alterations in ventricular repolarization with abnormal ST-s and T wave, and signs of chamber overload. Chest radiographs may show normal cardiac area, enlarged left chambers, right chambers, or both, or overall increase in cardiac area and pulmonary vascular congestion, depending on myocardial alterations, subjacent valves, or both.53

The Doppler echocardiogram is a safe examination for assessing ventricular function in MPS and should be used for assessment and monitoring of all patients affected by the disease, even in the absence of auscultatory findings, to assess ventricular function and progression of cardiac abnormalities with age.53, 54, 55 Several studies have demonstrated a higher frequency of lesion detection on echocardiogram, and the abnormalities seen by the method tend to be more severe than suspected on clinical examination. The echocardiogram confirms the high incidence of valve abnormalities in MPS. The most commonly found lesion is thickening of the mitral valve with regurgitation or stenosis, followed by aortic lesion. Aortic regurgitation is more common in MPS IV, whereas myocardiopathy with reduced ejection fraction is more frequent in severe MPS I.54, 56 Myocardial thickening, with hypertrophic myocardiopathy (asymmetric septal hypertrophy), endocardial thickening, global cardiomyopathy with reduced ejection fraction, and pulmonary hypertension have also been described. 22, 52, 53 According to echocardiographic assessment, cardiovascular abnormality occurs in almost 100% of patients with MPS.56 Assessment of ventricular function is important because it constitutes a risk factor for death in patients with MPS I.54 Patients with an attenuated form of MPS I can have valve abnormalities and abnormalities in systolic and diastolic function of the left ventricle.51

Treatment of cardiac involvement is largely supportive, involving identification and treatment of patients in whom CHF develops as a result of myocardiopathy or more rarely, because of severe valve dysfunction. In the latter case, patients must undergo catheter balloon valvuloplasty or surgical valve repair or replacement.50, 55, 57, 58 Detection of valve anomaly has treatment implications in the indication of endocarditis prophylaxis.50, 53

Musculoskeletal Manifestations 

Skeletal alterations typical of MPS I are multiple dysostosis, which include thickened calvarium, J-shaped sella turcica, odontoid process hypoplasia, thoraco-lumbar kyphosis, thoracic asymmetry, hypoplasia of the antero-superior portion of the vertebral body, platyspondyly, small and widened clavicles, elevated broadened scapulas, incompletely formed ischium and pubis, acetabular dysplasia, and coxa valga that can evolve to hip subluxation . Thoracic-lumbar kyphosis (gibbus deformity) is often the first clinically evident manifestation of the disease, which occurs at approximately 6 months of age.59 Additional alterations progressively emerge as the disease evolves. Carpal tunnel syndrome (compression of the median nerve in the carpal tunnel), stiffening of the interphalangeal joint, hook finger,60 and gripped hand are frequent, and impair hand function.61, 62 The early onset and high prevalence of carpal tunnel syndrome63 justifies routine electroneuromyography in children with MPS I.7, 64, 65, 66, 67 Atlanto-axial instability, in view of the potential risk of compression of the upper cervical spinal medulla and myelopathy is considered a severe manifestation. A dynamic radiograph of the cervical column (flexion, neutral position, and extension) is recommended at 2 years of age as a screening procedure. The clinical examination, associated with CT, MNR, or both, provides diagnosis confirmation. Thoracic-lumbar deformity can be identified with profile radiography of the vertebral column. Radiography is also suitable for diagnosing subluxation of the hip and coxa valga.

Physiotherapeutic rehabilitation that helps preserve joint mobility is an integral part of treatment for these manifestations.

Surgical decompression of the median nerve is indicated in cases of carpal tunnel syndrome. Surgical freeing of tendons can also improve hand function.68 Cervical fusion is controversial in cases with radiological evidence but no clinical signs of atlanto-axial instability. Bone marrow transplant (BMT), indicated in some MPS I cases, improves joint mobility but has no effect on evolution of hip subluxation, flexion deformities, or muscular weakness (probably caused by hip dislocation).66 Studies on enzyme replacement therapy have demonstrated improvement in joint mobility and skeletal growth69; long-term effects are still undergoing investigation.70

Ophthalmologic Manifestations 

Ocular manifestations of the lysosomal storage diseases (LSDs) vary according to the type of enzyme deficiency and the tissue location of the deficient enzyme. The cornea is a frequent site of lesions as a result of abnormal GAG deposits. GAGs are the main components of the amorphous substance contained in the corneal stroma, accounting for 4.0% to 4.5% of the dry weight of the cornea. Main GAG types in the cornea are keratan sulfate (corresponding to 50%), chondroitin and chondroitin sulfate (25%), and small quantities of heparan sulfate. Chondroitin is found exclusively in the cornea. Although scarce in the cornea, heparan sulfate can accumulate in the retina, causing retinal degeneration, as seen in all forms of MPS I and in MPS II and MPS III.71, 72, 73

Occular alterations in Hurler syndrome 

Diffuse corneal compromise leading to corneal opacity becomes detectable from 3 years of age, the most frequent symptoms being photophobia associated with slow and progressive loss of visual acuity. Pinhead opacities can be seen throughout the corneal stroma, but are most numerous in the central stroma. Initially, they are only visible by slit lamp, but later they become visible to the naked eye. For best visualization, a slit lamp examination with backlighting should be used. In cases of severe corneal opacity because of progressive buildup of stroma deposits, a penetrating keratoplasty can be performed to restore corneal transparency, although visual acuity is often limited by secondary compromise of the retina and optic nerve. In some cases, trabecula involvement results in secondary open-angle glaucoma. Progressive retina compromise with vascular narrowing, hyperpigmentation, and boney spicules are observed in an advanced stage. Papilledema and optic atrophy are common.

Ocular alterations in Scheie Syndrome 

Ocular abnormalities occur after 4 years of age and include loss of transparency (opacification) of the cornea, papilledema or late atrophy of the optic nerve, and pigmental degeneration of the retina. Corneal opacification occurs progressively and diffusely, involving the peripheral stroma to a greater extent. Glaucoma is more frequent in this type of MPS than in the severe form, and the success of cornea transplant may be limited by compromise of the posterior segment of the eye.

Occular alterations in Hurler-Scheie syndrome 

Loss of corneal transparency is seen earlier, between 2 and 4 years of age, and requires penetrating keratoplasty to restore sight within the first decade of life. As with the aforementioned types, there is compromise of the optic nerve, degeneration of the pigment epithelium of the retina, and glaucoma.

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Diagnosis 

The gene encoding alpha-iduronidase has been mapped to the 4p16 site on chromosome 474 and has 14 exons of 19 kb and a large intron of 13 kb separating the second from the third exon.75, 76 The W402X, Q70X, and P533R mutations are responsible for half the mutations in a population of European origin.75, 76 In Caucasians, the homozygote or compound heterozygote for the nonsense W402X and Q70X mutations are the most frequent causes of the Hurler syndrome, and the presence of R89Q can lead to a milder phenotype.75, 76, 77, 78, 79, 80 These alleles found in Europe are not the same as those found in Arab-Israeli or Japanese patients with Hurler syndrome, which have their own unique alleles.81, 82 In Brazil the W402X, P533R, R383H, 134del12, and R89Q mutations represent approximately 50% of the cases studied.83 One of the mutations described in the a-L-iduronidase gene, A300 T, causes pseudo-enzymatic deficiency,84 a situation in which there is an apparent enzyme deficiency in vitro yet not in vivo, which may lead the physician to making a false diagnosis when it is based solely on enzyme levels. Thus, diagnosis of MPS I is possible with molecular methods in approximately half the patients. In the remaining patients, gene sequencing must follow biochemical diagnosis to identify the mutation present. Detection of the mutation allows pre- and post-natal molecular diagnosis, and detecting heterozygotes allows for facilitating individual and family genetic counseling.

Analysis of urinary GAG with blue toluidine, cetyltrimethylammonium (CTMA) bromide tests, and through chromatography detect the presence of heparin and dermatan sulfate and are used as screening tests for diagnosing MPS I. The definitive diagnosis is carried out with measurement of α-L-iduronidase enzyme activity in leukocytes, fibroblasts, plasma, or serum.5 Testing of enzyme activity in dried blood spots on filter paper 85 has the added advantage of being easier to transport and handle. Enzymatic activity <10% of average reference values is compatible with MPS I diagnosis,85, 86 and each laboratory must determine its own reference values. Measuring the activity of another lysosomal enzyme in the same sample is recommended for control of preservation of the material. Measurement of α-L-iduronidase activity in cultivated chorionic villus or amniocytes is routinely used in pre-natal MPS I diagnosis.

