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PubMed1984

Morphologic and biochemical studies of canine mucopolysaccharidosis I.

This report presents the necropsy and biochemical findings on the first dog to die with alpha-L-iduronidase deficiency (mucopolysaccharidosis I, MPS I). Gross pathologic features, light- and electron-microscopic findings, and tissue enzyme, glycosaminoglycan (GAG), and sphingolipid levels are compared with the human disease counterpart and the previously described feline model. Results lend further support for the similarities of the canine disease and human MPS I.

Animals↗
PubMed1995

Generation of a mammalian cell line deficient in glucose-regulated protein stress induction through targeted ribozyme driven by a stress-inducible promoter.

GRP94 is an endoplasmic reticulum (ER) localized glycoprotein with Ca2+ binding and protein chaperoning properties. Using a ribozyme driven by a stress-inducible promoter and targeted against grp94 mRNA, we have generated a cell line deficient in its ability to induce GRP94. The effect of the ribozyme is mediated by the cleavage of the grp94 message just downstream of the initiation codon, and not by an antisense effect, as determined by the level of intact grp94 mRNA. Unexpectedly, this cell line's ability to induce GRP78 is also impaired. Transient overexpression of recombinant human lysosomal hydrolase alpha-L-iduronidase in the ribozyme expressing cells indicates that the secretion ratio of this enzyme is reduced by about 6-fold. Additionally, the ribozyme expressing cells showed increased sensitivity to Ca2+ depletion from ER caused by either A23187 or thapsigargin, an ER-Ca(2+)-ATPase inhibitor, but not to tunicamycin. These combined results show that the induction of GRP94 may play important roles in ER to nuclear signaling, protein sorting and secretion, and specific protection against Ca2+ depletion stress.

Animals↗
PubMed1976

Mucopolysaccharidosis type V. (Scheie syndrome). A postmortem study by multidisciplinary techniques with emphasis on the brain.

Multidisciplinary studies were conducted on the brain and other tissues of patients who died with the antemortem diagnosis of mucopolysaccharidosis (MPS) of one of the following types; type V, Scheie disease (MPS-V); type I, Hurler disease (MPS-I): and type II, Hunter disease (MPS-II). The principal new finding in the brain of the patient with MPS-V is the presence of lesions in the periadventitial mesenchymal tissue of the white matter, similar to those of MPS-I, while the nerve cells in MPS-V are histologically normal, in contradistinction to MPS-I, in which the neuronal abnormality is severe. Electron microscopical studies of the brain in MPS-I demonstrated numerous complex membranous inclusions in the neurons, whereas the neurons in MPS-V contained only a small number of lipofuscin-like inclusions and typical lipofuscin granules. There was a threefold increase of glycosaminoglycans (GAG) in the brain of MPS-I, but only a slight increase in the MPS-V; GAG in the liver and spleen of all patients was noticeably increased. alpha-L-iduronidase activity was not detectable in the brain and liver of patients with MPS-I and MPS-V, thus suggesting a similar enzymatic defect.

Adult↗
PubMed1993

Molecular analysis of Hurler syndrome in Druze and Muslim Arab patients in Israel: multiple allelic mutations of the IDUA gene in a small geographic area.

The mutations underlying Hurler syndrome (mucopolysaccharidosis IH) in Druze and Muslim Israeli Arab patients have been characterized. Four alleles were identified, using a combination of (a) PCR amplification of reverse-transcribed RNA or genomic DNA segments, (b) cycle sequencing of PCR products, and (c) restriction-enzyme analysis. One allele has two amino acid substitutions, Gly409-->Arg in exon 9 and Ter-->Cys in exon 14. The other three alleles have mutations in exon 2 (Tyr64-->Ter), exon 7 (Gln310-->Ter), or exon 8 (Thr366-->Pro). Transfection of mutagenized cDNAs into Cos-1 cells showed that two missense mutations, Thr366-->Pro and Ter-->Cys, permitted the expression of only trace amounts of alpha-L-iduronidase activity, whereas Gly409-->Arg permitted the expression of 60% as much enzyme as did the normal cDNA. The nonsense mutations were associated with abnormalities of RNA processing: (1) both a very low level of mRNA and skipping of exon 2 for Tyr64-->Ter and (2) utilization of a cryptic splice site for Gln310-->Ter. In all instances, the probands were found homozygous, and the parents heterozygous, for the mutant alleles, as anticipated from the consanguinity in each family. The two-mutation allele was identified in a family from Gaza; the other three alleles were found in seven families, five of them Druze, residing in a very small area of northern Israel. Since such clustering suggests a classic founder effect, the presence of three mutant alleles of the IDUA gene was unexpected.

