Hurler Syndrome

A number sign (#) is used with this entry because Hurler syndrome is caused by homozygous or compound heterozygous mutation in the gene encoding alpha-L-iduronidase (IDUA; 252800) on chromosome 4p16.

Description

The mucopolysaccharidoses are a group of inherited disorders caused by a lack of specific lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs), or mucopolysaccharides. The accumulation of partially degraded GAGs causes interference with cell, tissue, and organ function.

Deficiency of alpha-L-iduronidase can result in a wide range of phenotypic involvement with 3 major recognized clinical entities: Hurler (MPS IH), Scheie (MPS IS; 607016), and Hurler-Scheie (MPS IH/S; 607015) syndromes. Hurler and Scheie syndromes represent phenotypes at the severe and mild ends of the MPS I clinical spectrum, respectively, and the Hurler-Scheie syndrome is intermediate in phenotypic expression (McKusick, 1972).

MPS I is more frequent than MPS II (Hunter syndrome; 309900), which has no corneal clouding and pursues a slower course.

Nomenclature

McKusick et al. (1972) suggested that the Hurler syndrome might be called MPS IH and the Scheie syndrome MPS IS.

Clinical Features

The clinical features of Hurler syndrome include coarse facies, corneal clouding, mental retardation, hernias, dysostosis multiplex, and hepatosplenomegaly. Children with Hurler syndrome appear normal at birth and develop the characteristic appearance over the first years of life (Wraith et al., 1987).

Wraith et al. (1987) reviewed 27 Hurler patients, 10 of which were evaluated prior to biochemical diagnosis. Diagnosis was established at a mean age of 21 months (range, 5-63 months). Seventeen of the children (63%) came to clinical attention with hernia prior to the diagnosis of Hurler syndrome. The average age at death was 6.25 years in their series of 27 patients with a range of 1.3 to 10.9 years.

Cleary and Wraith (1995) described the presenting features of 39 patients with mucopolysaccharidosis type IH. The mean age at diagnosis was approximately 9 months in this study. An earlier age at diagnosis is likely to lead to better results following therapy such as bone marrow transplantation. Clinical features that should arouse suspicion of MPS IH include frequent ear, nose and throat surgery and recurrent hernias.

McDowell et al. (1993) described a family in which sibs with comparable deficiencies of alpha-L-iduronidase had rather different clinical severity and disease progression. The cases underscored the need for caution in counseling and the limitations of using sibs as controls in evaluating the outcome of treatment.

Head and Neck

Gorlin et al. (2001) described the facial phenotype. A slight coarsening of the facial features at 3 to 6 months of age is usually the first abnormality detected. The head is large with bulging frontal bones. The skull is often scaphocephalic secondary to premature closure of the metopic and sagittal sutures. The nasal bridge is depressed with broad nasal tip and anteverted nostrils. The cheeks are full. The lips are enlarged and the mouth is usually held open, particularly after age 3 years. Chronic nasal discharge is present.

Corneal clouding is common. Optic nerve head swelling was observed in 8 of 14 eyes of Hurler syndrome patients reported by Collins et al. (1990). Glaucoma has also been reported to occur in MPS IH (Nowaczyk et al., 1988). Retinal degeneration commonly occurs in MPS I (Caruso et al., 1986).

Huang et al. (2015) studied the chorioretinopathy in 3 patients with MPS I. The first patient (28 years old) exhibited multifocal depigmented retinopathy in both eyes. The second patient (12 years old) had mild parafoveal retinal folds and mild swollen discs in both eyes. The third patient (33 years old) had a myelinated nerve fiber layer in the right eye. In the first patient, spectal-domain optical coherence tomography (SD-OCT) showed focal choroidal thinning in the depigmented retinopathy areas. In the other 2 patients, SD-OCT showed a fuzzy and thickened external limiting membrane at the fovea.

The neck is short and there is odontoid hypoplasia. Vertebral subluxation with cord compression can occur (Thomas et al., 1985).

In a review of cervical spine x-rays in 21 children with mucopolysaccharidosis, Belani et al. (1993) found odontoid hypoplasia in 94%, with 38% demonstrating C1-C2 subluxation.

Cardiovascular Features

Cardiac disease is common. Acute cardiomyopathy associated with endocardial fibroelastosis has been a presenting condition in some infants with MPS I less than 1 year of age (Donaldson et al., 1989).

Krovetz et al. (1965) reviewed the cardiovascular findings in 58 autopsy reports. There was valvular involvement in 40 of 58 cases, coronary artery narrowing in 20 of 58 patients, and endocardial fibroelastosis in 11 of 58 patients. They suggested that coronary insufficiency can occur but that Hurler patients are prohibited by their retarded development to communicate this effectively.

Renteria et al. (1976) described the cardiac disease in 5 necropsy cases of Hurler syndrome. All had narrowing of the extramural coronary arteries, cardiac valve thickening (left-sided greater than right-sided), generalized thickening of mural endocardium, and 'stiffening' of the myocardial walls.

