Our objective was to assess how the diagnosis and treatment of mucopolysaccharidosis I (MPS I) have changed over time. We used data from 891 patients in the MPS I Registry, an international observational database, to analyze ages at symptom onset, diagnosis, treatment initiation, and treatment allocation (hematopoietic stem cell transplantation, enzyme replacement therapy with laronidase, both, or neither) over time for all disease phenotypes (Hurler, Hurler–Scheie, and Scheie syndromes). The interval between diagnosis and treatment has become shorter since laronidase became available in 2003 (gap during 2006–2009: Hurler—0.2 year, Hurler–Scheie—0.5 year, Scheie—1.4 years). However, the age at diagnosis has not decreased for any MPS I phenotype over time, and the interval between symptom onset and treatment initiation remains substantial for both Hurler–Scheie and Scheie patients (gap during 2006–2009, 2.42 and 6.71 years, respectively). Among transplanted patients, an increasing proportion received hematopoietic stem cells from cord blood (34 out of 64 patients by 2009) and was also treated with laronidase (42 out of 45 patients by 2009). Conclusions: Despite the availability of laronidase since 2003, the diagnosis of MPS I is still substantially delayed for patients with Hurler–Scheie and Scheie phenotypes, which can lead to a sub-optimal treatment outcome. Increased awareness of MPS I signs and symptoms by primary care providers and pediatric subspecialists is crucial to initiate early treatment and to improve the quality of life of MPS I patients.
Mucopolysaccharidosis I; Hurler; Hurler–Scheie; Scheie; Laronidase; Enzyme replacement therapy; Hematopoietic stem cell transplant
Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder that is caused by a deficiency of the enzyme α-l-iduronidase (IDUA). Of the 21 Czech and Slovak patients who have been diagnosed with MPS I in the last 30 years, 16 have a severe clinical presentation (Hurler syndrome), 2 less severe manifestations (Scheie syndrome), and 3 an intermediate severity (Hurler/Scheie phenotype). Mutation analysis was performed in 20 MPS I patients and 39 mutant alleles were identified. There was a high prevalence of the null mutations p.W402X (12 alleles) and p.Q70X (7 alleles) in this cohort. Four of the 13 different mutations were novel: p.V620F (3 alleles), p.W626X (1 allele), c.1727 + 2T > G (1 allele) and c.1918_1927del (2 alleles). The pathogenicity of the novel mutations was verified by transient expression studies in Chinese hamster ovary cells. Seven haplotypes were observed in the patient alleles using 13 intragenic polymorphisms. One of the two haplotypes associated with the mutation p.Q70X was not found in any of the controls. Haplotype analysis showed, that mutations p.Q70X, p.V620F, and p.D315Y probably have more than one ancestor. Missense mutations localized predominantly in the hydrophobic core of the enzyme are associated with the severe phenotype, whereas missense mutations localized to the surface of the enzyme are usually associated with the attenuated phenotypes. Mutations in the 130 C-terminal amino acids lead to clinical manifestations, which indicates a functional importance of the C-terminus of the IDUA protein. © 2009 Wiley-Liss, Inc.
mucopolysaccharidosis I; α-l-iduronidase; mutation; polymorphism; haplotype
Mucopolysaccharidosis I (MPS I) comprises a spectrum of clinical manifestations and is divided into three phenotypes reflecting clinical severity: Hurler, Hurler-Scheie, and Scheie syndromes. There may be important variations in clinical manifestations of this genetic disease in patients residing in different regions of the world.
Using data from the MPS I Registry (as of September 2009), we evaluated patients from Latin America (n = 118) compared with patients from the rest of the world [ROW (n = 727)].