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Clinical Follow-up 

The patient with MPS has a chronic, progressive, and multisystemic disease and routinely requires urgent care by numerous specialists and different physicians. Most physicians do not have knowledge or experience with this rare disease, and their lack of experience can create risks for patients. It is crucial that one physician continually cares for the patient, monitoring the evolution of the disease, providing guidance to the family, referring the patient to specialists as needed, and coordinating patient care as a whole. In children, follow-up may be performed by the pediatrician, provided he/she has knowledge of the disease. In adults, the general practitioner is usually the ideal care coordinator. The multidisciplinary team that works with the patient must include a clinical geneticist experienced in this group of diseases, who should accompany and guide the patient and the family, liaise with the pediatrician, clinician, or both, and remain at the disposal of other physicians and professionals for guidance and discussion of supportive care and therapeutic intervention. Moreover, it is important that patients and families are educated in detail about their disease and its possible complications and risks in a written report. Patients should also be instructed that in the event of an emergency the attending doctor must be informed of the disease and given a copy of the report.

The physician must carry out full anamnesis on each visit and collect data on height (standing or supine, and in the case of restrictions in lower limbs, per segment), weight and head circumference, preferably by using the same, properly calibrated instrument. The physical examination must be complete and include vital signs (temperature, heart rate, respiratory frequency, and arterial pressure). Sexual development assessment should be performed in adolescents, according to Tanner criteria. At visits, data on all assessments performed since the last appointment must be obtained, and the necessary tests must be ordered, including evaluation by specialists in neurology, otorhinolaryngology, ophthalmology, cardiology, and pneumology, and a sleep study and assessment of visceral volumes with MNR, CT, or, when the patient is unable to undergo these examinations, with ultrasound scanning. For the purposes of diagnosis and follow-up, radiographs of the skull (profile), spinal column (profile, including cervical region), thorax (postero-anterior), coxofemoral (postero-anterior), and both hands together should be performed. Overexposure to radiation should be avoided.87 Routine assessments should be peformed by child welfare appointments or annual reassessments by the pediatrician or clinician, besides gynecology appointments for adolescent girls and adults, with vaccines, dietary guidance, and examinations and preventative advice. Following the compulsory calendar of vaccinations, an annual immunization against Haemophilius influenza are recommended, and immunization every 5 years for pneumonia are recommended. The attending physician also must always request information about other family members affected or undergoing evaluation and periodically check whether the family has a good understanding of the disease and reproductive risks, providing them with or referring them for further genetic guidance and counseling whenever applicable.

Patients with MPS are also monitored by other professionals such as dentists,88, 89 physiotherapists,90, 91 speech and occupational therapists,90 nutritionists, and psychologists. It is the role of the accompanying doctor to give these professionals pertinent information, discuss the risks and benefits of interventions, and encourage the family to correctly follow therapies. The physician is also responsible, with the social worker, for identifying the difficulties encountered by families and should seek to assist them by carefully orienting them on assessments and treatment, activities of daily living, school activities, and social insertion of the patient and his or her family.

The Table presents the assessments considered appropriate for evaluating the condition of the patient and his or her evolution, whether following enzyme replacement therapy (ERT) treatment, BMT, hematopoietic stem cell transplant (HSCT), or otherwise. The periodicity presented in the Table must be considered for the minimum number of assessments to be carried out; indication of further assessment is at the discretion of the attending physician when deemed necessary, should the patient present a more severe or changed clinical picture or complications.87

Table. Minimum program of assessments for clinical follow up of patients with mucopolysaccharidosis type I87
Initial assessmentEvery 6-monthAnnualBi-annual
General
General dataX
DiagnosisX
Medical historyXX
Physical examinationXX
General aspectXX
Clinical assessments
Neurological/CNS
Cranial MRNX X
Spine MRNX X
Ophthalmologic
Visual acuityX X
Retina assessmentX X
Cornea assessmentX X
Auditory
AudiometryX X
Cardiac
EchocardiogramX X
ElectrocardiogramX X
Respiratory
FVC/FEV1XX
Sleep studyX X
Gastrointestinal
Volume of spleenX X
Volume of liverX X
Musculoskeletal
Bone inventory with radiographyX X
Biometry and laboratory examinations
Height/WeightXX
Cephalic perimeterXX
Arterial pressureXX
Enzymatic activityX
Urinary GAGsXX
Urine IXX
Health condition assessment
MPS health condition assessment questionnaireXX
Patients receiving ERT
At ERT CommencementBesides completing initial assessment on enrollment on register, full assessment documentation must be produced before 1st infusion of ERT
Administration of ERTData on ERT must be sent at least every 6 months or when changes occur
Adverse reactions form in the United States or International sent via FAX to 001(617) 761-8506.For patients receiving Aldurazyme (laronidase), periodic and continuous reports and monitoring are required, to be sent to the Pharmacovigilance Department of Genzyme. Manual/Protocol Safety Section
Antibody examinationsAntibody monitoring is recommended for all patients receiving treatment with Aldurazyme according to the following scheme: Before the 1st infusion with Aldurazyme Every 3 months in the first 24 months and once per year for the next 36 months By medical indication, monitoring may continue after 60 months.

FVC/FEV1, Forced vital capacity/forced expiratory volume in 1 second.

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Supporting Therapeutic Approaches 

Psychological assessment and follow-up 

From the time of MPS I diagnosis through follow-up and treatment of the disease, parents, caregivers, or both may experience pain, anguish, anxiety, fear, and uncertainty. This process develops in several stages, such as shock, denial, anger, feeling of being cheated or rejection, and depression, until final acceptance. The emotional reaction of the family is an important indicative factor of evolution and adaptation of the child to the disease. Family disarray often occurs, leading to social and family isolation and increased conflict between the parents and possible paternal absence in the home, hampering adherence to follow-up and treatment of the disease. It is the psychologist's role to help the family deal with the losses related to the disease, facilitate understanding, make space for expression of a wide range of emotions, encourage the process of mourning, promote adherence to treatment, boosting self-esteem, and providing new meaning for the disease, while bearing in mind that the time needed to absorb and work the information depends on each individual patient, caregiver, or both. The child will undergo numerous assessments of mental, motor, behavioral, and cognitive development. It is vital to inform parents, teachers and health professionals of the outcome of these assessments, so that they can follow closely potential impairment arising from disease evolution and the possibility of mental retardation. The assessments can also be helpful when choosing the most appropriate school for the patient, usually one of parents' major dilemmas. Therefore, these patients must undergo periodic assessment of cognitive functions, adaptive abilities, and behavior. Choice of assessment instruments should take into account the difficulties of each patient in auditory, visual, and motor complications, chronological age, and the aim of the study. In longitudinal studies, re-assessment of the intellectual level should be performed at least every year for school-aged children and every 6 months in preschool-aged children. 10, 92

Learning to live with the limitations and recognize and stimulate potentials can lead to satisfaction and well-being and help reduce suffering, whether it be physical, psychic, or social, of the patient, parent, and/or caregiver. Medical and educational therapeutic support is recommended in addition to psychological support, through individual psychotherapy, group psychotherapy, and support or self-help groups. Counseling guidance groups are also important intervention approaches, as are social support networks, which allow emotional support, material and medicinal help, and access to services and information.40, 41, 92

Hydrotherapy 

Hydrotherapy, or aquatic rehabilitation, is extremely pleasant for children with MPS because it is playful, fun, and stimulating.93 Within the water medium, children are able to feel freer, have liberty of movements, and experience greater mobility. Tepidness and buoyancy provided by the water help alleviate some of the symptoms of patients, and graded exercises should progressively be applied to strengthen weaker muscle groups.93 Buoyancy also helps increase the range of movement in larger joints, providing relief from weight while re-educating gait. The hydrostatic pressure working against the whole body aids balance. The therapy pool should be heated and fitted with stainless steel side rails, ladder, ramps, benches, board for walking, hydromassage, and Jacuzzi jet. Play materials such as floats, balls, toys that float and sink, boards, plastic dumbbells, aquatub, EVA mats, cervical, dorsal and pelvic jackets, pull-boys, ankle bands, hand waders, flippers, gloves, weights, proprioception boards, small balls, rubber mats, balancing board, and steps are used. Hydrotherapy can be used from the age of 6 months and helps prevent deformities and improve posture. The treatment program must be individualized and specific for each patient. The practice of therapeutic exercises can be associated to manipulation, massotherapy, and hydromassage. Relaxation, analgesia, and reduced impact and shock on joints are some of the beneficial therapeutic factors obtained with immersion in heated water. Hydrotherapy is contraindicated when the patient has infected wounds, skin, urinary, auditory, or gastrointestinal infections or cardiac dysfunction and low vital capacity. During immersion, vasodilatation occurs with increased peripheral blood supply, raised overall temperature, and increase in metabolism demanding oxygen. An increased heart rate (HR) and respiratory rate (RR) occurs, and a reduction in tonus occurs because of the heat. After immersion, when the patient leaves the pool, the HR, RR, metabolic rate, and blood distribution normalize. The therapeutic effects of exercises in the water are associated with relief of pain and muscle spasms, maintenance or increased range of joint movement, relaxation, strengthening of weakened muscles and increased tolerance during exercise, re-educating affected muscles, circulation improvement, gait and balance reeducation, improvement in motor coordination, increased self-esteem, confidence, and morale of the patient, stimulation of patient independence, and improvement in cardiovascular and RR.93, 94, 95, 96