Wippermann et al. (1995) studied 84 patients with MPS disorders. Echocardiography revealed mitral regurgitation in 10 of 12 MPS IH patients and aortic regurgitation in 4 of 12 MPS IH patients. Aortic and mitral valve thickening was also detected in the patients.

Respiratory Features

Frequent upper and lower respiratory tract infections are common. Respiratory obstruction occurs secondary to enlargement of tonsils and adenoids (Shapiro et al., 1985).

Narrow tracheas also contribute to upper airway construction. Peters et al. (1985) reported that 9 of 56 patients with MPS disorders had small tracheal diameters on their frontal chest radiographs. Autopsy of an MPS IH patient whose tracheal diameter measured 5 mm revealed that the epiglottis, aryepiglottic folds, and the vocal cords were enlarged and mainstem bronchi were thickened. This resulted primarily from glycosaminoglycan deposition in the connective tissues.

Semenza and Pyeritz (1988) studied respiratory complications in 4 patients with MPS IH. All had tonsillar and adenoidal hypertrophy, tongue enlargement, and supraglottic narrowing. Two patients studied by polysomnography had obstructive sleep apnea.

Belani et al. (1993) described the perioperative care in 30 children with MPS disorders, including 21 Hurler or Hurler-Scheie patients. They described anesthetic results in 14 patients with Hunter syndrome. During laryngoscopy, vocal cords were visible in only 19 of 55 anesthetic events. Following extubation, upper airway obstruction was noted 25 times.

Musculoskeletal System

Length is often normal until about 2 years of age when growth stops; by age 3 years height is less than the third percentile (Gorlin et al., 2001).

In infancy, bone trabeculation is coarse. In late infancy and childhood, a pattern of skeletal changes called 'dysostosis multiplex' develops (McKusick, 1972). The skull is large with narrow orbits. The calvaria is thickened and the sagittal and lambdoidal sutures close prematurely. The sella becomes J-shaped. The ribs have been described as oar-shaped with narrowing at the vertebral ends and broadening at the sternal ends. Clavicles are short, thick, and irregular. The vertebral bodies are dysplastic with biconcave endplates and hook-shaped configuration of the lower thoracic and upper lumbar vertebral bodies. The pelvis is poorly formed with small femoral heads and coxa valga. Iliac wings are flared. The long tubular bones show diaphyseal widening with small, deformed epiphyses. Phalanges are bullet-shaped with proximal pointing of the second to fifth metacarpals.

Neuhauser et al. (1968) concluded that subarachnoid cysts are often responsible for the enlarged sella in Hurler syndrome.

Joint stiffness is a common feature of all the MPS disorders with the exception of Morquio syndrome (253000; 253010). The joint function abnormalities probably result from a combination of the metaphyseal deformities and thickened joint capsules secondary to glycosaminoglycan deposition and fibrosis (Neufeld and Muenzer, 2001).

Progressive lumbar gibbus or kyphosis is commonly seen in the MPS disorders (Neufeld and Muenzer, 2001). Tandon et al. (1996) described the spinal problems and their management in 12 patients with Hurler syndrome who were followed up for a mean of 4.5 years following bone marrow transplantation. High lumbar kyphosis was seen in 10 patients and was associated with thoracic scoliosis in 1. Isolated thoracic scoliosis was seen in another. One patient had no significant problems in the thoracic or lumbar spine but had odontoid hypoplasia, which was also seen in 3 other children. Four of the 8 patients in whom MRI of the cervical spine had been performed had abnormal soft tissue around the tip of the odontoid. Neurologic problems were seen in 2 patients.

Carpal tunnel syndrome, a common complication in the mucopolysaccharidoses, probably results from a combination of excessive lysosomal storage in the connective tissue of the flexor retinaculum and a deformity secondary to the underlying skeletal dysplasia. Wraith and Alani (1990) performed nerve conduction studies on 18 patients with various forms of mucopolysaccharidoses and mucolipidosis III. All patients studied, with the exception of patients younger than 2 years, had evidence of thenar muscle wasting and a typical 'claw-hand' deformity. All 3 patients with MPS IH were found to have carpal tunnel syndrome. Two of the 3 received bone marrow transplantation at 14 months and 2.3 years, respectively. Neither showed improvement following transplantation.

Nervous System

Developmental delay is often apparent by 12 to 24 months of age, with a maximum functional age of 2 to 4 years followed by progressive deterioration. Most children develop limited language because of developmental delay, chronic hearing loss, and enlarged tongue (Neufeld and Muenzer, 2001).

In a study of 27 patients with MPS IH, Wraith et al. (1987) found that all had head circumferences at or above the 95th percentile. Only 5 children developed signs and symptoms of raised intracranial pressure which required shunt.

Lee et al. (1993) characterized cranial MRI findings in 6 children with Hurler syndrome. All exhibited cribriform or cystic changes: low signal intensity with respect to white matter on T1-weighted images and high-signal intensity on the T2-weighted images. The changes corresponded pathologically to perivascular accumulations of glycosaminoglycan within the foam cells in the Virchow-Robin spaces (Norman et al., 1959). Myelination delay, atrophy, and ventricular enlargement were also found in their patients.