Alleles↗
PubMed1997

Towards gene therapy of Hurler syndrome.

Allogeneic bone marrow transplantation is the most effective treatment for Hurler's syndrome. However, due to a lack of matched related donors and unacceptable morbidity of matched unrelated transplants, this therapy is not available to all patients. Therefore we have been developing an alternative approach based on transfer and expression of the normal gene in autologous bone marrow. A retroviral vector carrying the full length cDNA for alpha-L-iduronidase has been constructed and used to transduce bone marrow from patients with this disorder. A number of different gene transfer protocols have been assessed including the effect of intensive schedules of exposure of bone marrow to viral supernatant and the influence of growth factors. With these protocols we have demonstrated successful gene transfer into primitive CD34+ cells and subsequent enzyme expression in their maturing progeny. Also, using long-term bone marrow cultures, we have demonstrated high levels of enzyme expression sustained for several months. The efficiency of gene transfer has been assessed by PCR analysis of haemopoietic colonies as around 50%. No advantage has been demonstrated for the addition of growth factors or intensive viral exposure schedules. Indeed a possible disadvantage has been identified for the use of intensive transduction procedures. The enzyme is secreted into the medium and functional localisation has been demonstrated by reversal of the phenotypic effects of lysosomal storage in macrophages. This pre-clinical work forms the basis for a clinical trial of gene therapy for Hurler syndrome.

Bone Marrow Cells↗
PubMed1996

Mucopolysaccharidosis type I: identification of common mutations that cause Hurler and Scheie syndromes in Japanese populations.

alpha-L-Iduronidase (IDUA) deficiency (mucopolysaccharidosis type I; MPS-I) is an inborn error of lysosomal degradation of glycosaminoglycans that results in storage of undegraded glycosaminoglycans in lysosomes. Previous studies in Caucasian populations showed that (1) homozygosity or compound heterozygosity for the W402X and Q70X mutations are the common causes of MPS-I with a severe form (Hurler syndrome), and (2) the presence of R89Q may lead to a milder phenotype. We studied mutations in the IDUA gene from 19 MPS-I patients, including two pairs of siblings, with various clinical phenotypes (Hurler, 6 cases; Hurler/Scheie, 7 cases; Scheie, 6 cases). We report the presence of two common mutations that account for 42% of the 38 alleles in these patients. One is a novel 5-bp insertion between the thymidine at nt 704 and a cytosine at nt 705 (704ins5), which is seen only in the Japanese population. The other is a missense mutation, R89Q, which is also seen in Caucasians, although uncommonly. In the 19 Japanese MPS-I patients, the 704ins5 mutation accounted for 7 of 38 alleles (18%), while the R89Q accounted for 9 of 38 (24%). No Japanese patient was found to carry the W402X or Q70X alleles, the two most common MPS-I mutations in Caucasians. Homozygosity for the 704ins5 mutation is associated with a severe phenotype, and for the R89Q mutation with a mild phenotype. Compound heterozygosity for these two mutations produced an intermediate phenotype. Haplotype analysis using polymorphisms linked to the IDUA locus demonstrated that each mutation occurs on a different specific haplotype, suggesting that individuals with each of these common mutations derive from common founders. These data continue to document the molecular heterogeneity and racial differences in mutations in MPS-I.