Physiotherapy 

Children with MPS have significant bone compromise5 and require dynamic motor physiotherapy work, the main aim of which is preventing osteoarticular deformities, maintaining range of movement (ROM), and encouraging changes in decubitus, thereby facilitating activities of daily living (ADLs) and providing family guidance to promote improved quality of life. The most common orthopedic problems in MPS are impaired growth leading to short stature, multiple dysostosis with progressive deformities and movement difficulties, reduced joint range, alterations in the vertebral column (kyphosis, thoracic-lumbar hump, hyperlordosis, scoliosis), carpal tunnel syndrome, short trunk and neck, thorax protrusion, increasing muscle tension in the scapula girdle and the entire length of the posterior musculature of the dorsal, widening of the joints, shortening of long bones (type II and Scheie syndrome) influencing tension of musculature in balance and gait, contractures in elbow and knee flexion, and loss of grip and pincer grasp hampering both fine coordination and writing. Physiotherapy should focus on massotherapy to help relax all muscles, emphasizing the forearm and fist because of carpal tunnel syndrome, and maneuvers and manipulations of all joints with slow movements so as not to cause pain, according to criteria of myofascial mobilization technique. Other physiotherapy activities comprise stretching to reduce muscular contractions and increase joint range, strengthening musculature to improve gait and balance, dissociation of scapular and pelvic girdle, motor coordination exercises, proprioception, games (using accessories to work on fine movement), dancing, jumping, and rolling. It is important to avoid head hyperextension because of atlanto-axial compromise.90, 91

Respiratory physiotherapy aims to improve the pulmonary ventilation and respiratory biomechanics impaired in MPS. This occurs because of obstruction of upper airways, muscular shortening, postural deviations, thorax deformity, protruding abdomen, and bronchoaspiration caused by dysphagia, which normally leads to a reduction in abdominal thorax expansibility and mobility, inefficiency of cough, hypersecretion, recurrent infections, and sleep apnea classified in a restrictive, obstructive, or mixed pattern. In these cases, bronchial hygiene maneuvers (BHMs) are indicated, described in the classic physiotherapy literature as vibrocompression, postural drainage, governed cough through expiratory flow acceleration maneuver (EFA), nebulization, cleansing of upper airways with physiologic saline solution. and nasotracheal aspiration with sterile and disposable material associated to abdominal thorax rebalance (ATR), which encourages pulmonary ventilation and promotes bronchial hygiene through balance in inspiratory and expiratory muscles with dynamic maneuvers of stretching, strengthening, massages, and proper positioning. Guidance to caregivers and family members is of vital importance because respiratory physiotherapy must be carried out daily.90, 91

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Specific Treatment 

Bone marrow transplant 

Many patients with LSDs have been treated with BMT.97 Since 1980, after the initial work by Hobbs et al, many patients with MPS (most having MPS type I) have undergone allogenic BMT,5 or, more recently, umbilical cord blood transplant.98 Because the stem cell source can include bone marrow, umbilical cord blood, or peripheral blood, the term BMT has been largely replaced by the broader term HSCT.99, 100, 101, 102 The choice of best donor should initially focus on identifying a sibling with a genotypically identical histocompatibility antigen. In the absence of this, donors related or otherwise should be sought. It is recommended that leukocyte enzymatic activity of the donor be determined, because higher enzymatic levels acquired by the recipient have shown better results.99 The status of graft acceptance after HSCT can be monitored with α-L-iduronidase activity and peripheral leukocyte count for donor/receptor source through restriction fragment length polymorphism (RFLP) analysis.41, 100, 101, 102 Engraftment leads to rapid reduction of GAG in the liver, tonsils, conjunctiva, spinal fluid, and urine.99 Even after engraftment, clinical improvement is extremely variable. These results can be attributed to the quantity of enzyme that may be transferred from hematopoietic cells derived from bone marrow of the donor, to deficient tissues in the recipient. The organs in the monocytic-phagocytic immunologic system such as the liver and spleen generally reduce rapidly as soon as macrophages capture the enzyme. However, some characteristics of the disease have shown poor response to HSCT because of low penetration of α-L-iduronidase in certain tissues.99

Successful transplantation can preserve neurocognition, improve some aspects of the somatic disease, and markedly increase survival.4, 5 One year after successful HSCT, disappearance or reduction of hepatosplenomegaly, of the characteristic facial phenotype, joint stiffness, sleep apnea, cardiac disease, CH, and hearing loss are observed.5, 99, 103, 104 For cardiac disease, improvement or stabilization of myocardial function and preservation of permeability in coronaries are seen. However, in some patients progressive thickening of valves occurs, evolving to prolapse and insufficiency.105 A number of ocular characteristics improve temporarily after HSCT, such as corneal cloudiness and optic nerve edema, which is related to reduced intracranial pressure. However, the effect of HSCT on retinal function is inconsistent, and progressive degeneration occurs,5, 105 where the effect on the cornea appears to be very limited.104

HSCT has little impact in bone disease, probably because of poor penetration of the enzyme in chondriocytes and failure to correct or replace osteocytes. In general, multiple dysostosis coupled with progression in osteo-articular alterations tends to develop in patients who undergo transplant. Thoracic-lumbar kyphosis also evolves and can lead to compression of the spinal channel.48, 99, 104 As a result of complications, with increased survival, invasive orthopedic procedures are usually necessary.5, 99, 106

Improvements in the CNS are slower because of turnover of microglia and their slow replacement by donor-derived cells. Microglia of the CNS seem to be a source of the enzyme in the brain after HSCT. Thus, particularly in the first post-transplant year, deterioration in intellect and development may take place.5, 99 Neuropsychological evolution is closely correlated with age at HSCT. Children who undergo transplantation at <24 months of age demonstrated significantly better development than older patients, even more so when normal enzymatic levels were maintained during follow-up.5, 99, 104, 107, 108, 109, 110

Most of the positive effects occur within the first few years after HSCT and improve quality of life.99 However, with time there is a relatively high incidence of graft failure (approximately 30%), with reconstitution of autolog marrow that may require further transplant.111, 112 Failure of the graft and graft versus host disease (GVHD) are important obstacles to procedure success. In addition to these factors, morbidity is also linked to infection and renal, cardiopulmonary, hemorrhagic, and thrombotic complications and the disease itself.108, 113, 114

Mortality associated with HSCT has improved with evolution of transplant protocols. Earlier case series report transplant-related mortality as approximately 44% for transplant with a related donor and 18% with an HLA-identical sibling,113 with a probability of 5-year survival rate ranging between 50% and 64% when the donor was related or unrelated, and 75% when the donor was an HLA-identical sibling.112, 113 More recent studies have reported a mortality rate of 15% overall.115 There are scant Brazilian studies on outcomes of HSCT in patients with storage diseases, although results available reveal findings compatible with the literature.114

Because of the new therapeutic approach available for treating patients with MPS I, namely enzyme replacement therapy (ERT) with laronidase, several studies have been conducted to assess the efficacy of combined ERT and HSCT. These studies have indicated that patients in poor clinical condition and with respiratory and cardiologic morbidities seem to benefit from this combination.116, 117, 118, 119 Treatment of patients with short-term ERT before and after transplantation was well tolerated and did not interfere with engraftment or increase post-transplant morbidity.

Enzyme replacement therapy 

The pioneering work of Brady and collaborators in the development of modified placental glucocerebrosidase to treat Gaucher disease provided the first evidence that ERT can successfully treat LSDs. However, treatment of MPS with ERT was more challenging because it necessitated the production of recombinant enzymes, and the naturally occurring enzyme could not be isolated in sufficient quantities because it is present at such low levels in tissues and does not have high affinity markers that facilitate absorption.120 The animal models available for the study of MPS are based on naturally occurring mutations.