Dermatologic Features

Hanson et al. (2003) described 2 infants with extensive dermal melanocytosis in association with GM1-gangliosidosis type I (230500) and Hurler syndrome, respectively. Clinically, dermal melanocytosis associated with lysosomal storage disease is characterized by extensive, blue cutaneous pigmentation with dorsal and ventral distribution, indistinct borders, and persistent and/or 'progressive' behavior. A literature analysis revealed 37 additional cases. The most common lysosomal storage disease associated with dermal melanocytosis was Hurler syndrome (24 of 39 cases), followed by GM1-gangliosidosis (11 of 39 cases). Hanson et al. (2003) concluded that in the appropriate clinical setting, an unusual presentation of dermal melanocytosis in an infant may be a cutaneous sign of an underlying lysosomal storage disease.

Biochemical Features

The enzyme deficient in Hurler syndrome is alpha-L-iduronidase (252800).

Danes and Bearn (1965) found that cellular accumulation of mucopolysaccharides persists in cultured fibroblasts. Fratantoni et al. (1968) showed that the accumulation results from inefficient degradation of intracellular mucopolysaccharide rather than excessive synthesis or reduced secretion. Furthermore, they found that mixing of fibroblasts from Hurler and Hunter patients causes mutual correction of the intracellular accumulation of mucopolysaccharides. Medium in which cells of the other type or normal cells had been incubated was also effective in correcting the defect. Thus, isolation and identification of the corrective factor in the medium opened up possibilities of clarifying the normal mechanisms of MPS degradation, as well as therapy. Differentiation of the Sanfilippo syndrome (MPS III; see 252900) from the Hurler and Hunter syndromes was also possible by this mixed culture method.

Wiesmann and Neufeld (1970) found no cross-correction of Scheie and Hurler fibroblasts with those from Sanfilippo and Hunter patients. Both disorders showed deficiencies of alpha-L-iduronidase.

Schuchman and Desnick (1988) reported the presence of cross-reactive immunologic material (CRIM) in individuals from each of the 3 MPS I subtypes. Furthermore, they identified effector compounds that enhanced the residual activities in subtype extracts into the heterozygote range. The polyclonal antibody with which this work was done, however, is under suspicion because of the findings of Scott et al. (1990) that it gave a fallacious result when used for the mapping of the IDUA gene in somatic cell hybrids.

Brooks et al. (1992) found that a clinically typical patient with Hurler syndrome, the source of cell line GM2827, had, despite severe deficiency of enzyme, an activity level of alpha-L-iduronidase protein at least 6 times greater than the mean level found in normal control fibroblasts. This was the only 1 of 23 patients who had protein levels greater than 7% of the mean level detected in normal controls.

Diagnosis

Biochemical Diagnosis

The earliest diagnostic tests for the MPS disorders were based on the urinary excretion of glycosaminoglycans. Pennock (1976) noted several methods that had been developed from semiquantitative spot tests to more precise qualitative and quantitative assays.

Spot tests are quick and inexpensive but are subject to both false-positive and false-negative results. De Jong et al. (1991) checked the reliability of the Ames MPS paper spot test, which is based on the Azure A dye. They sent a series of urine samples to 3 laboratories where the spot test is part of the metabolic screening for mucopolysaccharidoses. In these laboratories, false-negative results ranged between 19% and 35% and false-positive results ranged between 12 and 29% of all samples submitted. In contrast, the quantitative dimethylmethylene blue test detected an increased glycosaminoglycan content in all urine samples from mucopolysaccharidosis patients and gave no false-positive results.

Definitive diagnosis is established by alpha-L-iduronidase enzyme assay using artificial substrates (fluorogenic or chromogenic) in cultured fibroblasts or isolated leukocytes (Hall et al., 1978).

Carrier testing can be performed by differentiating normal enzyme activity from half-normal levels of enzyme activity. Wappner and Brandt (1976) studied alpha-L-iduronidase activity in mixed leukocyte preparations in 10 families in which the Hurler syndrome had occurred. Affected patients, heterozygotes, and normal subjects were clearly distinguished by alpha-L-iduronidase activity alone. Patients had 0 to 3%, obligate heterozygotes 19 to 60%, and normal subjects 83 to 121% of the mean normal activity. There was no overlap between heterozygotes and normal subjects.

Low activity 'pseudodeficiency' alleles exist, however, and complicate biochemical carrier testing. Taylor and Thomas (1993) reported apparent deficiency of alpha-iduronidase in a clinically normal individual. The same finding was made in leukocytes and skin fibroblasts which functioned normally in correction assays in mixed culture. Previously reported instances of pseudodeficiency involved individuals who were obligate heterozygotes for Hurler syndrome, having 1 Hurler allele and presumably 1 pseudodeficiency allele (Gatti et al., 1985; Whitley et al., 1987). Whitley et al. (1987) described a low activity 'pseudodeficiency' allele at the alpha-L-iduronidase locus. It was found in a phenotypically normal obligate heterozygote with exceedingly low levels of enzyme activity. The presence of this allele can complicate carrier detection and prenatal diagnosis.