Phenotype distribution differed among patients in Latin America compared to ROW (Hurler 31 vs. 62%, Hurler-Scheie 36 vs. 21%, Scheie 10 vs. 11%, and unknown 22 vs. 6%). The frequency of certain symptoms, such as cardiac valve abnormalities, sleep impairment, and joint contractures, also differed between Latin America and ROW for some phenotypes. Median age at MPS I diagnosis was earlier in the ROW than Latin America for all phenotypes, and age at first treatment for Hurler and Hurler-Scheie patients was also earlier in the ROW. Hurler patients in Latin America showed a gap of 3.1 years between median ages of diagnosis and first treatment compared to only 0.5 years in the ROW. Treatment allocation in Latin America compared to ROW was as follows: enzyme replacement therapy (ERT) only, 80 vs. 45%; hematopoietic stem cell transplantation (HSCT) only, 0.9 vs. 27%; both ERT and HSCT, 0 vs. 16%; and neither treatment, 19 vs. 13%.
These data highlight important differences in MPS I patients between Latin America and ROW in terms of phenotypic distribution, clinical manifestations, and treatment practices.
Mucopolysaccharidosis I (MPS I) is a rare inherited disorder that belongs to a group of clinically progressive disorders and is caused by the deficiency of the lysosomal enzyme, α1-iduronidase. MPS I has been recently classified into a severe (Hurler syndrome) and an attenuated type (Hurler-Scheie and Scheie syndromes). The purpose of this article was to describe a rare case of MPS type I, attenuated type (Hurler-Scheie) affecting a 15-year-old Indian child.
Autosomal recessive; iduronidase; mucopolysaccharidosis
Mucopolysaccharidosis type I (MPS I) arises from a deficiency in the α-L-iduronidase (IDUA) enzyme. Although the clinical spectrum in MPS I patients is continuous, it was possible to recognize 3 phenotypes reflecting the severity of symptoms, viz., the Hurler, Scheie and Hurler/Scheie syndromes. In this study, 10 unrelated Chinese MPS I families (nine Hurler and one Hurler/Scheie) were investigated, and 16 mutant alleles were identified. Three novel mutations in IDUA genes, one missense p.R363H (c.1088G > A) and two splice-site mutations (c.1190-1G > A and c.792+1G > T), were found. Notably, 45% (nine out of 20) and 30% (six out of 20) of the mutant alleles in the 10 families studied were c.1190-1G > A and c.792+1G > T, respectively. The novel missense mutation p.R363H was transiently expressed in CHO cells, and showed retention of 2.3% IDUA activity. Neither p.W402X nor p.Q70X associated with the Hurler phenotype, or even p.R89Q associated with the Scheie phenotype, was found in this group. Finally, it was noted that the Chinese MPS I patients proved to be characterized with a unique set of IDUA gene mutations, not only entirely different from those encountered among Europeans and Americans, but also apparently not even the same as those found in other Asian countries.
mucopolysaccharidosis type I; α-L-iduronidase; mutation; polymorphism
Scheie syndrome is the most attenuated and rarest form of mucopolysaccharidosis type I (MPS I), an inherited lysosomal storage disorder. Only small patient series have previously been reported. Using natural history data from the uniquely large population of 78 Scheie patients enrolled in the MPS I Registry, we characterized the onset and prevalence of clinical manifestations and explored reasons for delayed diagnosis of the disease. Median patient age was 17.5 years; 46% of the patients were male, and 88% were Caucasian. Of 25 MPS I-related clinical features, cardiac valve abnormalities, joint contractures, and corneal clouding were each reported by >80% and all three by 53% of patients. Carpal tunnel syndrome, hernia, coarse facial features, and hepatomegaly were each reported by >50% of patients. Age at onset of the clinical features varied widely between individuals, but the median age at onset was 3 years for hernia and between 5 and 12 years for most features, including coarse facial features, hepatomegaly, joint contractures, bone deformities, cardiac valve abnormalities, cognitive impairment, and corneal clouding. Carpal tunnel syndrome, cardiomyopathy, and myelopathy arose more commonly during adolescence or adulthood. Delays up to 47 years intervened between symptom onset and disease diagnosis, and the longest delays were associated with later age at symptom onset and symptom onset before 1980. In summary, Scheie syndrome usually emerges during childhood, and recognition of attenuated MPS I requires awareness of the multisystemic disease manifestations and their diverse presentation. Given the availability of etiologic treatment, prompt diagnosis is important.
Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder that results in the accumulation of glycosaminoglycans causing progressive multi-organ dysfunction. Its clinical spectrum is very broad and varies from the severe Hurler phenotype (MPS I-H) which is characterized by early and progressive central nervous system (CNS) involvement to the attenuated Scheie phenotype (MPS I-S) with no CNS involvement. Indication, optimal timing, safety and efficacy of the two available treatment options for MPS I, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT), are subject to continuing debate. A European consensus procedure was organized to reach consensus about the use of these two treatment strategies.
A panel of specialists, including 8 specialists for metabolic disorders and 7 bone marrow transplant physicians, all with acknowledged expertise in MPS I, participated in a modified Delphi process to develop consensus-based statements on MPS I treatment. Fifteen MPS I case histories were used to initiate the discussion and to anchor decisions around either treatment mode. Before and at the meeting all experts gave their opinion on the cases (YES/NO transplantation) and reasons for their decisions were collected. A set of draft statements on MPS I treatment options composed by a planning committee were discussed and revised during the meeting until full consensus.
Full consensus was reached on several important issues, including the following: 1) The preferred treatment for patients with MPS I-H diagnosed before age 2.5 yrs is HSCT; 2) In individual patients with an intermediate phenotype HSCT may be considered if there is a suitable donor. However, there are no data on efficacy of HSCT in patients with this phenotype; 3) All MPS I patients including those who have not been transplanted or whose graft has failed may benefit significantly from ERT; 4) ERT should be started at diagnosis and may be of value in patients awaiting HSCT.
This multidisciplinary consensus procedure yielded consensus on the main issues related to therapeutic choices and research for MPS I. This is an important step towards an international, collaborative approach, the only way to obtain useful evidence in rare diseases.
Biochemical and pathological observations on tissues from two patients with Hurler disease (mucopolysaccharidosis IH; alpha-L-iduronidase deficiency) who had been treated by fibroblast transplants as a means of enzyme replacement treatment are reported. These results and those obtained in three surgical specimens [ligamentum flavum with dura mater from a case of Scheie disease (mucopolysaccharidosis IS; alpha-L-iduronidase deficiency); a fetus with Hurler disease; and tonsil from a patient with Hunter disease (mucopolysaccharidosis II; alpha-L-idurono-2-sulphate sulphatase deficiency)] illustrate the inadequacy of routine histological processing to demonstrate the abnormal glycosaminoglycan accumulation in this group of diseases. A combined approach using histochemistry and electron microscopy enables the extent of both extracellular and intracellular involvement to be assessed. The fetus (20 wk gestation) already showed evidence of Hurler disease. The pathological appearances in both of the fibroblast-transplanted patients were those which would have been expected in patients dying with unmodified Hurler disease. There was no detectable alpha-L-iduronidase activity in the brain, liver, kidney or in fibroblasts cultured from either the transplantation sites or from remote subcutaneous sites in either of the transplanted patients. These results are discussed from the viewpoint of their bearing on the pathophysiology of the mucopolysaccharidoses and proposals for their treatment by enzyme replacement.
