Mucopolysaccharidosis Type I: Current Treatments, Limitations, and Prospects for Improvement.
ABSTRACT: Mucopolysaccharidosis type I (MPS I) is a lysosomal disease, caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA). IDUA catalyzes the degradation of the glycosaminoglycans dermatan and heparan sulfate (DS and HS, respectively). Lack of the enzyme leads to pathologic accumulation of undegraded HS and DS with subsequent disease manifestations in multiple organs. The disease can be divided into severe (Hurler syndrome) and attenuated (Hurler-Scheie, Scheie) forms. Currently approved treatments consist of enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). Patients with attenuated disease are often treated with ERT alone, while the recommended therapy for patients with Hurler syndrome consists of HSCT. While these treatments significantly improve disease manifestations and prolong life, a considerable burden of disease remains. Notably, treatment can partially prevent, but not significantly improve, clinical manifestations, necessitating early diagnosis of disease and commencement of treatment. This review discusses these standard therapies and their impact on common disease manifestations in patients with MPS I. Where relevant, results of animal models of MPS I will be included. Finally, we highlight alternative and emerging treatments for the most common disease manifestations.
Project description:<h4>Background</h4>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.<h4>Methods</h4>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)].<h4>Results</h4>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%.<h4>Conclusion</h4>These data highlight important differences in MPS I patients between Latin America and ROW in terms of phenotypic distribution, clinical manifestations, and treatment practices.
Project description:Mucopolysaccharidosis type I (MPS I) is caused by deficiency of ?-l-iduronidase (IDUA), a lysosomal enzyme involved in the breakdown and recycling of glycosaminoglycans (GAGs). Although enzyme replacement therapy is available, the efficacy of the treatment for neuropathic manifestations is limited. To facilitate drug discovery and model disease pathophysiology, we generated neural stem cells (NSCs) from MPS I patient-derived induced pluripotent stem cells (iPSCs). The NSCs exhibited characteristic disease phenotypes with deficiency of IDUA, accumulation of GAGs and enlargement of lysosomes, in agreement with the severity of clinical subgroups of MPS I. Transcriptome profiling of NSCs revealed 429 genes that demonstrated a more extensive change in expression in the most severe Hurler syndrome subgroup compared to the intermediate Hurler-Scheie or the least severe Scheie syndrome subgroups. Clustering and pathway analysis revealed high concordance of the severity of neurological defects with marked dysregulation of GAG biosynthesis, GAG degradation, lysosomal function and autophagy. Gene ontology (GO) analysis identified a dramatic upregulation of the autophagy pathway, especially in the Hurler syndrome subgroup. We conclude that GAG accumulation in the patient-derived cells disrupts lysosomal homeostasis, affecting multiple related cellular pathways in response to IDUA deficiency. These dysregulated processes likely lead to enhanced autophagy and progressively severe disease states. Our study provides potentially useful targets for clinical biomarker development, disease diagnosis and prognosis, and drug discovery.
Project description:Mucopolysaccharidosis type I (MPS I, Hurler and Scheie syndromes) is an autosomal recessive lysosomal storage disorder that results from a deficiency of the hydrolase alpha-L-iduronidase (IDUA) which is involved in the lysosomal degradation of both heparan sulphate (HS) and dermatan sulphate (DS). Patients with MPS I store and excrete large amounts of partially degraded HS and DS. In order to evaluate enzyme replacement therapy for MPS I patients we have expressed human IDUA cDNA in Chinese Hamster Ovary (CHO)-K1 cells utilizing a plasmid vector that places the cDNA under the transcriptional control of the human polypeptide-chain-elongation factor I alpha gene promoter. A clonal cell-line that secreted recombinant IDUA in a precursor form at approximately 2.2 micrograms/10(6) cells per day was identified. This enzyme was shown to be endocytosed into cultured MPS I fibroblasts via mannose-6-phosphate receptors and to correct the storage phenotype of these cells by enabling the lysosomal-digestion of accumulated sulphated glycosaminoglycans. The recombinant IDUA had on SDS/PAGE a molecular mass of 85 kDa and was processed to 74 kDa and smaller forms following its uptake by fibroblasts. Milligram quantities of the recombinant IDUA were immunopurified and the enzyme was shown to have pH optimum and kinetic parameters differing from those of the mature enzyme purified from human liver. The specific activity of the recombinant enzyme was shown to increase on dilution and on incubation with reducing agents. This was in contrast to the mature IDUA form (74 kDa) which did not have its activity stimulated by reducing agents or dilution.