Prenatal Diagnosis

Prenatal diagnosis is possible on both cultured amniotic fluid cells and chorionic villus biopsies. Young (1992) stressed the importance of obtaining an adequate chorionic villi tissue sample. Twenty-four pregnancies at risk for Hurler disease were monitored by measurement of alpha-iduronidase in chorionic villi. Adequate samples were obtained for direct assay of the villi in 22 pregnancies. Pregnancies were terminated in 5 samples found to be affected. In another pregnancy, an equivocal result was obtained on direct assay, but analysis of the cultured chorionic cells showed the fetus to be affected. In 1 pregnancy in which a very small sample was obtained, direct assay indicated the fetus to be unaffected. However, amniocentesis revealed an affected pregnancy.

Molecular Diagnosis

Molecular diagnosis of Hurler syndrome is difficult because of the genetic heterogeneity in MPS I. Using a combination of mutation analysis and mutation scanning in a study of 85 MPS I families (73 Hurler, 5 Hurler/Scheie, 7 Scheie), Beesley et al. (2001) identified both IDUA mutations in 81 (95%) families, one IDUA mutation in 3 (3.5%) families, and none in 1 (1.1%) family. The families were screened for 9 known mutations. W402X (252800.0001) was the most frequent mutation in their population (45.3%), followed by Q70X (252800.0002) (15.9%). In 30 families, one or both of the mutations were not identified, which accounted for 25.9% of the total alleles. Therefore, all 14 exons of the IDUA gene were screened in these patients and 23 different sequence changes were found, 17 of which were previously unknown.

Clinical Management

Wang et al. (2011) described the ACMG standards and guidelines for the diagnostic confirmation and management of presymptomatic individuals with lysosomal storage diseases.

Anesthesia

Belani et al. (1993) described the perioperative care, morbidity, and mortality in 30 patients with mucopolysaccharidosis, including 21 patients with Hurler or Hurler-Scheie syndrome. During 141 anesthetic administrations, 2 children with Hurler syndrome died intraoperatively. The first death occurred in a boy, aged 3 years 9 months, who demonstrated a sudden elevation of ST-T segments on ECG, then rapid bradycardia and death. At autopsy, both his coronary vessels were occluded. The other death occurred in a 14-month-old child who had normal preoperative ECG and cardiac echocardiogram. During cardiac catheterization, he developed ventricular tachycardia and subsequent cardiac arrest. At autopsy, there was marked concentric intimal and subintimal fibrosis of both coronary arteries, which was not substantiated on the coronary angiogram.

Plasma Infusion/Fibroblast Transplantation

Improvement, clinical and chemical, with plasma infusions was claimed by Di Ferrante et al. (1971), but further trials were disappointing. Gibbs et al. (1983) did not find fibroblast transplantation to be therapeutically useful in either Hurler syndrome or Sanfilippo syndrome.

Bone Marrow Transplantation (BMT)

Hugh-Jones (1983) pointed out the importance of early diagnosis of mucopolysaccharidoses because of the effectiveness of bone marrow transplantation. He reported that hernia was a feature in 13 of 15 cases of MPS I and in 7 of 9 cases of MPS II, and suggested that hernia before the age of 6 months may be a valuable diagnostic clue.

Hopwood et al. (1993) described the outcome of bone marrow transplantation in 2 patients who were subsequently found to be homozygous for the relatively common W402X mutation (252800.0001). They received BMT at the ages of 14 and 11 months and were 12% and 14 years old, respectively, at the time of report. Untreated patients homozygous for this mutation have a very severe clinical phenotype with rapid clinical deterioration and death before 6 years of age. The 12-year-old patient showed limited mobility but was coping well at school; the other patient was wheelchair-bound with severe disability in his lower limbs and attended a school for the physically handicapped. Both patients had less than normal intelligence with slowly continuing losses.

The Storage Disease Collaborative Study Group (Peters et al., 1998) reported their findings on 54 patients with MPS I. The patients received high-dose chemotherapy with or without irradiation and BMT from HLA-genotypically identical sib (GIS) or HLA-haploidentical-related (HIR) donors between 1983 and 1995. Thirty-nine of 54 patients (72%) were engrafted following the first BMT. The probability of grade II to IV acute graft-vs-host disease (GVHD; see 614395) at 100 days was 32% for GIS and 55% for HIR patients. The actuarial probability of survival at 5 years was 64% for all patients, 75% for GIS patients, 53% for HIR patients, and 53% for patients with donor marrow engraftment. The baseline Mental Developmental Index (MDI) was examined both for children less than and greater than 24 months of age at BMT. Children who received a transplant before 24 months had a mean baseline MDI of 78, whereas those who received a transplant after 24 months of age had a mean baseline MDI of 63 (P = 0.0002). Both baseline and post-BMT neuropsychologic data were available for 26 of 30 engrafted survivors. Of 14 patients who received a transplant before 24 months of age, 9 demonstrated developmental trajectories that were normal or somewhat slower than normal. In contrast, of 12 patients who received a transplant after 24 months of age, only 3 showed developmental trajectories that were normal or somewhat slower than normal (P = 0.01). Children were more likely to maintain normal cognitive development if they were fully engrafted following BMT from a donor with homozygous normal leukocyte alpha-L-iduronidase enzyme activity.