The enzymatic and immunologic properties of the defective residual alpha-L-iduronidase activities were investigated in fibroblast extracts from the three subtypes of mucopolysaccharidosis type I, Hurler (MPS IH), Scheie (MPS IS), and Hurler-Scheie (MPS IH-S) diseases. Using 4-methylumbelliferyl-alpha-L-iduronide (4MU-alpha-Id), the activities in fibroblast extracts from all three subtypes were less than 0.1% of normal. Rocket immunoelectrophoresis with monospecific rabbit anti-human alpha-L-iduronidase polyclonal antibodies, as well as immunoblots using a monoclonal antibody, revealed the presence of cross-reactive immunologic material (CRIM) in extracts prepared from each subtype. When the samples were equalized for beta-hexosaminidase A activity, 38-105% of normal enzyme protein was detected. The sequential addition of cystamine, MgCl2 and pyridoxal phosphate increased the residual 4MU-alpha-Id activities in subtype extracts up to about 35% of normal mean fibroblast activity. Cystamine, MgCl2 or pyridoxal phosphate alone enhanced the residual activities two- to fourfold, whereas the sequential addition of all three compounds was required for maximal effect. Of the six B6 vitamers evaluated, only the negatively charged forms, pyridoxamine (PLN), pyridoxamine phosphate (PNP), and pyridoxal phosphate (PLP), stimulated the residual activities. The addition of dermatan sulfate or heparan sulfate to the subtype extracts, followed by treatment with the effector compounds, similarly inhibited both the normal and enhanced MPS I activities. Heat inactivation experiments confirmed the fact that the mutant iduronidase activity was reconstituted and that the observed increase in enzymatic activity was not an artifact of the fluorogenic assay. These results suggest that the presence of certain thiol reducing agents, divalent cations and negatively charged B6 vitamers can alter the conformation of the mutant alpha-L-iduronidase in vitro such that the hydrolysis of 4MU-alpha-Id is enhanced into the heterozygote range.
Mucopolysaccharidosis type I (MPS I) is traditionally divided into three phenotypes: the severe Hurler (MPS I-H) phenotype, the intermediate Hurler-Scheie (MPS I-H/S) phenotype and the attenuated Scheie (MPS I-S) phenotype. However, there are no clear criteria for delineating the different phenotypes. Because decisions about optimal treatment (enzyme replacement therapy or hematopoietic stem cell transplantation) need to be made quickly and depend on the presumed phenotype, an assessment of phenotypic severity should be performed soon after diagnosis. Therefore, a numerical severity scale for classifying different MPS I phenotypes at diagnosis based on clinical signs and symptoms was developed.
A consensus procedure based on a combined modified Delphi method and a nominal group technique was undertaken. It consisted of two written rounds and a face-to-face meeting. Sixteen MPS I experts participated in the process. The main goal was to identify the most important indicators of phenotypic severity and include these in a numerical severity scale. The correlation between the median subjective expert MPS I rating and the scores derived from this severity scale was used as an indicator of validity.
Full consensus was reached on six key clinical items for assessing severity: age of onset of signs and symptoms, developmental delay, joint stiffness/arthropathy/contractures, kyphosis, cardiomyopathy and large head/frontal bossing. Due to the remarkably large variability in the expert MPS I assessments, however, a reliable numerical scale could not be constructed. Because of this variability, such a scale would always result in patients whose calculated severity score differed unacceptably from the median expert severity score, which was considered to be the 'gold standard'.
Although consensus was reached on the six key items for assessing phenotypic severity in MPS I, expert opinion on phenotypic severity at diagnosis proved to be highly variable. This subjectivity emphasizes the need for validated biomarkers and improved genotype-phenotype correlations that can be incorporated into phenotypic severity assessments at diagnosis.
Mucopolysaccharidosis type I; Iduronidase; Classification; Consensus; Phenotype; Hematopoietic stem cell transplantation
Five dogs with mucopolysaccharidosis I, a model of human Hurler/Scheie syndrome, were transplanted with marrow from phenotypically normal littermates at 5 mo of age. At 3 and 9 mo posttransplantation, biopsies of cerebral cortex, liver, and cerebrospinal fluid were obtained. The alpha-L-iduronidase levels in these tissues were 0.8-7.4, 26-45, and 6.3-14.9% of the paired donor tissues, respectively. Although iduronidase was present in relatively low levels in the recipients' brains and cerebrospinal fluid at both biopsy times, reduction in brain glycosaminoglycan (GAG) was comparable to that observed in liver. Ultrastructural studies of cells within the transplanted dogs' brains showed less lysosomal distension and storage product than in affected, nontransplanted, littermate controls. The most marked clearing of stored GAG was in cells surrounding blood vessels, but decreased lysosomal storage in neurons and glial cells was also observed. Urinary GAG excretion also decreased to near normal levels by 5 mo posttransplantation.