The biochemistry, pathology, and clinical manifestations of MPS in animal models are generally very similar to those in human beings, although these manifestations can progress at a slower pace.5 Purification of enzymes and cloning of genes corresponding to MPS took place in the late 1980s and early 1990s. Development of recombinant systems allowed the first studies in animal models for MPS I, VI, and VII in the 1990s. These studies demonstrated through biochemical trials and microscopic histopathology that recombinant enzymes can be administered intravenously, carried to tissues, and reduce lysosomal deposits.120, 121 Experiments with animal models and their promising results paved the way for clinical trials, which have culminated in the availability of ERT for MPS I.

Laronidase (Aldurazyme; Genzyme Corporation, Cambridge, Massachusetts) is an enzyme produced by recombinant DNA technology and was approved for commercial use by the United States Food and Drug Administration122 on Apr 30, 2003, and by the European Agency for the Evaluation of Medicinal Products121 on Jun 10, 2003. It is used solely and exclusively for treating patients with a confirmed diagnosis of MPS I. Long-term ERT with laronidase restores sufficient enzyme activity to hydrolyze the accumulated substrate and prevent its subsequent accumulation.122, 123 A dose-ranging study conducted primarily in Brazil determined that the labeled dose (0.58 mg/kg every week) offers the best benefit to risk profile and that a 1.2-mg/kg dose every 2 weeks may be an acceptable and convenient alternative for patients, particularly those with difficulty receiving weekly infusions.124 However, because this was a short-term study, the long-term effects of this regimen are not known.

Clinical benefits of ERT with laronidase include decreased hepatomegaly, improved respiratory function, improved walking ability, increased joint ROM, decreased left ventricular hypertrophy, improved growth, improved quality of life (as shown by a clinically meaningful change in the CHAQ/HAQ disability index), and reduced urinary excretion of GAG.69, 70, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134 Laronidase does not cross the blood-brain barrier at the labeled dose and therefore is not expected to have neurocognitive benefit. In a 1-year clinical trial of patients <5 years of age, developmental gains were observed in patients with Hurler syndrome who began treatment before age 2 years, but longer term follow-up of these patients will be necessary to determine whether this benefit will be sustained. ERT has been available for only 5 years, and its impact on patient survival cannot yet be quantified. Because MPS I is a progressive disease with some irreversible features, the earlier treatment is initiated, the better the potential outcome.

The most frequent adverse effects are mild infusion-related reactions, such as flushing and headache. Infusion-related reactions typically decrease in frequency to low levels after 6 months of treatment.125 During infusion, anaphylactic reactions may occur. However, data are available in the literature on a 6-year follow-up of patients receiving ERT130, 131, 134 and patients aged <5 years with the severe form of MPSI71, 125, 135, 136 showing good response to treatment. Because they are naïve to enzyme, immunogloblulin G antibodies to laronidase develops in most patients (approximately 90%) with MPS I, but they usually decline with time. Although urinary GAG reduction correlates inversely with antibody titer, no correlation has been seen between direct measures of clinical efficacy and antibody titer.70, 125

Inclusion criteria for ERT initiation69, 70, 125, 126, 127Inclusion for ERT includes patients with MPS I of any age with:

1)Deficiency in α-L-iduronidase activity confirmed in 2 biological samples (blood spot filter paper, leukocytes, fibroblasts, or other relevant tissues), genotyping, or both and

2)At least 1 of the clinical MPS I manifestations that are known to respond to ERT:
a.Obstructive, restrictive and interstitial respiratory disease, sleep apnea/hyperpnea syndrome;

b.Osteoarticular compromise which compromises mobility and independence in activities of daily living;

c.Cardiac compromise (myocardiopathy, cor pulmonale).


Currently, there is no evidence indicating or contraindicating treatment of patients with no symptoms detected with neonatal or family screening. These cases must be referred for assessment by the Committee of Specialists in MPS I. Patients with less severe forms of MPS who initially do not fulfill the clinical criteria for commencing ERT should be periodically reviewed.

Exclusion criteria for ERT initiation or temporary suspension include:

1)Pregnancy or breastfeeding;

2)Presence of irreversible alteration which imply imminent death, independent of treatment, as a result of MPS I or associated disease, ascertained by >1 specialist;

3)Severe adverse reaction (anaphylactic shock, risk of death) which cannot be controlled safely using proper therapeutic measures;

4)Emergence of irreversible and irrecoverable associated diseases, ascertained by >1 specialist.

Administration of laronidase 

The commercial presentation of laronidase contains 0.58 mg/mL, in 5-mL flasks. Before use, the product should be stored in a refrigerator at a temperature between 2°C and 8°C. After preparation of the medicine for infusion, it can be stored for a maximum of 24 hours, from preparation time to end of infusion, provided it is kept refrigerated (2°C-8°C). Storage of the product at room temperature is not recommended.122, 123 Currently, the US Food and Drug Administration recommends including 0.1% human serum albumin to the infusion solution, whereas this practice is not followed in the European Agency for the Evaluation of Medicinal Products. No differences have been reported on action of the enzyme or frequency of adverse effect related to the presence or absence of albumin, and we therefore leave this conduct decision to medical discretion.

These recommendations are made:

1)Weigh the patient at each infusion;

2)Check vital signs (temperature, cardiac and respiratory frequency, and arterial pressure), and oxygen saturation, before commencing infusion, before each change in infusion rate, during scaling of the drug, and after conclusion of the infusion;

3)The patient must be pre-medicated with antipyretics and antihistamines, between 30 and 60 minutes before commencing infusion according to weight. Also suggested are:
a.Paracetamol, 15-mg/kg dose, orally, or ibuprofen, 10- to 15-mg/kg dose AND hydroxizin at a dose of 0.5 mg/kg orally or difenidramin, 1.25 mg/kg, endovenously, or another routinely used drug;

b.Dose calculation: 0.58 mg/kg of patient weight (ie, the quantity of laronidase is the weight of the patient in milliliters [mL])


4)Preparation method and infusion rate:
a.A 0.2-micron, low protein-binding filter is recommended in the infusion equipment;

b.The total infusion volume should be administered endovenously in a 3- to 4-hour period;

c.Up to 20 kg: dilute the laronidase in 100 mL of SF saline solution to 0.9% (discount laronidase volume), starting administration at an infusion rate of 2 mL/hour and doubling the speed every 15 minutes until attaining a maximum rate of 32 mL/hour;

d.Above 20 kg: dilute the laronidase in 250 mL of SF saline solution at 0.9% (discount laronidase volume), starting administration at an infusion rate of 5 mL/hour and doubling the speed every 15 minutes until attaining a maximum rate of 80 mL/hour.122, 123


The escalation of infusion rate must be carried out after having checked the vital signs of the patient. The infusion must be administrated with an infusion pump.

Should there be any reaction to the infusion, velocity must be reduced, and when necessary, antihistamines and antipyretics can be repeated. Corticosteroid, subcutaneous adrenalin, or other medication should be used according to the clinical indication and severity of adverse events.122, 123 In the case of infusion reaction, blood sample collection is suggested to determine antibody levels.

It is strongly recommended not to discontinue ERT treatment except in the cases outlined because the beneficial climical effects are soon lost when treatment is interrupted.137, 138

Gene therapy 

A number of in vitro and in vivo studies have demonstrated the potential of gene therapy to treat MPS I, especially with stem cells from bone marrow as target tissue for carrying out ex vivo gene therapy. The first study on gene transfer in MPS I was performed with fibroblast cultures yielding partial results.139 The vector with greatest levels of expression presented lesser efficiency in correcting the enzymatic defect. This implies that vectors used in gene therapy for LSDs must regulate levels of expression of the enzyme in question. Most gene studies involving MPS I have focused on modifying bone marrow cells for performing an autotransplant. Almost all studies have used retroviral vectors, with the exception of the investigation by Hartung et al,140 which used an adenoviral vector. The levels of expression obtained were elevated and sustained for a long period in culture. Moreover, the transduced cells were able to correct the biochemical defect in other untreated cells. Similar results were achieved in mesenchymal stem cells transduced with retroviral vectors, and with lentivirus in fibroblasts. However, in vivo studies conducted in dog models have presented inconsistent results, when the chief difficulty was maintaining therapeutic levels of enzymatic expression. Lutzko et al141 demonstrated, by using a canine model, that despite a good proportion of cells (6%) with proviral markers present 2 years after autotransplant in hematopoietic progenitors and 0.001% to 1.000% in leukocytes, IDUA enzymatic activity was not detected. In spite of this, the expression of the enzyme in long-term in vitro cultures was 200 times greater than the control, suggesting that the lack of activity is caused by the silencing of the gene in vivo. This silencing most likely occurs because of a cellular and humoral immune response against the transduced cells and protein produced. Also, in contrast to ERT, there was no improvement in symptoms of animals treated with gene therapy. Similar results were obtained by Shull et al142 with myoblasts as target cells. The canine model was also used for in utero gene transfer using a retroviral vector. The presence of the transgene in different tissues was observed in animals, but they did not present any detectable enzymatic activity in adult tissues, although the vector used had demonstrated stable expression in cell culture. These data indicate that further studies must be conducted in a bid to address the issue of gene inactivation, which could explore the use of other alternatives of correcting defective genes, such as correction mediated by oligonucleotides.