Enzyme Replacement

Kakkis et al. (2001) treated 10 patients with MPS I (aged 5 to 22 years) with recombinant human alpha-L-iduronidase at a dose of 125,000 U per kg of body weight given intravenously once weekly for 52 weeks. Hepatosplenomegaly decreased significantly in all patients, and the size of the liver was normal for body weight and age in 8 patients by 26 weeks. The rate of growth in height and weight increased by a mean of 85%% and 131%, respectively, at 52 weeks in the 6 prepubertal patients. The mean maximum range of motion of shoulder flexion and elbow extension increased significantly. The number of episodes of apnea and hypopnea during sleep decreased by 61%. New York Heart Association functional class improved by 1 or 2 classes in all patients. Urinary glycosaminoglycan excretion decreased after 3 to 4 weeks of treatment; the mean reduction at 52 weeks was 63% of baseline values. Five patients had transient urticaria during infusions. Serum antibodies to alpha-L-iduronidase were detected in 4 patients.

Wang et al. (2009) reported a girl with severe MPS I who began enzyme replacement therapy (ERT) at age 15 months and underwent hematopoietic stem cell transplantation at age 20 months. At that time, she had begun to walk and spoke a few words. She had complete engraftment with normalization of plasma IDUA activity. At age 4 years, she was slightly developmentally delayed with mild to moderate sensorineural hearing loss, but was making progress. Brain imaging studies showed improvement of white matter abnormalities and ventricular dilatation following ERT even before stem cell transplant, with continued improvement in brain imaging abnormalities until the time of the report. The findings suggested that ERT may improve brain MRI abnormalities in patients with MPS, even though ERT had previously been thought not to cross into the brain. Wang et al. (2009) offered some explanations, including lessening of somatic GAG accumulation, repair of damaged brain endothelium, and possibly small amounts of enzyme being able to permeate the brain.

Gene Therapy

Because allogeneic bone marrow transplantation is not available to all patients, Fairbairn et al. (1996) considered an alternative approach based on transfer and expression of the normal gene in autologous bone marrow. They constructed a retroviral vector carrying the full-length cDNA for alpha-L-iduronidase and used it to transduce bone marrow from patients with this disorder. They demonstrated successful gene transfer into primitive CD34+ cells and subsequent enzyme expression in their maturing progeny. The efficiency of gene transfer as assessed by PCR analysis of hematopoietic colonies was 25 to 56%. The enzyme was secreted into the medium and functional localization was demonstrated by reversal of the phenotypic effects of lysosomal storage in macrophages. Fairbairn et al. (1996) concluded that retroviral gene transfer into human bone marrow may offer effective gene therapy of Hurler syndrome in young patients without a matched sib donor.

Keeling et al. (2001) found that a Hurler syndrome fibroblast cell line heterozygous for the IDUA stop mutations Q70X and W402X showed a significant increase in alpha-L-iduronidase activity when cultured in the presence of gentamicin, resulting in the restoration of 2.8% of normal alpha-L-iduronidase activity. Gentamicin treatment reduced glycosaminoglycan accumulation in Hurler cells to a normal level for at least 2 days after gentamicin treatment was discontinued. The reduction in the GAG level was also reflected in a marked reduction in lysosomal vacuolation, as shown by fluorescence microscopy. The authors suggested that partial suppression of premature stop mutations by gentamicin may provide an effective treatment for Hurler syndrome patients with these mutations in the IDUA gene.

Di Natale et al. (2002) used a late-generation lentiviral vector to evaluate the usefulness of this vector system for the transfer and expression of the human IDUA cDNA in MPS I fibroblasts. They observed that the level found in normal cells and expression persisted for at least 2 months. In addition, transduced MPS I fibroblasts were capable of clearing intracellular radiolabeled glycosaminoglycan. Pulse-chase experiments on transduced fibroblasts showed that the recombinant enzyme was synthesized as a 76-kD precursor form and processed to a mature form; it was released from transduced cells and was endocytosed into a second population of untreated MPS I fibroblasts via a mannose 6-phosphate receptor.

Allogeneic bone marrow transplantation before the age of 2 years halts disease progression in Hurler syndrome and prolongs life, but many children lack a bone marrow donor. Staba et al. (2004) investigated the feasibility of using cord blood transplants from unrelated donors and a myeloablative preparative regimen that did not involve total-body irradiation in young children with Hurler syndrome. Over a 7-year period, they gave 20 consecutive children with Hurler syndrome busulfan, cyclophosphamide, and antithymocyte globulin in preparation for receiving cord blood transplants from unrelated donors. Cord blood donors were discordant for up to 3 of 6 HLA markers. Neutrophil engraftment occurred a median of 24 days after transplantation. Grade II or grade III acute graft-versus-host disease occurred in 5 patients; none had extensive chronic graft-versus-host disease. Seventeen of the 20 children were alive a median of 905 days after transplantation, with complete donor chimerism and normal peripheral blood alpha-L-iduronidase activity. Transplantation improved neurocognitive performance and decreased somatic features of Hurler syndrome.

