43 results on '"Otto P. van Diggelen"'
Search Results
2. Defects in degradation of blood group A and B glycosphingolipids in Schindler and Fabry diseases
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Befekadu Asfaw, Jana Ledvinová, Robert Dobrovolńy, Henk D. Bakker, Robert J. Desnick, Otto P. van Diggelen, Jan G.N. de Jong, Tamotsu Kanzaki, Amparo Chabas, Irene Maire, Ernst Conzelmann, and Detlev Schindler
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α-N-acetylgalactosaminidase deficiency ,α-galactosidase A deficiency ,skin fibroblasts ,in situ metabolism ,lysosome targeting ,blood group glycolipids ,Biochemistry ,QD415-436 - Abstract
Skin fibroblast cultures from patients with inherited lysosomal enzymopathies, α-N-acetylgalactosaminidase (α-NAGA) and α-galactosidase A deficiencies (Schindler and Fabry disease, respectively), and from normal controls were used to study in situ degradation of blood group A and B glycosphingolipids. Glycosphingolipids A-6-2 (GalNAc (α1→3)[Fucα1→2]Gal(β1→4)GlcNAc(β1→3)Gal(β1→ 4)Glc (β1→1′)Cer, IV2-α-fucosyl-IV3-α-N-acetylgalactosaminylneolactotetraosylceramide), B-6-2 (Gal(α1→3)[Fucα1→ 2] Gal (β1→4)GlcNAc(β1→3)Gal(β1→4)Glc(β1→1′)Cer, IV2- α-fucosyl-IV3-α-galactosylneolactotetraosylceramide), and globoside (GalNAc(β1→3)Gal(α1→4)Gal(β1→4)Glc(β1→1′) Cer, globotetraosylceramide) were tritium labeled in their ceramide moiety and used as natural substrates. The degradation rate of glycolipid A-6-2 was very low in fibroblasts of all the α-NAGA-deficient patients (less than 7% of controls), despite very heterogeneous clinical pictures, ruling out different residual enzyme activities as an explanation for the clinical heterogeneity. Strongly elevated urinary excretion of blood group A glycolipids was detected in one patient with blood group A, secretor status (five times higher than upper limit of controls), in support of the notion that blood group A-active glycolipids may contribute as storage compounds in blood group A patients. When glycolipid B-6-2 was fed to α-galactosidase A-deficient cells, the degradation rate was surprisingly high (50% of controls), while that of globotriaosylceramide was reduced to less than 15% of control average, presumably reflecting differences in the lysosomal enzymology of polar glycolipids versus less-polar ones.Relatively high-degree degradation of substrates with α-d-Galactosyl moieties hints at a possible contribution of other enzymes.
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- 2002
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3. Molecular defects underlying Wolman disease appear to be more heterogeneous than those resulting in cholesteryl ester storage disease
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Peter Lohse, Sylke Maas, Pia Lohse, Adrian C. Sewell, Otto P. van Diggelen, and Dietrich Seidel
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lipid metabolism ,lysosomal acid lipase ,enzyme deficiency ,genotype ,mutation analysis ,Biochemistry ,QD415-436 - Abstract
Human lysosomal acid lipase/cholesteryl ester hydrolase (hLAL) is essential for the intralysosomal metabolism of cholesteryl esters and triglycerides taken up by receptor-mediated endocytosis of lipoprotein particles. The key role of the enzyme in intracellular lipid homeostasis is illustrated by two lysosomal storage diseases inherited as autosomal recessive traits. Wolman disease, associated with deficient hLAL activity, leads to massive intracellular substrate accumulation and is always fatal in early infancy. Cholesteryl ester storage disease (CESD), in contrast, is characterized by very low levels of enzymic activity sufficient to allow survival of the affected patients into adulthood. In order to elucidate the underlying molecular defects in Wolman disease, we have characterized the hLAL gene in two female Wolman patients of German and Turkish origin by SSCP and DNA sequence analysis. Our results demonstrate that the German proband was compound heterozygous for an 8-bp deletion in exon 3 and a 2-bp deletion in exon 4 of the hLAL gene. These frameshift mutations lead to protein truncation at amino acid positions 24 and 116 and to complete loss of hydrolytic activity. The Turkish proband, in contrast, was homozygous for a G1064→T substitution in exon 10 of the hLAL gene which converts the completely conserved glycine (GGG) residue at position 321 of the mature enzyme to tryptophan (TGG). In vitro expression of the hLAL(Gly321→Trp) cDNA construct revealed that the amino acid replacement results in a more than 99% reduction of neutral lipid hydrolysis. The mutations provide new insights into the molecular basis of Wolman disease which is apparently more heterogeneous at the genetic level than cholesteryl ester storage disease.—Lohse, P., S. Maas, P. Lohse, A. C. Sewell, O. P. van Diggelen, and D. Seidel. Molecular defects underlying Wolman disease appear to be more heterogeneous than those resulting in cholesteryl ester storage disease. J. Lipid Res. 1999. 40: 221–228.