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Considerations 

In rare diseases such as MPS I, it is fundamental to be able to share clinical experience gleaned worldwide on the natural history of the disease and how different interventions can alter its course. To this end, it is important that Brazilian patients with MPS I undergoing HSCT, ERT, or other treatments are placed on a registry that, when pooled with international data, can help achieve the goal of gaining more insight on both the disease and response to treatment (www.MPSRegistry.com).

The MPS I Registry is a multicenter, international, observational database that involves no experimental intervention.87 It comprises a data base that tracks the evolution of patients with MPS I. The main objectives of the registry study are to: characterize and describe the MPS I population as a whole, including variability, evolution and natural history of the disease; assist the medical community involved with follow-up of patients with MPS I in developing recommendations for patients and result reports to optimize treatment; and observe the long-term effectiveness and safety of laronidase use in patients receiving ERT. The registry is not used to test medication, only to track evolution of patients who are undergoing treatment or not. The MPS I Registry was set up at the behest of the regulatory agencies of the United States and European Union on approval of laronidase use in patients with MPS I. The MPS I Registry is supported financially and maintained by Genzyme Corporation, and it is overseen by independent international, regional, and national boards of medical advisors. It is difficult to predict the potential number of individuals who may be a part of the registry because new patients continue to come to light, not all of whom are able or willing to participate. The data gathered by the registry are providing information that enables the natural history and evolution of MPS I to be better characterized. This information will also be used to monitor the clinical responses of patients treated with ERT, other modes of therapy such as HSCT, or both. Before commencing treatment with laronidase, physicians should encourage patients to enroll in the MPS I Registry and undergo periodic medical assessments that will provide long-term data on efficacy and safety. Patient participation in the registry study does not exclude them from taking part in other clinical studies on MPS I.86 Brazilian health professionals should be encouraged to acquire and share their experience in the diagnosis, management, and treatment of patients with mucopolyssacharidosis type I using ERT.

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Author Disclosures 

Ana Maria Martins, MD, PhD has received from Genzyme travel expenses as part of continuous medical education and grants as coordinator for the Fabry Registry in Brasil (since 2002) and Member of the International Board of Advisors for the Fabry Registry (from 2007). Denise Norato, MD, PhD declared that have received from Genzyme travel expenses as part of continuous medical education and grants as Coordinator for the MPS I Registry in Brasil (since 2004) and Member of the International Board of Advisors for the MPS I Registry (from 2004 to 2007). Ricardo Flores Pires, MD was a Genzyme Associate Medical Director from October, 2006 to May, 2007 and before this period he had received travel expenses from Genzyme Brazil as part of continuous medical education. Ana Paula Dualibi, MD, PhD, Emerson S. Santos, MD, Gilda Porta, MD, PhD, Helena Pimentel, MD, Janice Coelho, PhD, José Semionato Filho, MD, Marcelo Soares Kerstenetzky, MD, Paulo Cesar Aranda, MD, Ronald Moura Vale Mota, MD, Úrsula Matte, PhD received travel expenses from Genzyme Brazil as part of continuous medical education. The following authors have no financial arrangement or affiliation with a corporate organization or a manufacturer of a product discussed in this supplement: Edna T. Takata, MD, Eugênia Ribeiro Valadares, MD, PhD, Gisele de Luca, MD, Gustavo Moreira, MD, PhD, Jaime Moritz Brum, MD, PhD, Marcia R. Guimaraes, MD, Maria Verónica Muñoz Rojas, MD, Rodrigo G.C Faria, MD, Zelita Guedes, PhD.

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The authors wish to thank the following individuals for their contributions to this manuscript: Ana F. J. Gabarra, Carmem S.C. Mendes, Elaine F. de Martin, Irineu M. Brodbeck, Marisa F. Azevedo and Zilda M.A. Meira. We extend our thanks to Dr Nestor A. Chamoles (in memoriam) and Dr Elvira Ponce for their valuable contributions as international scientific consultants.