Umbilical Cord Blood Transplantation

Poe et al. (2014) reported 31 patients with Hurler syndrome who underwent umbilical cord blood transplantation between June 1997 and February 2013 and were evaluated at baseline and every 6 to 12 months thereafter. All 31 patients underwent complete neurodevelopmental evaluation (median follow-up 7.3 years, range 2-21.7) and a median of 7.0 evaluations (range 3-18 ). Younger age at transplantation was associated with improved cognitive function (p = 0.001), receptive and expressive language (p = 0.004 and p = 0.01), and adaptive behavior (p = 0.03). Early age at transplantation was a strong predictor of cognitive, language, and adaptive behavior outcomes. Children younger than 9 months at the time of transplant showed normal cognitive development.

Inheritance

Hurler syndrome is an autosomal recessive disorder (Bunge et al., 1995; Yamagishi et al., 1996).

Molecular Genetics

Bunge et al. (1995) identified 13 novel and 7 previously reported mutations of the IDUA gene, covering 88% of mutant alleles and 86% of genotypes, in a total of 29 patients with MPS I of differing clinical severity.

Matte et al. (2000) analyzed 24 Brazilian MPS I patients for 10 known mutations in the IDUA gene. Only 37% of genotypes and 54% of the alleles were defined using this method, demonstrating a low frequency of these 10 mutations in this population.

Population Genetics

If the mutation rates are the same and the heterozygotes for the Hurler and Hunter syndromes have no reproductive advantage or disadvantage, the Hunter syndrome should be 1.5 times more frequent among newborns than the Hurler syndrome (McKusick, 1970). Lowry and Renwick (1971) gave estimates of the frequency of the Hurler syndrome and the Hunter syndrome in the province of British Columbia. Lowry et al. (1990) stated that no case of the Hurler syndrome had been encountered since 1981 and no case of the Hunter syndrome since 1971. The frequency of the Hunter syndrome between 1952 and 1986 was estimated to be 1 in 110,950 live male births; the frequency of the Hurler syndrome was estimated to be 1 in 144,274 live births. Over a period of years during which he was responsible for identification of essentially all cases of mucopolysaccharidosis in Israel, Bach (1990) found no cases of Hurler syndrome in Ashkenazim. Hurler syndrome in Ashkenazi Jews appears to be rare in the experience of others; thus, this gene may be similar to the PKU gene, which is rare in this group.

Using multiple ascertainment sources, Nelson et al. (2003) obtained an incidence rate of MPS IH in western Australia for the period 1969 to 1996 of approximately 1 in 107,000.

By analyzing allele and haplotype frequencies for 2 polymorphisms within the IDUA gene in the normal population and in MPS IH patients, Scott et al. (1992) found linkage disequilibrium. One VNTR allele was present in 57% of MPS I patients as compared with 37% in the normal population. They interpreted this as indicating the presence of a major MPS I allele.

Relevant to the question of the relative frequency and birth prevalence of Hurler syndrome and Hunter syndrome is the report by Poorthuis et al. (1999) on the frequency of lysosomal storage diseases in the Netherlands. MPS I had the highest calculated birth prevalence of 1.19 per 100,000 (25% of all cases of MPS diagnosed); the birth prevalence of MPS II was 0.67 per 100,000 (1.30 per 100,000 male live births). (The second most frequent mucopolysaccharidosis was MPS IIIA (Sanfilippo syndrome type A; 252900) with an estimated birth prevalence of 1.16 per 100,000.)

In a group of 46 European patients with MPS I, Bunge et al. (1994) found that the 2 common nonsense mutations, W402X (252800.0001) and Q70X (252800.0002), were identified in 37% and 35% of mutant alleles, respectively. Considerable differences were seen in the frequency of these 2 mutations in patients from Norway and Finland as compared with other European countries, mainly the Netherlands and Germany. In Scandinavia, W402X and Q70X accounted for 17% and 62% of the MPS I alleles, respectively, while in other European countries W402X was about 2.5 times more frequent (48%) than Q70X (19%). Bunge et al. (1994) also described 8 novel mutations, including 4 missense mutations, 1 nonsense mutation, 1 insertion of 2 basepairs, and 2 deletions of 1 and 12 basepairs. All the patients in this study had a typical, severe form of the disease, MPS IH, with marked skeletal changes, hepatosplenomegaly, and mental retardation.