Adult↗
PubMed2000

Profile of glycosaminoglycan-degrading glycosidases and glycoside sulfatases secreted by human articular chondrocytes in homeostasis and inflammation.

OBJECTIVE: To determine enzymatic activities of the 8 key glycosaminoglycan-degrading glycosidases and glycoside sulfatases in cultured human articular chondrocytes and in synovial fluid from patients with osteoarthritis. METHODS: The following enzymes were analyzed: hexosaminidase and its isoenzyme A, N-acetyl-alpha-D-glucosaminidase, beta-galactosidase, beta-glucuronidase, alpha-L-iduronidase, aryl sulfatase, and galactose-6-sulfate sulfatase. Activity of the selected enzymes was analyzed by fluorometry with the aid of 4-methylumbelliferryl derivatives of the appropriate monosaccharides. RESULTS: Hexosaminidase was found to be the dominant enzyme released by chondrocytes into the extracellular compartment. Stimulation of chondrocytes with interleukin-1beta resulted in a selective increase of the extracellular hexosaminidase activity and, to a lesser degree, of the extracellular beta-galactosidase activity, without significant changes in the activity of the other studied enzymes. Analysis of the pH dependency of the enzymatic activities revealed that even at neutral pH, hexosaminidase expressed a measurable activity, much higher than the activity of the other studied enzymes. Chondrocyte apoptosis did not result in increased extracellular glycosidase activities, including hexosaminidase activity. The spectrum of glycosidase and glycoside sulfatase activities in the synovial fluid from patients with osteoarthritis was similar to that in cultured human articular chondrocytes. CONCLUSION: These data support the concept that lysosomal glycosidases, in particular hexosaminidase, represent a distinct subset of cartilage matrix-degrading enzymes that are activated by proinflammatory stimuli.

Apoptosis↗
PubMed1989

Radiologic nosology of bone dysplasias.

The usefulness of radiodiagnostics in the delineation of bone dysplasias is exemplified by an attempt to classify the lethal osteochondrodysplasias. Based on morphologic criteria these disorders are subdivided into 11 major categories. Within these categories pathogenetically related bone dysplasia families can be discerned. Radiology meets its limits when different mutations lead to identical or overlapping phenotypes. In the future radiology will keep its prominent place in the diagnosis and nosology of inborn errors of skeletal development because of its ready availability, speed, non-invasiveness, and discriminating power. As shown by disorders such as metatropic dysplasia or iduronidase deficiency, radiology is most important to evaluate the prognosis of a given condition.

Bone Diseases, Developmental↗
PubMed1993

Intrafamilial variability in Hurler syndrome and Sanfilippo syndrome type A: implications for evaluation of new therapies.

Intrafamilial variability has not been reported previously in Hurler syndrome or Sanfilippo syndrome type A. We describe two families in which sibs with comparable deficiencies of alpha-iduronidase (Hurler) or sulfamidase (Sanfilippo type A) activities in vitro nonetheless have divergence in clinical severity and disease progression. These cases underscore the need for caution in counseling as well as the limitations of using sibs as controls in evaluating the outcome of treatment.

Adolescent↗
PubMed1998

Noncirrhotic portal hypertension and nodular regenerative hyperplasia of the liver in dogs with mucopolysaccharidosis type I.