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References 

  1. Meikle P, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysossomal storage disorders. JAMA. 1999;281:249–254
  2. Lowry RB, et al. An update on the frequency of mucopolysaccharide syndromes in British Columbia. Hum Genet. 1990;86:389–390
  3. Poorthuis BJHM, et al. The frequency of lysosomal storage disease in the Netherlands. Hum Genet. 1999;105:151–156
  4. Moore D, Connock MJ, Wraith E, Lavery C. The prevalence of and survival in mucopolysaccharidosis I: Hurler, Hurler-Scheie, and Scheie syndromes in the UK. Orphanet J Rare Dis. 2008;3:24;[Epub ahead of print]
  5. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In:  Scriver C,  Beaudet A,  Sly W, et al. editor. The metabolic and molecular bases of inherited disease. New York: McGraw Hill; 2001;p. 3421–3452
  6. Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 607014, last edited: 10/6/2003. Available at: http://www.ncbi.nlm.nih.gov/omim.
  7. Wraith JE. The mucopolysaccharidoses: a clinical review and guide to management. Arch Dis Child. 1995;72:263–267
  8. Martins AM, et al. Mucopolissacaridoses: Manual de Orientações. Avaliable at: http://www.unifesp.br/centros/creim/downloads/gz-mps-apostila-2003.pdf.
  9. Wraith JE. MPS I management and treatment guidelines. Am J Hum Genet. 2003;73:621
  10. Shapiro J, Strome M, Croker AC. Airway obstruction and sleep apnea in Hurler and Hunter syndromes. Ann Otol Rhinol Laryngol. 1985;94:458–461
  11. Carroll JL, Loughlin GM. Obstructive sleep apnea syndrome in infants and children: diagnosis and management. In:  Ferber R,  Kryger M editor. Principles and practice of sleep medicine in the child. Philadelphia: W.B. Saunders Company; 1995;p. 193–216
  12. Moreira GA., Pradella-Hallinan MC., Rueda AD, Barbisan BN, Tufik S. Nasal positive pressure for children with sleep disordered breathing. In: Latin American Sleep Congress, 8, Sao Paulo, 2000. Abstracts. Hypnos 2000;1:73.
  13. Chan D, Li AM, Yam MC, Li CK, Fok TF. Hurler's syndrome with cor pulmonale secondary to obstructive sleep apnoea treated by continuous positive airway pressure. J Pediatric Child Health. 2003;39:558–559
  14. American Thoracic Society . Indications and standards for cardiopulmonary sleep studies. Am Rev Respir Dis. 1989;139:559–568
  15. American Thoracic Society . Cardiorespiratory sleep studies in children. Establishment of normative data and polysomnographic predictors of morbidity. Am J Respir Crit Care Med. 1999;160:1381–1387
  16. Marcus CL. Sleep-disordered breathing in children. Am J Respir Crit Care Med. 2001;164:16–30
  17. Mcnamara F, Sullivan CE. Obstructive sleep apnea in infants and its management with nasal continuous positive airway pressure. Chest. 1999;116:10–16
  18. Moreira GA, Pradella-Hallinan MC, Barbisan BN, Tufik S. Sleep disorders in children with mucopolysaccharidosis. In: Associated Professionals Sleep Society Annual Meeting, 15, Chicago, June 17-22, 2001. Abstracts. Sleep, 2001;24(abstract suppl):A210.
  19. Guilleminault C, Pelayo R, Leger D, Clerk A, Bocian RC. Recognition of sleep-disordered breathing in children. Pediatrics. 1996;98:871–882
  20. Myer CM. Airway obstruction in Hurler's syndrome: radiographic features. Int J Pediatr Otorhinolsryngol. 1991;22:91–96
  21. Casselbrant ML. Methods of examination. In:  Bluestone CD,  Stool SE,  Kenna MA editor. Pediatric otolaryngology. 3rd ed. Philadelphia: W B Saunders Co; 1996;
  22. Semenza GL, Pyeritz RE. Respiratory complications of mucopolysaccharide storage disorders. Medicine. 1988;67:209–219
  23. Bredenkamp JK, Smith ME, Dudley JP, Williams JC, Crumley RL, Crockett DM. Otolayngologic manifestations of the mucopolysaccharidoses. Ann Otol Rhinol Layngol. 1992;101:472–478
  24. Mac Arthur, Glicklich R, McGill TJI, Perez-Atayde A. Sinus complications in mucopolysaccharidoses I H/S (Hurler-Scheie syndrome). Int J Pediatr Otorhinolsryngol. 1993;26:79–87
  25. Wald ER. Rhinitis and acute and chronic sinusitis. In:  Bluestone CD,  Stool SE,  Kenna MA editor. Pediatric otolaryngology. 3rd ed. Philadelphia: W B Saunders Co; 1996;
  26. Nayak DR, Balakrishnan R, Adolph S. Endoscopic adenoidectomy in a case of Scheie syndrome. Int J Pediatr Otorhinolaryngol. 1998;44:177–181
  27. Wetmore R. Tracheotomy. In:  Bluestone CD,  Stool SE,  Kenna MA editor. Pediatric otolaryngology. 3rd ed. Philadelphia: W B Saunders Co; 1996;
  28. Maddern BR. Obstructive sleep disorders. In:  Bluestone CD,  Stool SE,  Kenna MA editor. Pediatric otolaryngology. 3rd ed. Philadelphia: W B Saunders Co; 1996;
  29. Allen JL. Treatment of respiratory system (not just lung!) abnormalities in mucopolysaccharidosis I. J Pediatr. 2004;144:581–588
  30. Shinhar SY, Zablocki H, Madgy DN. Airway management in mucopolysaccharide storage disorders. Arch Otolaryngol Head Neck Surg. 2004;130:233–237
  31. Ard JL, Bekker A, Frempong-Boadu AK. Anesthesia for an adult with mucopolysaccharidosis I. J Clin Anesth. 2005;17:624–626
  32. Walker RWM, Colovic V, Robinson DN, Dearlove OR. Postobstrutive pulmonary oedema during anaesthesia in children with mucopolysaccharidoses. Paed Anaesth. 2003;13C:441–447
  33. Ruckenstein MJ, MacDonald RE, Clarke JTR, Forte V. The management of otolaryngological problems in the mucopolysaccharidoses: a retrospective review. J Otolaryngol. 1991;20:177–183
  34. Motamed M, Thorne S, Narula A. Treatment of otitis media with effusion in children with mucopolysaccharidoses. Int J Pediatr Otorhinolaryngol. 2000;53:121–124
  35. Hayes E, Babin R, Platz C. The otologic manifestatiosn of mucopolysaccharidoses. Am J Otol. 1980;2:65–69
  36. Friedmann I, Spellacy E, Crow J, Watts RWE. Histopathological studies of the temporal bones in Hurler's disease. J Laryngol Otol. 1985;99:29–41
  37. Schachern PA, Shea DA, Papparella MM. Mucopolysaccharidoses IH (Hurler's syndrome) and human temporal bone histopatholoy. Ann Otol Rhinol Laryngol. 1984;93:65–69
  38. Oghan F, Harputluoglu U, Guclu E, Guvey A, Turan N, Ozturk O. Permanent t-tube insertion in two patients with Hurler's syndrome. Int J Audiol. 2007;46:94–96
  39. Wraith JE, Cleary MA. The presenting features of mucopolysaccharidosis type IH (Hurler syndrome). Acta Pediatr. 1995;
  40. Martins M, Fonseca MH. Repercussões psico-sociais na criança com Mucopolissacaridose. Acta Medica Portuguesa. 1995;5:329–334
  41. Becker E. Deficiências: alternativas de intervenção. Casa do Psicólogo. 1997;95:31–52
  42. Seto T, et al. Brain magnetic resonance imaging in 23 patients with mucopolysaccharidoses and the effect of bone marrow transplantation. Ann Neurol. 2001;50:79–92
  43. Watts RWE, Spellacy E, Kendall BE, du Boulay G, Gibbs DA. Computed tomography studies on patients with mucopolysaccharidoses. Neuroradiology. 1981;21:9–23
  44. Sheridan M, Johnston . Hydrocephalus and pseudomotor cerebri in the mucopolysaccharidoses. Childs Nerv Syst. 1994;10:148–150
  45. Barone R, Parano E, Trifiletti RR, Fiumara A, Pavone P. White matter changes mimicking a leukodystrophy in a patient with mucopolysaccharidosis: characterization by MRI. J Neurolog Sci. 2002;195:171–175
  46. Herman MJ, Pizzutillo PD. Cervical spine disorders in children. Orthoped Clin North Am. 1999;30:457–466
  47. Taccone A, Donati PT, Marzoli A, Acqua AD, Gatti R, Leone D. Mucopolysaccharidosis: thickening of dura mater at the craniocervical junction and other CT/MRI findings. Pediatr Radiol. 1993;23:349–352
  48. Kachur E, Maestro RD. Mucopolysaccharidoses and spinal cord compression: case report and review of the literature with implications of bone marrow transplantation. Neurosurgery. 2000;47:223–229
  49. Dalvie SS, Noorden FRCS, Vellodi A. Anterior instrumented fusion for thoracolumbar kyphosis in mucopolysaccharidosis. Spine. 2001;(26):E539–E541
  50. Pierpont MEM, Moller JH. Cardiac manifestations of genetic disease. In:  Moss Adams editors. Heart disease in infants, children, and adolescents. 5th ed. London: Williams & Wilkins; 1995;p. 1486–1520
  51. Soliman OII, Timmermans RGM, Nemes A, et al. Cardiac abnormalities in adults with the attenuated form of mucopolysaccharidosis type I. J Inherit Metab Dis. 2007;Published online
  52. Donaldson MDC, Pennock CA, Berry PJ, et al. Hurler syndrome with cardiomyiopathy in infancy. J Pediatr. 1989;114:430–432