Yamagishi et al. (1996) defined the IDUA mutations in 19 Japanese MPS I patients, including 2 pairs of sibs, with various clinical phenotypes; Hurler syndrome, 6 cases; Hurler/Scheie syndrome, 7 cases; Scheie syndrome, 6 cases. Two common mutations accounted for 42% of the 38 alleles in these patients. One was a novel 5-bp insertion between the T at nucleotide 704 and the C at nucleotide 705 (704ins5; 252800.0014), which was seen only in the Japanese population. The other was a missense mutation, R89Q (252800.0015), which is seen also in Caucasians, although uncommonly. No Japanese patient was found to carry the W402X or Q70X alleles, the 2 most common MPS I mutations in Caucasians. Homozygosity for the 704ins5 mutation was associated with a severe phenotype; homozygosity for the R89Q mutation was associated with a mild phenotype. Compound heterozygosity for these 2 mutations produced an intermediate phenotype. Haplotype analysis using polymorphisms linked to IDUA locus demonstrated that each of these 2 common mutations occurred on a different specific haplotype, suggesting that individuals with each of these common mutations derived from a common founder. The mild-intermediate-severe phenotypic relationships of the 2 common Japanese mutations fulfill the prediction of McKusick et al. (1972).

Scott et al. (1995) indicated that a total of 46 mutations in the IDUA gene had been defined: 8 nonsense mutations, 21 missense mutations, 3 splice site mutations, and 14 minor deletions and/or insertions. Furthermore, 30 polymorphisms or nonpathogenic sequence variants had been defined, including 7 amino acid substitutions. Among patients of European origin, there were 2 major mutations associated with MPS I: W402X and Q70X, which together accounted for between 24% (Italian) and 84% (Scandinavian) of the MPS I alleles in patients of European origin. Different alleles predominate in Japanese patients.

Gatti et al. (1997) screened for IDUA mutations in 27 Italian patients with MPS I. Mutations were found in 18 patients, with 28 alleles identified. The 2 most common mutations in northern Europeans, W402X and Q70X, accounted for 11 and 13% of the alleles, respectively. The P533R (252800.0003) mutation accounted for 11% of the 54 alleles and seemed to be confined to Sicily; the frequency of P533R was 3% in a British/Australian study. Two P533R homozygotes were stated to have an intermediate phenotype in one and a mild phenotype in a second.

Lin et al. (2009) analyzed the incidence of MPS in Taiwan between 1984 and 2004 and found that the combined birth incidence for all MPS cases was 2.04 per 100,000 live births. MPS II (Hunter syndrome) had the highest calculated birth incidence (1.07 per 100,000 live births), comprising 52% of all MPS cases diagnosed. The birth incidences of MPS I, III (Sanfilippo syndrome), IV (Morquio syndrome), and VI (Maroteaux-Lamy syndrome) were 0.11, 0.39, 0.33, and 0.14 per 100,000 live births, respectively, and accounted for 6%, 19%, 16%, and 7% of all MPS, respectively. Although the overall incidence of MPS in Taiwan was consistent with reports from Western populations, Lin et al. (2009) noted that in contrast to reports of a higher incidence of MPS I in most Western populations, their study showed a higher incidence of MPS II in Taiwan.

Vazna et al. (2009) reported that 21 Czech and Slovak patients had been diagnosed with MPS I over the past 30 years, 16 with a severe clinical presentation (Hurler syndrome), 2 less severe (Scheie syndrome), and 3 of intermediate severity (Hurler-Scheie syndrome). Mutation analysis in 22 patients showed a high prevalence of the null mutations W402X and Q70X (12 and 7 alleles, respectively). The authors stated that missense mutations located predominantly in the hydrophobic core of the enzyme were associated with the severe phenotype, whereas missense mutations localized to the surface of the enzyme were usually associated with the attenuated phenotypes. Mutations in the 130 C-terminal amino acids led to clinical manifestations, indicating functional importance of the C terminus of the IDUA protein.

Khan et al. (2017) analyzed the epidemiology of the mucopolysaccharidoses in Japan and Switzerland and compared them to similar data from other countries. Data for Japan was collected between 1982 and 2009, and 467 cases with MPS were identified. The combined birth prevalence was 1.53 per 100,000 live births. The highest birth prevalence was 0.84 for MPS II (309900), accounting for 55% of all MPS. MPS I, III (see 252900), and IV (see 253000) accounted for 15%, 16%, and 10%, respectively. MPS VI (253200) and VII (253220) were more rare and accounted for 1.7% and 1.3%, respectively. A retrospective epidemiologic data collection was performed in Switzerland between 1975 and 2008 (34 years), and 41 living MPS patients were identified. The combined birth prevalence was 1.56 per 100,000 live births. The highest birth prevalence was 0.46 for MPS II, accounting for 29% of all MPS. MPS I, III, and IV accounted for 12%, 24%, and 24%, respectively. As seen in the Japanese population, MPS VI and VII were more rare and accounted for 7.3% and 2.4%, respectively. The high birth prevalence of MPS II in Japan was comparable to that seen in other East Asian countries where this MPS accounted for approximately 50% of all forms of MPS. Birth prevalence was also similar in some European countries (Germany, Northern Ireland, Portugal and the Netherlands) although the prevalence of other forms of MPS was also reported to be higher in these countries.

Animal Model

Haskins et al. (1979) described a model of MPS I in the cat, and Shull et al. (1982) and Spellacy et al. (1983) described a model in the dog.