The urinary excretion of glycosaminoglycans in 28 cases of gargoylism, embracing the Hurler, Hunter, Sanfilippo, Morquio, and Scheie syndromes (McKusick, 1966), has been examined using the cetylpyridinium chloride (CPC) turbidity test, the uronic acid/creatinine ratio, and the electrophoretic pattern of urine concentrates, as routine procedures. Ion-exchange column chromatographic techniques were also employed for the fractionation of glycosaminoglycans and aminosugars. Molecular weights were investigated by gel filtration and ultracentrifugation.
The CPC turbidity test was positive in every case. The uronic acid/creatinine ratio provided a sensitive index of increased glycosaminoglycan excretion. Cases of the Hurler syndrome showed the highest, and cases of the Morquio and Scheie syndromes the lowest, ratios. A correlation was observed between the uronic acid/creatinine ratio and the clinical severity of the disease. Cellulose acetate electrophoresis differentiated clearly between the two major forms of gargoylism, the Hurler and Sanfilippo syndromes, but differentiation between the Hurler, Hunter, and Scheie syndromes was more difficult on electrophoretic data alone. Results obtained with cases diagnosed as the Morquio syndrome were disappointing. The existence of formes frustes of the Sanfilippo syndrome among the mentally subnormal is predicted. Errors caused by bacterial contamination of urine samples are emphasized. The atypical behaviour of urinary glycosaminoglycans in analytical procedures is discussed. Molecular weight studies suggested heterogeneity. The nature of the basic defect in gargoylism is discussed.
A 5-year-old Caucasian girl with known Hurler-Scheie's syndrome (mucopolysaccharidosis) developed a right Brown's syndrome while under orthoptic review. There was no evidence of trauma or inflammation of the superior oblique tendon, trochlea, or surrounding tissues. The Brown's syndrome in this case may be due to shortening of the superior oblique tendon, associated with the shortening of long tendons of the arms and feet, which is common in Hurler-Scheie's syndrome.
To characterize the pathogenic mutations causing mucopolysaccharidosis type I (MPS I) in two Thai patients: one with Hurler syndrome (MPS IH), the most severe form, and the other with Scheie syndrome (MPS IS), the mildest. Both presented with distinctive phenotype including corneal clouding.
The entire coding regions of the α-L-iduronidase (IDUA) gene were amplified by PCR and sequenced. Functional characterization of the mutant IDUA was determined by transient transfection of the construct into COS-7 cells.
Mutation analyses revealed that the MPS IH patient was homozygous for a previously reported mutation, c.252insC, while the MPS IS patient was found to harbor a novel c.826G>A (p.E276K) mutation. The novel p.E276K mutation was not detected in 100 unaffected ethnic-matched control chromosomes. In addition, the glutamic acid residue at codon 276 was located at a well conserved residue. Transient transfection of the p.E276K construct revealed a significant reduction of IDUA activity compared to that of the wild-type IDUA suggesting it as a disease-causing mutation.
This study reports a novel mutation, expanding the mutational spectrum for MPS I.
Suppression therapy utilizes compounds that suppress translation termination at in-frame premature termination codons (PTCs) to restore full-length, functional protein. This approach may provide a treatment for diseases caused by nonsense mutations such as mucopolysaccharidosis type I-Hurler (MPS I-H). MPS I-H is a lysosomal storage disease caused by severe α-L-iduronidase deficiency and subsequent lysosomal glycosaminoglycan (GAG) accumulation. MPS I-H represents a good target for suppression therapy because the majority of MPS I-H patients carry nonsense mutations, and restoration of even a small amount of functional α-L-iduronidase may attenuate the MPS I-H phenotype. In this study, we investigated the efficiency of suppression therapy agents to suppress the Idua-W392X nonsense mutation in an MPS I-H mouse model. The drugs tested included the conventional aminoglycosides gentamicin, G418, amikacin, and paromomycin. In addition, the designer aminoglycosides NB54 and NB84, two compounds previously designed to mediate efficient PTC suppression with reduced toxicity, were also examined. Overall, NB84 suppressed the Idua-W392X nonsense mutation much more efficiently than any of the other compounds tested. NB84 treatment restored enough functional α-L-iduronidase activity to partially reverse abnormal GAG accumulation and lysosomal abundance in mouse embryonic fibroblasts derived from the Idua-W392X mouse. Finally, in vivo administration of NB84 to Idua-W392X mice significantly reduced urine GAG excretion and tissue GAG storage. Together, these results suggest that NB84-mediated suppression therapy has the potential to attenuate the MPS I-H disease phenotype.