  53. Farina V, Leva F, Caso P, et al. Echo-Doppler abnormalities in mucopolysaccharide storage diseases. Acta Paediatr. 1992;81:702–704
  54. Mohan UR, Hay AA, Cleary MA, et al. Cardiovascular changes in children with mucopysaccharide disorders. Acta Paediatr. 2002;91:799–804
  55. Dangel JH. Cardiovascular changes in children with mucopolysaccharide storage diseases and related disorders—clinical and echocardiographic findings in 64 patients. Eur J Pediatr. 1998;157:534–538
  56. Rigante D, Segni G. Cardiac structural involviment in mucopolysaccharidoses. Cardiology. 2002;98:18–20
  57. Fischer TA, Lehr HA, Nixdorff U, Meyer J. Combined aortic and mitral stenosis in mucopolysaccharidosis type I-S (Ullrich-Scheie syndrome). Heart. 1999;81:97–99
  58. Minakata K, Konishi Y, Matsumoto M, Miwa S. Surgical treatment for Scheie syndrome (mucopolysaccharidosis type I-S)—report of two cases. Jpn Circ J. 1998;62:700–703
  59. Belmont PJ. Early diagnosis of Hurler's syndrome with the aid of the identification of the characteristic gibbus deformity. Mil Med. 1998;10:711–714
  60. Matsui Y, Kawabata H, Nakayama M, Ozono , Keiichi , Kitoch H, et al. Sheie syndrome (MPS-IS) presented as bilateral trigger thumb. Pediatr Int. 2003;
  61. Grossman H. Progress in pediatric radiology, intrinsic desease of bones. In: Kaufmann HJ, editor. Philadelphia:1973. p. 495–544.
  62. Taybi H, Lachman RS. Radiology of syndromes, metabolic disorders, and skeletal dysplasias. Mosby; 1996;p. 670-81
  63. Khanna G, Van Heest AE, Agel J, Bjoraker K, Grewal S, Abel S, et al. Analysis of factors affecting development of carpal tunnel syndrome in patients with Hurler syndrome after hematopoietic cell transplantation. Bone Marrow Transplant. 2007;39:331–334
  64. Haddad FS, Jones DHA, Vellodi A, et al. Carpal tunel syndrome in the mucopolysaccharidoses. J Bone Joint Surg. 1997;(79-B):576–582
  65. Sillence D. Neurological complications of MPS. In: 4th International Symposium on Mucopolysaccharide and Related Diseases program. Wollongong, Australia. 1996;p. 36
  66. Masterson EL, Murphy PG, O'Meara A, Moore DP, Dowling FE, Fogarty EE. Hid dysplasia in Hurler's syndrome: orthopaedic management after bone marrow transplantation. J Paediatr Orthopaed. 1996;16:731–733
  67. Wraith JE, Alani SM. Carpal tunnel syndrome in the mucopolysaccharidosis and related disorders. Arch Dis Child. 1990;65:962–963
  68. Pronicka E, Tylki-Szymanska A, Kwast O, Chmielik J, Maciejko D, Cedro A. Carpal tunnel syndrome in children with mucopolysaccharidoses: needs for surgical tendons and median nerve release. J Ment Defic Res. 1988;32(Pt 1):79–82
  69. Kakkis ED, Muenzer J, Tiller GE, et al. Enzyme replacement therapy in, ucopolysaccharidosis I. N Engl J Med. 2001;344:182–188
  70. Wraith JE, Beck M, Lane R, et al. Enzyme replacement therapy in patients who have mucopolysaccharidosis I and are younger than 5 years: results of a multinational study of recombinant human alpha- L-iduronidase (laronidase). Pediatrics. 2007;120:e37–e46
  71. Grupcheva CN, Craig J, McGhee NJ. In vivo microstructural analysis of the cornea in Schei's syndrome. Cornea. 2003;22:76–79
  72. Ashworth JL, Biswas S, Wraith E, Lloyd C. The ocular features of the mucopolysaccharidoses. Eye. 2005;20:553
  73. Ashworth JL, Biswas S, Wraith E, Lloyd C. Mucoppolysaccharidoses and the eye. Surv Ophthalmol. 2006;51:1–17
  74. Scott HS, Ashton LJ, Eyre HJ, Baker E, Brooks DA, Callen DF, et al. Chromosomal localization of the human alpha-L-iduronidase gene (IDUA) to 4p16.3. Am J Hum Genet. 1990;47:802–807
  75. Scott HS, Litjens T, Hopwood JJ, Morris CP. A common mutation for mucopolysaccharidosis type I associated with a severe Hurler phenotype. Hum Mutat. 1992;1:103–108
  76. Scott HS, Guo XH, Hopwood JJ, Morris CP. Structure and sequence of the human alpha-L-iduronidase gene. Genomics. 1992;13:1311–1313
  77. Scott HS, et al. Alpha-L-iduronidase mutations (Q70X and P533R) associated with a severe Hurler phenotype. Hum Mutat. 1992;1:333–339
  78. Bunge S, Kleijer WJ, Steglich C, Beck M, Zuther C, Morris CP, et al. Mucopolysaccharidosis type I: identification of 8 novel mutations and determination of the frequency of the two commom alpha-L-iduronidase mutations (W402X and Q70X) among European patients. Hum Mol Genet. 1994;3:861
  79. Gort L, Chabs Coll MJ. Analysis of five mutations in 20 mucopolysaccharidosis type I patients: high prevalence of the W402X mutation. Hum Mutat. 1998;11:332
  80. Voskoboeva EY, Krasnopolskaya XD, Mirenburg TV, Weber B, Hopwood JJ. Molecular genetics of mucopolysaccharidosis type I: mutation analysis among the patients of the former Soviet Union. Mol Genet Metab. 1998;65:174
  81. Bach G, Moskowitz SM, Tieu PT, Matynia A, Neufeld EF. Molecular analysis of Hurler syndrome in Druze and Muslim patients in Israel: multiple allelic mutations of the IDUA gene in a small geographic area. Am J Hum Genet. 1993;53:330
  82. Yamagishi A, Tomatsu S, Fukuda S, Uchiyama A, Shimozawa N, Susuki Y, et al. Mucopolysaccharidosis type I patients: identification of common mutations that cause Hurler and Scheie syndromes in Japanese populations. Hum Mutat. 1996;7:23
  83. Matte U, Yogalingam G, Brooks D, Leistner S, Schwatz I, Lima L, et al. Identification and characterization of 13 new mutations in mucopolysaccharidosis type I patients. Mol Genet Metab. 2003;78:37–43
  84. Aronovich EL, Pan D, Whiteley CB. Molecular genetic defect underlying alpha-L-iduronidase pseudodeficiency. Am J Hum Genet. 1996;58:75–85
  85. Chamoles NA, Blanco M, Gaggioli D. Diagnosis of alpha-L-iduronidase deficiency in dried blood spots on filter paper: the possibility 0f newborn diagnosis. Clin Chem. 2001;47:780–781
  86. Chamoles NA, Blanco M, Gaggioli D, Casentini C. Hurler-like phenotype: enzuimatic diagnosis in dried blood spots on filter paper. Clin Chem. 2001;47:2098–2102
  87. Pastores GM, Arn P, Beck M, Clarke JT, Guffon N, Kaplan P, et al. The MPS I registry: design, methodology, and early findings of a global disease registry for monitoring patients with mucopolysaccharidosis type I. Mol Genet Metab. 2007;91:37–47
  88. Hingston EJ, Hunter ML, Hunter B, Drage N. Hurler's syndrome: dental findings in a case treated with bone marrow transplantation in infancy. Int J Paediatr Dent. 2006;16:207–212
  89. Guven G, Cehreli ZC, Altun C, Sencimen M, Ide S, Bayari SH, et al. Mucopolysaccharidosis type I (Hurler syndrome): oral and radiographic findings and ultrastructural/chemical features of enamel and dentin. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Jun 27, 2007;[Epub ahead of print]
  90. Dusing SC, Thorpe D, Rosenberg A, Mercer V, Escolar ML. Gross motor abilities in children with Hurler syndrome. Dev Med Child Neurol. 2006;48:927–930
  91. Haley SM, Fragala , Pinkham MA, Dumas HM, Ni P, Skrinar AM, et al. A physical performance measure for individuals with mucopolysaccharidosis type I. Dev Med Child Neurol. 2006;48:576–581
  92. Evangelista LMC. As novas abordagens do diagnóstico psicológico da deficiência mental. 1st ed. São Paulo: Vetor; 2002;p. 33-76, 217-50
  93. Skinner-Thompson. Exercícios na água. São Paulo: Editora: Manole; 1985.
  94. Kelly M, Darrah J. Aquatic exercise for children with cerebral palsy. Dev Med Child Neurol. 2005;47:838–842
  95. Norm A, Hanson B. Exercícios aquáticos terapêuticos. São Paulo: Manole. 1998;
  96. Ruoti RG, Morris DM, Cole AJ. Efeitos fisiológicos da imersão em repouso. In:  Bookspan J editors. Reabilitação aquatica. São Paulo: Manole; 2000;p. 29–42
  97. Schiffmann R, Brady RO. New prospects for the treatment of lysosomal storage diseases. Drugs. 2002;62:733–742
  98. Staba SL, Escolar ML, Poe M, Kim Y, Martin PL, Szabolcs P, et al. Cord-bood transplants from unrelated donors in patients with Hurler's syndrome. N Engl J Med. 2004;350:1960–1969
  99. Peters C, Steward CG. Hematopoietic cell transplantation for inherited metabolic diseases: an overview of outcomes and practice guidelines. Bone Marrow Transplant. 2003;31:229–239
  100. Fujisaki G, Kami M, Kishi Y. Cord-blood transplants from unrelated donors in Hurler's syndrome. N Engl J Med. 2004;350:1960–1969