Nodular regenerative hyperplasia (NRH) is an uncommon hepatic lesion often associated with noncirrhotic portal hypertension (PHT). We have noted that NRH and PHT are frequent occurrences in a colony of dogs with the genetic storage disease, mucopolysaccharidosis I (MPS-I). This observation provides the opportunity to study the histology and pathogenesis of NRH and noncirrhotic PHT in a new animal model. Thirteen of 32 dogs (41%) with MPS-I developed multiple portocaval shunts between 4 and 48 months of age that were grossly visible at necropsy. Seven of the 13 developed marked ascites, whereas all those without shunts and littermates (n = 24) heterozygous for the mutated alpha-L-iduronidase allele (carriers unaffected by the storage disease) did not. The large and medium-sized portal veins were widely patent without thrombosis or vascular malformations. Hepatic parenchymal fibrosis was absent or mild and did not correlate with shunt formation. All 32 livers had varying degrees of diffuse periportal hepatocellular hyperplasia with multifocal atrophy and compression of centrolobular cords (NRH) most prominent in dogs with shunts. Many small portal veins were reduced in diameter or absent, especially in animals with shunts. Noncirrhotic PHT and NRH appear to be related to the obliteration of small portal veins in these dogs, but the pathogenesis of this vascular change remains unknown.

Animals↗
PubMedDate not supplied

Comparative study of 15 lysosomal enzymes in chorionic villi and cultured amniotic fluid cells. Early prenatal diagnosis in seven pregnancies at risk for lysosomal storage diseases.

A large number of chorionic villi samples obtained from women undergoing elective first trimester termination of pregnancy was analysed by enzyme assays similar to those applied to cultured amniotic cells. The levels of 15 lysosomal enzymes were compared to those observed in tissue cultures of amniotic cells obtained through amniocentesis at 16-18 weeks of pregnancy and the results were discussed in order to assess the usefulness of trophoblast biopsy for first trimester diagnosis of hereditary lysosomal diseases. The data suggest the applicability of this source of fetal cells for prenatal diagnosis of fifteen respective genetically determined enzyme deficiencies with the probable exception of alpha-L-iduronidase deficiency. Enzyme determinations were performed on chorionic villi samples of two pregnancies at risk for Tay-Sachs disease, three pregnancies for GM1 gangliosidosis type 1, one for mucopolysaccharidosis type VI and one for Wolman's disease.

Amniocentesis↗
PubMed2000

Purification and characterization of recombinant human alpha-N-acetylglucosaminidase secreted by Chinese hamster ovary cells.

alpha-N-Acetylglucosaminidase (EC 3.2.1.50) is a lysosomal enzyme that is deficient in the genetic disorder Sanfilippo syndrome type B. To study the human enzyme, we expressed its cDNA in Lec1 mutant Chinese hamster ovary (CHO) cells, which do not synthesize complex oligosaccharides. The enzyme was purified to apparent homogeneity from culture medium by chromatography on concanavalin A-Sepharose, Poros 20-heparin, and aminooctyl-agarose. The purified enzyme migrated as a single band of 83 kDa on SDS-PAGE and as two peaks corresponding to monomeric and dimeric forms on Sephacryl-300. It had an apparent K(m) of 0.22 mM toward 4-methylumbelliferyl-alpha-N-acetylglucosaminide and was competitively inhibited by two potential transition analogs, 2-acetamido-1,2-dideoxynojirimycin (K(i) = 0.45 microM) and 6-acetamido-6-deoxycastanospermine (K(i) = 0.087 microM). Activity was also inhibited by mercurials but not by N-ethylmaleimide or iodoacetamide, suggesting the presence of essential sulfhydryl residues that are buried. The purified enzyme preparation corrected the abnormal [(35)S]glycosaminoglycan catabolism of Sanfilippo B fibroblasts in a mannose 6-phosphate-inhibitable manner, but its effectiveness was surprisingly low. Metabolic labeling experiments showed that the recombinant alpha-N-acetylglucosaminidase secreted by CHO cells had only a trace of mannose 6-phosphate, probably derived from contaminating endogenous CHO enzyme. This contrasts with the presence of mannose 6-phosphate on naturally occurring alpha-N-acetylglucosaminidase secreted by diploid human fibroblasts and on recombinant human alpha-l-iduronidase secreted by the same CHO cells. Thus contrary to current belief, overexpressing CHO cells do not necessarily secrete recombinant lysosomal enzyme with the mannose 6-phosphate-targeting signal; this finding has implications for the preparation of such enzymes for therapeutic purposes.