Here we report the characterization of a knock-in mouse model for the autosomal recessive disorder mucopolysaccharidosis type I-Hurler (MPS I-H), also known as Hurler syndrome. MPS I-H is the most severe form of α-L-iduronidase deficiency. α-L-iduronidase (encoded by the IDUA gene) is a lysosomal enzyme that participates in the degradation of dermatan sulfate and heparan sulfate. Using gene replacement methodology, a nucleotide change was introduced into the mouse Idua locus that resulted in a nonsense mutation at codon W392. The Idua-W392X mutation is analogous to the human IDUA-W402X mutation commonly found in MPS I-H patients. We found that the phenotype in homozygous Idua-W392X mice closely correlated with the human MPS I-H disease. Homozygous W392X mice showed no detectable α-L-iduronidase activity. We observed a defect in GAG degradation as evidenced by an increase in sulfated GAGs excreted in the urine and stored in multiple tissues. Histology and electron microscopy also revealed evidence of GAG storage in all tissues examined. Additional assessment revealed bone abnormalities and altered metabolism within the Idua-W392X mouse. This new mouse will provide an important tool to investigate therapeutic approaches for MPS I-H that cannot be addressed using current MPS I-H animal models.
MPS I; Hurler syndrome; mouse; W402X mutation; α-L-iduronidase
An adolescent with Hurler-Scheie syndrome is reported. This now 15 year-old-young woman was initially diagnosed at age 4. She was assessed for neurocognitive functioning at ages 5, 13, and 15 years. Results show a significant decline in intellectual functioning from the superior range to the average range from age 5 to age 13, and then no change from age 13 to age 15. The relationship between Hurler-Scheie syndrome, premorbid intellectual functioning, and cognitive–behavioral interventions are discussed in light of the longitudinal neurocognitive effects of this disease.
Hurler-Scheie syndrome; adolescent; neurocognitive function
An 18-year-old student presented with a two-year history of daytime sleepiness and noisy breathing during sleep. Both he and his brother, aged 25 years, had Scheie's syndrome, a mucopolysaccharidosis characterised by small stature, micrognathia, corneal clouding, hepatosplenomegaly, raised urinary mucopolysaccharides, and undetectable levels of alpha-L-iduronidase assayed in cultured fibroblasts. Both brothers had sleep apnoea (apnoea index, 59 and 35 respectively) during which there was a significant fall in heart rate and arterial oxygen saturation. One brother had EEG changes suggestive of cerebral hypoxia and the other had ventricular extrasystoles at the end of several episodes. Tracheostomy in the younger brother produced a dramatic symptomatic improvement and reduced the number and severity of apnoeic episodes (post-tracheostomy apnoea index 2.4).
The introduction of hematopoietic stem cell transplantation (HSCT) has significantly improved the life-span of Hurler patients (mucopolysaccharidosis type I-H, MPS I-H). Yet, the musculoskeletal manifestations seem largely unresponsive to HSCT. In order to facilitate evidence based management, the aim of the current study was to give a systematic overview of the orthopaedic complications and motor functioning of Hurler’s patients after HSCT.
A systematic review was conducted of the medical literature published from January 1981 to June 2010. Two reviewers independently assessed all eligible citations, as identified from the Pubmed and Embase databases. A pre-developed data extraction form was used to systematically collect information on the prevalence of radiological and clinical signs, and on the orthopaedic treatments and outcomes.