Project description:BACKGROUND:The mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease resulting from the defective activity of the enzyme ?-L-iduronidase (IDUA). The disease has three major clinical subtypes (severe Hurler syndrome, intermediate Hurler-Scheie syndrome and attenuated Scheie syndrome). We aim to identify the genetic variants in MPS I patients and to investigate the effect of the novel splice site mutation on splicing of IDUA- mRNA variability using bioinformatics tools. METHODS:The IDUA mutations were determined in four MPS I patients from four families from Northern Tunisia, by amplifying and sequencing each of the IDUA exons and intron-exon junctions. RESULTS:One novel splice site IDUA mutation, c.1650?+?1G?>?T in intron 11 and two previously reported mutations, p.A75T and p.R555H, were detected. The patients in families 1 and 2 who have the Hurler phenotype were homozygotes for the novel splice site mutation c.1650?+?1G?>?T. The patient in family 3, who also had the Hurler phenotype, was a compound heterozygote for the novel splice site mutation c.1650?+?1G?>?T and for the previously reported missense mutation p.A75T. The patient in family 4 who had the Hurler-Scheie phenotype was a compound heterozygote for the novel splice site mutation c.1650?+?1G?>?T and for the previously reported missense mutation p.R555H. In addition, four known IDUA polymorphisms were identified. Bioinformatics tools allowed us to associate the variant c.1650?+?1G?>?T with the severe clinical phenotype of MPS I. This variant affects the essential nucleotide +?1 (G to T) of the donor splice site of IDUA intron 11. The G?>?T in intron 11 leads to wild type donor site broken with minus 19.97% value compared to normal value with 0%, hence the new splice site acceptor has plus 5.59%. CONCLUSIONS:The present findings indicate that the identified mutations facilitate the accurate carrier detection (genetic counseling of at-risk relatives) and the molecular prenatal diagnosis in Tunisia.
Project description:Mucopolysaccharidosis (MPS) type I and II are two closely related lysosomal storage diseases associated with disrupted glycosaminoglycan catabolism. In MPS II, the first step of degradation of heparan sulfate (HS) and dermatan sulfate (DS) is blocked by a deficiency in the lysosomal enzyme iduronate 2-sulfatase (IDS), while, in MPS I, blockage of the second step is caused by a deficiency in iduronidase (IDUA). The subsequent accumulation of HS and DS causes lysosomal hypertrophy and an increase in the number of lysosomes in cells, and impacts cellular functions, like cell adhesion, endocytosis, intracellular trafficking of different molecules, intracellular ionic balance, and inflammation. Characteristic phenotypical manifestations of both MPS I and II include skeletal disease, reflected in short stature, inguinal and umbilical hernias, hydrocephalus, hearing loss, coarse facial features, protruded abdomen with hepatosplenomegaly, and neurological involvement with varying functional concerns. However, a few manifestations are disease-specific, including corneal clouding in MPS I, epidermal manifestations in MPS II, and differences in the severity and nature of behavioral concerns. These phenotypic differences appear to be related to different ratios between DS and HS, and their sulfation levels. MPS I is characterized by higher DS/HS levels and lower sulfation levels, while HS levels dominate over DS levels in MPS II and sulfation levels are higher. The high presence of DS in the cornea and its involvement in the arrangement of collagen fibrils potentially causes corneal clouding to be prevalent in MPS I, but not in MPS II. The differences in neurological involvement may be due to the increased HS levels in MPS II, because of the involvement of HS in neuronal development. Current treatment options for patients with MPS II are often restricted to enzyme replacement therapy (ERT). While ERT has beneficial effects on respiratory and cardiopulmonary function and extends the lifespan of the patients, it does not significantly affect CNS manifestations, probably because the enzyme cannot pass the blood-brain barrier at sufficient levels. Many experimental therapies, therefore, aim at delivery of IDS to the CNS in an attempt to prevent neurocognitive decline in the patients.