Acetylglucosaminidase↗
PubMed1984

Diagnostic application of first trimester trophoblast sampling in 100 pregnancies.

The results of the diagnostic application of first trimester trophoblast sampling in 100 pregnancies are reported in detail. Further improvement of the method for routine, direct chromosome analysis resulted in a technique which proved to be fast, simple, and efficient. We found that short-term incubation of villi permits the application of many experimental methods, such as visualization of sister chromatid exchanges and bromodeoxyuridine (BrdU) incorporation. Fetal karyotyping was successful in each of the 96 pregnancies in which fetal material was obtained from a total of 98 fetuses. There were 42 males and 56 females, and an abnormal chromosome constitution was found in 12 cases. Two trisomic fetuses were found among the eight pregnancies at risk for Duchenne muscular dystrophy, and this indicates that fetal sexing (which is achieved with our method in two hours) should not be performed without chromosome visualization. The results indicate a risk of 8% of an abnormal fetus for mothers aged 35 years or more, while the risk of failure of sampling and of spontaneous abortion after villi sampling were 4 and 6%, respectively. Enzyme determinations were performed in three pregnancies at risk for gangliosidosis GM1, Niemann-Pick disease, and Hurler syndrome. In this last case inconsistency between the results of the assay of iduronidase on chorionic villi and amniotic fluid cells was found. This unexplained error indicates the need for extensive characterisation in chorionic villi of the series of enzymes involved in metabolic diseases.

Adult↗
PubMed1985

Lysosomal hydrolase activity in chorionic villi and embryonic cells in culture.

Fourteen lysosomal enzymes were compared in 20 cultured cell lines from chorionic biopsy and corresponding embryonic tissue after voluntary abortions. Enzymatic expression appears to be similar in cultured cells from both sources with some slightly higher levels for chorionic villi. We stress the importance of culturing chorionic villi especially in the case of enzymes (alpha-L-iduronidase) or diseases (I cell disease) whose expression is unusual in fresh trophoblast tissue.

Cells, Cultured↗
PubMed1988

Alterations in neuron morphology in mucopolysaccharidosis type I. A Golgi study.

Morphological changes in neurons with inborn defects of the lysosomal hydrolase, alpha-L-iduronidase, and with concomitant storage of glycosaminoglycans, were evaluated by Golgi staining in two animal models and compared to a similar study of a child with the same disease. Cortical pyramidal neurons in feline mucopolysaccharidosis type I often displayed axon hillock enlargements (meganeurites) and/or ectopic, secondary neuritic processes sprouting from this same region of the cell. The latter structures were prominent and often appeared longer than similar neurites reported in other neuronal storage diseases. Although most meganeurites were aspiny, a few were observed which possessed spine-like processes or neurites. Other than these morphological changes in cortical pyramidal neurons, few other cell types displayed abnormalities demonstrable by Golgi impregnation. In the canine model of this disorder, abnormal Golgi-impregnated cortical neurons resembled more closely those seen in human mucopolysaccharidosis. That is, they possessed meganeurites which typically were aspiny in appearance. Ectopic neurite growth was not observed on any Golgi-impregnated neurons in the cases of canine or human mucopolysaccharidosis used in this study. The latter finding, given the advanced ages of these cases, is consistent with the view that ectopic neuritogenesis seen in neuronal storage diseases may be subject to a developmental window, albeit one open well beyond the period of early postnatal maturation.

Animals↗
PubMed1989

Chorionic villus sampling: diagnostic uses and limitations of enzyme assays.