A total of 32 studies, including 399 patient reports were identified. The most frequent musculoskeletal abnormalities were odontoid hypoplasia (72%), thoracolumbar kyphosis (81%), genu valgum (70%), hip dysplasia (90%) and carpal tunnel syndrome (63%), which were often treated surgically during the first decade of life. The overall complication rate of surgical interventions was 13.5%. Motor functioning was further hampered due to reduced joint mobility, hand dexterity, motor development and longitudinal growth.
Stem cell transplantation does not halt the progression of a large range of disabling musculoskeletal abnormalities in Hurler’s disease. Although prospective data on the quantification, progression and treatment of these deformities were very limited, early surgical intervention is often advocated. Prospective data collection will be mandatory to achieve better evidence on the effect of treatment strategies.
Treatment of brain disease with recombinant proteins is difficult due to the blood-brain barrier. As an alternative to direct injections into the brain, we studied whether application of high concentrations of therapeutic enzymes via intrathecal (IT) injections could successfully drive uptake across the ependyma to treat brain disease. We studied IT enzyme replacement therapy with recombinant human iduronidase (rhIDU) in canine mucopolysaccharidosis I (MPS I, Hurler syndrome), a lysosomal storage disorder with brain and meningeal involvement. Monthly or quarterly IT treatment regimens with rhIDU achieved supranormal iduronidase enzyme levels in the brain, spinal cord, and spinal meninges. All regimens normalized total brain glycosaminoglycan (GAG) storage and reduced spinal meningeal GAG storage by 58–70%. The improvement in GAG storage levels persisted three months after the final IT dose. The successful use of enzyme therapy via the CSF represents a potentially useful approach for lysosomal storage disorders.
Mucopolysaccharidosis I; lysosomal storage disorder; intrathecal; enzyme replacement therapy; central nervous system; cerebrospinal fluid; Hurler; Scheie; Hurler-Scheie; pachymeningitis
Hurler syndrome (MPS-IH) is a rare autosomal recessive lysosomal storage disease. Besides a variety of other features, Hurler syndrome is characterized by a range of skeletal abnormalities known as dysostosis multiplex. Despite the successful effect of haematopoietic stem cell transplantation on the other features, dysostosis remains a disabling symptom of the disease. This study analyzed the status and development of the orthopaedic manifestations of 14 Dutch Hurler patients after stem cell transplantation.
Data were obtained retrospectively by reviewing patients’ charts, radiographs and MRIs. Existing methods to measure the deficiencies were modified to optimally address the dysostosis. These measurements were done by two of the authors independently. The odontoïd/body ratio, kyphotic angle, scoliotic angle and parameters for hip dysplasia and genu valgum were measured and plotted against age. The degree of progression was determined. The intraclass correlation coefficient (ICC) was calculated to determine the reliability of the measurements.
All patients showed hypoplasia of the odontoïd, which significantly improved during growth. Kyphosis in the thoracolumbar area was present in 13 patients and proved to be progressive. Scoliosis was observed in eight patients. Hip dysplasia was present in all patients and showed no tendency of improvement. In all but one patient, knee valgus remained more than two standard deviations above normal.
Dysostosis remains a major problem after haematopoietic stem cell transplantation in Hurler patients. Moreover, except for dens hypoplasia, it appears to be progressive and therefore surgical interventions may be necessary in the majority of these patients.
The electron microscopic appearances of the corneoscleral and iris tissue removed at operation from a child with Hurler disease and glaucoma showed distinctive swollen cells with intracellular inclusions similar to those which are observed in other tissues in these patients and which are due to abnormal lysosomal storages of mucopolysaccharides. Some recent observations on the possible relationship between mucopolysaccharides and the drainage of fluid from the anterior chamber are briefly reviewed and correlated with the present observations. The development of glaucoma in this patient is thought to be associated with the presence of the mucopolysaccharide-containing cells in the region of the aqueous drainage channels.