Shull et al. (1994) reported results of enzyme replacement in the canine model. Recombinant human alpha-L-iduronidase, purified to apparent homogeneity from secretions of a stably transfected Chinese hamster ovary cell line, was administered intravenously to homozygous affected animals in doses of approximately 1 mg. The enzyme rapidly disappeared from the circulation in a biphasic manner, with a half-life of 0.9 and 19 min, respectively, and was taken up primarily by the liver. Biopsy of the liver before and after a trial of 7 doses administered over 12 days showed remarkable resolution of lysosomal storage in both hepatocytes and Kupffer cells. After weekly administration of enzyme to 3 affected animals over a period of 3 months, the level of enzyme was about normal in liver and spleen, lower but significant in kidney and lung, and barely detectable (0-5% of normal) in brain, heart valve, myocardium, cartilage, and cornea. Light and electron microscopic examination showed normalization of lysosomal storage in liver, spleen, and kidney glomeruli, but there was no improvement in brain, heart valves, or cornea. The treated dogs developed complement-activating antibodies against the enzyme but clinical symptoms could be avoided by slow infusion of enzyme and premedication with antihistamine and sedative.

Grosson et al. (1994) mapped the homologous locus in the mouse, Idua, to chromosome 5 in a continuous linkage group that included the homolog of the Huntington disease gene. Clarke et al. (1997) created a mouse strain completely deficient in iduronidase by targeted disruption of the Idua gene. Russell et al. (1998) reported on the long-term clinical, biochemical, and pathologic course of MPS I in mice, with emphasis on the skeletal and CNS manifestations. Affected mice showed a progressive clinical course with the development of coarse features, altered growth characteristics, and a shortened life span. Progressive lysosomal accumulation was seen in all tissues. Skeletal manifestations represented the earliest clinical findings, with histologic analysis of growth plate and cortical bone revealing evidence of significant early pathology. Analysis of the CNS showed progressive neuronal loss within the cerebellum. In addition, brain tissue from MPS I mice showed increased levels of GM2 and GM3 gangliosides.

Ohmi et al. (2003) studied the brain of mouse models of MPS I and MPS IIIB (252920) in connection with previous evidence of microglial involvement in the pathogenesis of mucopolysaccharidoses. The studies showed an inflammatory component of brain disease in both of these forms of MPS.

Immune responses can interfere with the effective use of enzyme replacement in treatment of Hurler syndrome and other genetic deficiencies. To address this problem, Kakkis et al. (2004) studied methods of immune tolerance used in canine organ transplantation research, extending it to the use of soluble proteins in therapeutics. They developed a tolerization regimen for use in a canine model of MPS I. The tolerizing regimen consisted of a limited 60-day course of cyclosporin A and azathioprine combined with weekly intravenous infusions of low-dose recombinant human alpha-L-iduronidase. The experimental dogs tolerized with this regimen maintained a reduced immune response for up to 6 months despite weekly therapeutic doses of enzyme in the absence of immunosuppressive drugs. Successful tolerization depended on high plasma levels of cyclosporin A combined with azathioprine. In addition, the induction of tolerance may require mannose 6-phosphate receptor-mediated uptake because alpha-L-iduronidase and alpha-glucosidase (606800) induced tolerance with the drug regimen whereas ovalbumin and dephosphorylated alpha-L-iduronidase did not. Kakkis et al. (2004) suggested that this approach should be applicable to the treatment of other lysosomal storage disorders and that the strategy might be used for reduction in antibodies associated with autoimmune disease.

Zheng et al. (2003) transduced bone marrow from Idua knockout male mice with human IDUA cDNA in an MND vector and transplanted it into 6-to-8-week-old, lethally irradiated female Idua -/- mice. Sham-treated mice received Idua -/- bone marrow that was either unmodified or transduced with enhanced GFP. Transplantation of unmodified wildtype bone marrow was effective in reducing storage in liver and spleen but not in kidney or brain. The level of alpha-L-iduronidase activity achieved by transplantation of IDUA-transduced bone marrow varied greatly between experiments. Even modest activity resulted in correction of pathology of kidney, bladder epithelium, fibrocartilage, choroid plexus, and thalamus, as seen by light microscopy; electron microscopy showed the presence of some normal neurons in the cortex. The partial correction of brain pathology was attributed to migration of donor hematopoietic cells, demonstrated by the presence of the Y chromosome and of normal microglia in the brain of mice receiving IDUA cDNA.

Desmaris et al. (2004) used adenoviral vectors (AAV2 and AAV5) to inject human IDUA into the right putamen in a mouse model of MPS I. After a single injection, enzyme activity was detected throughout the brain, including the contralateral hemisphere, the cerebellum, and the brainstem. In the treated mouse brains, neuropathologic examination showed decreased ganglioside accumulation as well as evidence suggesting reversal of disease pathology in some areas.

Ciron et al. (2006) reported stereotactic adenoviral-mediated injection of human IDUA into the brains of dogs with MPS1. The dogs were treated between 3 and 4.8 months of age after symptoms had developed. Neuropathologic analysis showed broad and efficient IDUA delivery in the brain, reduced pathology, and improvement of biochemical disease markers in most areas. Clinical improvement