Project description:Mucopolysaccharidosis type I (MPS I) is caused by genetic defects in alpha-L-iduronidase (IDUA), a lysosomal enzyme involved in the breakdown and recycling of glycosaminoglycans (GAGs). Although an enzyme replacement therapy is available, the efficacy for the treatment of neuropathic symptoms is limited. To facilitate drug discovery and model disease pathophysiology, we have generated neural stem cells (NSCs) from MPS I patient-derived iPSCs. NSCs exhibited characteristic disease phenotypes with deficiency of alpha-L-iduronidase (IDUA), accumulation of glycosaminoglycans (GAGs) and enlargement of lysosomes, correlating with the severity of clinical symptoms. Transcriptome profiling of NSCs revealed differential expression of 429 genes that changed more extensively in the more severe Hurler syndrome subgroup compared to the Hurler-Scheie (median severe) and Scheie (less severe) subgroups. Clustering and pathway analyses demonstrated high concordance of the severity of neurological defects with marked dysregulation of GAG biosynthesis and degradation, lysosomal function and extracellular matrix. Gene Ontology (GO) analysis identified a dramatic upregulation of autophagy pathway, especially in the Hurler syndrome. Thus, GAG accumulation in the patient cells disrupts lysosomal homeostasis affecting multiple related cellular pathways which compensates for IDUA deficiency. These dysregulated process likely lead to enhanced autophagy and more severe disease states. Our studies provide useful tools for clinical biomarker development and potential targets for drug development. Overall design: Patient iPSC-derived and control neural stem cells from Scheie, Hurler-Scheie, and Hurler disease were expression profiled in triplicate using RNA-seq.
Project description:BACKGROUND:Mucopolysaccharidosis type I (MPS I) is a rare autosomal storage disorder resulting from the defective alpha-L-iduronidase (encoded by IDUA) enzyme activity and accumulation of glycosaminoglycans (GAGs) in lysosomes. So far, more than 100 IDUA causative mutations have been identified leading to three MPS I phenotypic subtypes: Hurler syndrome (severe form), Hurler/Scheie syndrome (intermediate form), and Scheie syndrome (mild form). METHODS:Whole-exome sequencing (WES) was performed to identify the underlying genetic mutations. To verify the identified variations, Sanger sequencing was performed for all available family members following PCR amplification. The impact on IDUA protein was analyzed by sequential analysis and homology modeling. RESULTS:A novel IDUA heterozygous single base insertion (c.1815dupT, p.V606Cfs51* ) and a known missence mutation (c.T1037G, p.L346R) were detected in our patient diagnosed as congenital heart disease with heart valve abnormalities. The novel frameshift mutation results in a complete loss of 48 amino acids in the Ig-like domain and causes the formation of a putative protein product which might affect the IDUA enzyme activity. CONCLUSIONS:A novel compound heterozygous IDUA mutation (c.1815dupT, p.V606Cfs51* ) was found in a Chinese MPS I family. The identification of the mutation facilitated accurate genetic counseling and precise medical intervention for MPS I in China.
Project description:Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder resulting from pathogenic variants in the ?-L-iduronidase (IDUA) gene. Clinical phenotypes range from severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes) and vary in age of onset, severity, and rate of progression. Defining the phenotype at diagnosis is essential for disease management. To date, no systematic analysis of genotype-phenotype correlation in large MPS I cohorts have been performed. Understanding genotype-phenotype is critical now that newborn screening for MPS I is being implemented. Data from 538 patients from the MPS I Registry (380 severe, 158 attenuated) who had 2 IDUA alleles identified were examined. In the 1076 alleles identified, 148 pathogenic variants were reported; of those, 75 were unique. Of the 538 genotypes, 147 (27%) were unique; 40% of patients with attenuated and 22% of patients with severe MPS I had unique genotypes. About 67.6% of severe patients had genotypes where both variants identified are predicted to severely disrupt protein/gene function and 96.1% of attenuated patients had at least one missense or intronic variant. This dataset illustrates a close genotype/phenotype correlation in MPS I but the presence of unique IDUA missense variants remains a challenge for disease prediction.
Project description:Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder that is caused by a deficiency of the enzyme alpha-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.
Project description:PURPOSE: 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. METHODS: The entire coding regions of the ?-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. RESULTS: 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. CONCLUSIONS: This study reports a novel mutation, expanding the mutational spectrum for MPS I.