The complementary and genomic DNA segments of the alpha-L-iduronidase gene from two Chinese mucopolysaccharidosis type I Hurler/Scheie (MPS IH/S) patients were amplified by polymerase chain reaction (PCR) and DNA sequencing was done to study their molecular lesions. Patient W3 has heterozygous mutations; the maternal allele has M1I (G to A transition in the initiation codon ATG) and the paternal allele has Y343X (C to G transversion in exon 8 leading to in frame deletion of codons 325-343 from the mRNA owing to false splicing). Patient W2 is homozygous for mutation T364M (C to T transition in codon 364). The mutation was paternally inherited. A de novo deletion or gene conversion event may have resulted in apparent homozygosity for T364M. Expression of Y343X and T364M showed trace amounts of alpha-L-iduronidase activity compared to that of normal cDNA upon transfection into COS-7 cells.
Mucolipidosis II (ML II) or inclusion cell disease (I-cell disease) is a rarely occurring autosomal recessive lysosomal enzyme-targeting disease. This disease is usually found to occur in individuals aged between 6 and 12 months, with a clinical phenotype resembling that of Hurler syndrome and radiological findings resembling those of dysostosis multiplex. However, we encountered a rare case of an infant with ML II who presented with prenatal skeletal dysplasia and typical clinical features of severe secondary hyperparathyroidism at birth. A female infant was born at 37+1 weeks of gestation with a birth weight of 1,690 g (<3rd percentile). Prenatal ultrasonographic findings revealed intrauterine growth retardation and skeletal dysplasia. At birth, the patient had characteristic features of ML II, and skeletal radiographs revealed dysostosis multiplex, similar to rickets. In addition, the patient had high levels of alkaline phosphatase and parathyroid hormone, consistent with severe secondary neonatal hyperparathyroidism. The activities of β-D-hexosaminidase and α-N-acetylglucosaminidase were moderately decreased in the leukocytes but were 5- to 10-fold higher in the plasma. Examination of a placental biopsy specimen showed foamy vacuolar changes in trophoblasts and syncytiotrophoblasts. The diagnosis of ML II was confirmed via GNPTAB genetic testing, which revealed compound heterozygosity of c.3091C>T (p.Arg1031X) and c.3456_3459dupCAAC (p.Ile1154GlnfsX3), the latter being a novel mutation. The infant was treated with vitamin D supplements but expired because of asphyxia at the age of 2 months.
Mucolipidosis; Newborn infant; Secondary hyperparathyroidism; Enzyme assays; Human GNPTAB protein
Structures of tert-butylcarbamate ions in the gas phase and methanol solution were studied for simple secondary and tertiary carbamates as well as for carbamate-containing products and internal standards for lysosomal enzyme assays used in newborn screening of a α-galactosidase A deficiency (GLA, Fabry disease), mucopolysaccharidosis I (Hurler disease), and mucopolysaccharidosis II (Hunter disease). Protonation of simple t-butylcarbamates can occur at the carbonyl group which is the preferred site in the gas phase. Protonation in methanol solution is more favorable if occurring at the carbamate nitrogen atom. Protonation of more complex t-butylcarbamates occurs at amide and carbamate carbonyl groups, and the ions are stabilized by intramolecular hydrogen bonding which is affected by solvation. Tertiary carbamates containing aminophenol amide groups were calculated to have substantially greater gas-phase basicities than secondary carbamates containing coumarin amide groups. The main diagnostically important ion dissociation by elimination of 2-methylpropene (isobutylene, i-C4H8) and carbon dioxide is shown by experiment and theory to proceed in two steps. Energy-resolved collision-induced dissociation of the Hurler’s disease enzymatic product ion, which is a coumarin-diamine linker-t-butylcarbamate conjugate (3a+), indicated separate energy thresholds for the loss of i-C4H8 and CO2. Computational investigation of the potential energy surface along two presumed reaction pathways indicated kinetic preference for the migration of a t-butyl hydrogen atom to the carbamate carbonyl resulting in the isobutylene loss. The consequent loss of CO2 required further proton migrations that had to overcome energy barriers.