  101. Baxter MA, Wynn RF, Schyma L, Holmes DK, Wraith JE, Fairbairn LJ, et al. Marrow stromal cells from patients affected by MPS I differentially support haematopoietic progenitor cell development. J Inherit Metab Dis. 2005;28:1045–1053
  102. Church H, Tylee K, Cooper A, Thornley M, Mercer J, Wraith E, et al. Biochemical monitoring after haemopoietic stem cell transplant for Hurler syndrome (MPSIH): implications for functional outcome after transplant in metabolic disease. Bone Marrow Transplant. 2007;39:207–210
  103. Braunlin EA, Rose AG, Hopwood JJ, Candel RD, Krivit W. Coronary artery patency following long-term successful engraftment 14 years after bone marrow transplantation in the Hurler syndrome. Am J Cardiol. 2001;88:1075–1077
  104. Souillet G, Guffon N, Maire I, Pujol M, Taylor P, Sevin F, et al. Outcome of 27 patients with Hurler's syndrome transplanted from either related or unrelated haematopoietic stem cell sources. Bone Marrow Transplant. 2003;31:1105–1117
  105. Braunlin EA, Stauffer NR, Peters CH, Bass JL, Berry JM, Hopwood JJ. Usefulness of bone marrow transplantation in the Hurler syndrome. Am J Cardiol. 2003;92:882–886
  106. Taylor C, Brady P, O'Meara A, Moore D, Dowling F, Fogarty E. Mobility in Hurler syndrome. J Pediatr Orthop. 2008;28:163–168
  107. Hugh-Jones K. Psychomotor development of children with mucopolysaccharidoses type 1-H following bone marrow transplantation. Birth Defects. 1986;22:25
  108. Peters C, Balthazor M, Shapiro EG, King RJ, Kollman C, Hegland JD, et al. Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome. Blood. 1996;87:4894–4902
  109. Vellodi A, Young EP, Cooper A, Wraith JE, Winchester B, Meaney C, et al. Bone marrow transplantation for mucopolysaccharidosis type I: experience of two British centers. Arch Dis Child. 1997;76:92–99
  110. Soni S. Allogeneic stem cell transplantation for genetic disorders. J Ky Med Assoc. 2007;105:12–16
  111. Fleming DR, Henslee-Downey PJ, Ciocci G, Romond EH, Marciniak E, Munn RK, et al. The use of partially HLA-mismatched donors for allogenic transplantation in patients with mucopolysacharidosis-I. Pediatr Transplant. 1998;2:299–304
  112. Grewal SS, Krivit W, Defor TE, Shapiro EG, Orchard PJ, Abel SL, et al. Outcome of second hematopoietic cell transplantation in Hurler syndrome. Bone Marrow Transplant. 2002;29:491–496
  113. Peters C, Shapiro EG, Anderson J, Henslee-Downey PJ, Klemperer MR, Cowan MJ, et al. Hurler syndrome: II. Outcome of HLA-genotypically identical sibling and HLA-haploidentical related donor bone marrow transplantation in fifty-four children. Blood. 1998;91:2601–2608
  114. Lange MC, Teive HA, Troiano AR, Bitencourt M, Funke VA, Setúbal DC, et al. Bone marrow transplantation in patients with storage diseases: a developing country experience. Arq Neuropsiquiatr. 2006;64:1–4
  115. Boelens JJ, Wynn RF, O'Meara A, et al. Outcomes of hematopoietic stem cell transplantation for Hurler's syndrome in Europe: a risk factor analysis for graft failure. Bone Marrow Transplant. 2007;40:225–233
  116. Grewal SS, Wynn R, Abdenur JE, Burton BK, Gharib M, Haase C, et al. Safety and efficacy of enzyme replacement therapy in combination with hematopoietic stem cell transplantation in Hurler syndrome. Genet Med. 2005;7:143–146
  117. Boelens JJ. Trends in haematopoietic cell transplantation for inborn errors of metabolism. J Inherit Metab Dis. 2006;29:413–420
  118. Cox-Brinkman J, Boelens JJ, Wraith JE, O'Meara A, Veys P, Wijburg FA, et al. Haematopoietic cell transplantation (HCT) in combination with enzyme replacement therapy (ERT) in patients with Hurler syndrome. Bone Marrow Transplant. 2006;38:17–21
  119. Tolar J, Grewal SS, Bjoraker KJ, et al. Combination of enzyme replacement and hematopoietic stem cell transplantation as therapy for Hurler syndrome. Bone Marrow Transplant. 2007;41:531–535
  120. Kakkis ED. Enzyme replacement therapy for the mucopolysaccharide storage disorders. Expert Opin Investig Drugs. 2002;11:675–685
  121. Wraith JE. Enzyme replacement therapy in mucopolysacccharidosis type I: progress and emerging difficulties. J Inherit Metab Dis. 2001;24:245–250
  122. United States Food and Drug Administration. Aldurazyme approval information. Available at http://www.fda.gov/cder/biologics/products/larobio043003.htm2003;
  123. European Agency for the Evaluation of Medical Products. Aldurazyme approval information. Available at http://www.emea.eu.int/humandocs/Humans/EPAR/aldurazyme/aldurazyme.htm2003;
  124. Giugliani R, Muñoz Rojas V, Martins AM, Valadares ER, Clarke JTR, Góes J, et al. A dose-optimization trial of laronidase (Aldurazyme) in patients with mucopolysaccharidosis I. Mol Genet Metab. 2008;In press
  125. Clarke L, Wraith JE, Beck M, et al. Long-term efficacy and safety of laronidase in the treatment of mucopolysaccharidosis I. Pediatrics. 2009;In press
  126. Pastores GM, Wraith JE, Clarke LA, et al. The clinical benefit of Aldurazyme (laronidase) for the treatment of MPS I. Am J Hum Genet. 2003;73:624
  127. Bajbouj M, Beck M, Wraith JE, et al. Efficacy of Aldurazyme enzyme replacement therapy on joint mobility I MPS I. Am J Hum Genet. 2003;73:621
  128. Wraith JE, Clarke LA, Beck M, Kolodny EH, Pastores GM, Muenzer J, et al. Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase). J Pediatr. 2004;144:561–562
  129. Miebach E. Enzyme replacement therapy in mucopolysaccharidosis type I. Acta Paediatr Suppl. 2005;94:58–60
  130. Wraith JE. The first 5 years of clinical experience with laronidase enzyme replacement therapy for mucopolysaccharidosis I. Expert Opin Pharmacother. 2005;6:489–506
  131. Wraith JE, Hopwood JJ, Fuller M, Meikle PJ, Brooks DA. Laronidase treatment of mucopolysaccharidosis I. BioDrugs. 2005;19:1–7
  132. Braunlin EA, Berry JM, Whitley CB. Cardiac findings after enzyme replacement therapy for mucopolysaccharidosis type I. Am J Cardiol. 2006;98:416–418
  133. Soutar RL, Mercer J, Wraith JE. Impact of 144 weeks of laronidase therapy on body functions, endurance and general well-being in a Hurler-Scheie patient. J Inherit Metab Dis. 2006;29:590
  134. Sifuentes M, Doroshow R, Hoft R, Mason G, Walot I, Diament M, et al. A follow-up study of MPS I patients treated with laronidase enzyme replacement therapy for 6 years. Mol Genet Metab. 2007;90:171–180
  135. Sardón O, García Pardos C, Mintegui J, Pérez Ruiz E, Coll MJ, Chabás A, et al. Outcome of two patients with Hurler's syndrome under enzyme replacement therapy with human recombinant alpha-L-iduronidase. Ann Pediatr (Barc). 2005;63:61–67
  136. Tokic V, Barisic I, Huzjak N, Petkovic G, Fumic K, Paschke E. Enzyme replacement therapy in two patients with an advanced severe (Hurler) phenotype of mucopolysaccharidosis I. Eur J Pediatr. 2007;166:727–732
  137. Anbu AT, Mercer J, Wraith JE. Effect of discontinuing of laronidase in a patient with mucopolysaccharidosis type I. J Inherit Metab Dis. 2006;29:230–231
  138. Wegrzyn G, Tylki-Szymańska A, Liberek A, Piotrowska E, Jakóbkiewicz-Banecka J, Marucha J, et al. Rapid deterioration of a patient with mucopolysaccharidosis type I during interruption of enzyme replacement therapy. Am J Med Genet A. 2007;143:1925–1927
  139. Anson DS, Bielicki J, Hopwood JJ. Correction of mucopolysaccharidosis type I fibroblasts by retroviral-mediated transfer of the human alpha-L-iduronidase gene. Hum Gene Ther. 1992;3:371–379
  140. Hartung SD, Frandsen JL, Pan D, Koniar BL, Graupman P, Gunther R, et al. Correction of metabolic, craniofacial, and neurologic abnormalities in MPS I mice treated at birth with adeno-associated virus vector transducing the human alpha-L-iduronidase gene. Mol Ther. 2004;9:866–875
  141. Lutzko C, Kruth S, Abrams-Ogg AC, Lau K, Li L, Clark BR, et al. Genetically corrected autologous stem cells engraft, but host immune responses limit their utility in canine alpha-L-iduronidase deficiency. Blood. 1999;93:1895–1905
  142. Shull RM, Lu X, McEntee MF, Bright RM, Pepper KA, Kohn DB. Myoblast gene therapy in canine mucopolysaccharidosis. I: abrogation by an immune response to alpha-L-iduronidase. Hum Gene Ther. 1996;7:1595–1603

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PII: S0022-3476(09)00675-1

doi:10.1016/j.jpeds.2009.07.005

The Journal of Pediatrics
Volume 155, Issue 4, Supplement , Pages S32-S46, October 2009

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