Control ranges for enzymes in uncultured chorionic villi were established, based on: (1) 21 of 22 enzymes (mainly lysosomal) in villi had similar properties to the enzyme in cultured fibroblasts; (2) isoenzyme patterns in villi were similar to those in fibroblasts for five lysosomal enzymes but different for aryl sulphatases; (3) control ranges were determined for 12 enzymes in abortion villi and for 21 enzymes in biopsy villi, values tending to be higher in the latter for those enzymes studied in both types of sample; (4) storage of samples under various conditions revealed no major changes in activity of seven lysosomal enzymes. A number of potential pitfalls in the use of chorionic villus samples for diagnosis of metabolic disorders by enzyme assay are described: (1) the presence of aryl sulphatase C in chorionic villi, an isoenzyme which may interfere in assays of aryl sulphatase A; (2) the presence of maternal enzyme in chorionic villus material illustrated by the detection of the A isoenzyme of B-hexosaminidase in chorionic villus from a pregnancy affected with Sandhoff's disease; (3) the finding of falsely normal levels of alpha-iduronidase in chorionic villus samples from a pregnancy affected with Hurler's disease, probably due to contamination with maternal tissue which has relatively high levels of this enzyme compared with fetal chorionic material: (4) the inadequacy of indirect assays of incorporation of radiolabel into macromolecules using chorionic villi, for example [14C]propionate incorporation for prenatal diagnosis of methylmalonic aciduria. Provided that such pitfalls are recognized and great care is taken in selection of villus samples and interpretation of results, chorionic villus sampling allows reliable prenatal diagnosis of a large number of disorders using enzyme assays.

Chorionic Villi Sampling↗
PubMed2005

Nonviral in vivo gene transfer in the mucopolysaccharidosis I murine model.

Mucopolysaccharidosis I (MPS I) is a lysosomal disorder characterized by a deficiency of the enzyme alpha-L: -iduronidase (IDUA), which is responsible for the degradation of glycosaminoglycans (GAGs). This deficiency leads to the accumulation of dermatan and heparan sulphate in lysosomes. Presently available treatments include bone marrow transplantation and enzyme replacement therapies, both of which are limited in their effects. In this work, knockout (KO) MPS I mice were treated with a nonviral vector containing the human IDUA cDNA. KO mice were transfected by hydrodynamic injection of pRIDUA in the caudal vein (i.v., n = 3) or by intraperitoneal injection of pRIDUA/Superfect complexes (i.p., n = 3). GAG concentration and IDUA activity were analysed in the kidneys, spleen, lungs, brain and liver. The expression of IDUA in the organs of i.v.- and i.p.-treated mice was also analysed by real-time reverse-transcription (RT) PCR and compared by relative quantification. The concentration of GAGs in the organs differed between KO and wild-type mice. In the spleen and liver, GAG levels were lower in i.v.- and i.p.-treated KO mice than in control nontreated animals. Real-time RT-PCR showed that the transgene is expressed in all the analysed organs of i.p.- and i.v.-treated KO mice. Enzyme activity was similarly observed in all the organs analysed. Our data suggest that this kind of transfection may be a useful tool for studies of nonviral protocols for gene therapy of MPS.

Animals↗
PubMed2006

Restricted upper extremity range of motion in mucopolysaccharidosis type I: no response to one year of enzyme replacement therapy.

BACKGROUND: Mucopolysaccharidosis type I (MPS I) results from deficiency of the lysosomal enzyme alpha-L: -iduronidase (IDUA). Glycosaminoglycans (GAGs) accumulate in multiple organs and the storage in connective tissues results in restricted mobility. Previous studies provided evidence of an improvement in range of motion (ROM), as measured by goniometry, after supplementation of recombinant enzyme (ERT). AIM: The aim of the study was to evaluate the efficacy of ERT in improving ROM in patients with MPS I, using a blinded three-dimensional (3D) video analysis of unrestricted movements of the upper extremities. METHODS: In 6 patients with the attenuated phenotype of MPS I, the longitudinal changes in the upper extremity ROM were analysed by 3D video analysis during one year of ERT. RESULTS: At baseline, all studied movements except for elbow flexion were restricted. No significant improvement of the restricted upper extremity ROM was observed after one year of ERT. CONCLUSION: Long-standing restrictions in ROM probably cannot be reversed by ERT. Early initiation of treatment might be essential to prevent irreversible functional defects.

Child↗