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- 1999
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4. The use of dried blood spot samples in the diagnosis of lysosomal storage disorders - Current status and perspectives
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Arnold J. J. Reuser, Adolf Mühl, Kate Zhang, Petra Olivova, Dominique P. Germain, Deeksha Bali, Otto P. van Diggelen, Zoltan Lukacs, Birgit Wuyts, Monique Piraud, Frans W. Verheijen, Joan Keutzer, Wuh-Liang Hwu, and Clinical Genetics
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Quality Control ,Research Report ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Lysosomal storage disorders ,Biochemistry ,Endocrinology ,Genetics ,Lysosomal storage disease ,medicine ,Screening programs ,Humans ,Sampling (medicine) ,Intensive care medicine ,Molecular Biology ,Newborn screening ,business.industry ,Early disease ,Enzyme replacement therapy ,Reference Standards ,medicine.disease ,Dried blood spot ,Lysosomal Storage Diseases ,Immunology ,Dried Blood Spot Testing ,business - Abstract
Dried blood spot (DBS) methods are currently available for identification of a range of lysosomal storage disorders (LSDs). These disorders are generally characterized by a deficiency of activity of a lysosomal enzyme and by a broad spectrum of phenotypes. Diagnosis of LSD patients is often delayed, which is of particular concern as therapeutic outcomes (e.g. enzyme replacement therapy) are generally more favorable in early disease stages. Experts in the field of LSDs diagnostics and screening programs convened and reviewed experiences with the use of DBS methods, and discuss the diagnostic challenges, possible applications and quality programs in this paper. Given the easy sampling and shipping and stability of samples, DBS has evident advantages over other laboratory methods and can be particularly helpful in the early identification of affected LSD patients through neonatal screening, high-risk population screening or family screening. (C) 2011 Elsevier Inc. All rights reserved.
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- 2011
5. Mucopolysaccharidosis Type IIIA: Clinical Spectrum and Genotype-Phenotype Correlations
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George J G Ruijter, Otto P. van Diggelen, Dicky J. Halley, Hennie T. Brüggenwirth, Ron A. Wevers, Marlies J. Valstar, Renske Olmer, Ben J. H. M. Poorthuis, Frits A. Wijburg, Sanne Neijs, Paediatric Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Medical Biochemistry, Pediatrics, and Clinical Genetics
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Male ,Pathology ,Hydrolases ,Mucopolysaccharidosis ,DNA Mutational Analysis ,Behavioral Symptoms ,Kaplan-Meier Estimate ,Compound heterozygosity ,Gastroenterology ,Severity of Illness Index ,Cohort Studies ,Mucopolysaccharidosis III ,Pregnancy ,Genotype ,Medicine ,Missense mutation ,Child ,Mucopolysaccharidosis Type IIIA ,Hearing Disorders ,Cells, Cultured ,Sanfilippo syndrome ,Skin ,Middle Aged ,Phenotype ,Neurology ,Child, Preschool ,Regression Analysis ,Female ,Functional Neurogenomics [DCN 2] ,Adult ,Sleep Wake Disorders ,medicine.medical_specialty ,Adolescent ,Vision Disorders ,Mucopolysaccharidosis type III ,Young Adult ,SDG 3 - Good Health and Well-being ,Internal medicine ,Humans ,Genetic Association Studies ,Epilepsy ,business.industry ,Glycostation disorders [IGMD 4] ,Fibroblasts ,medicine.disease ,Mutation ,Neurology (clinical) ,business - Abstract
Contains fulltext : 89261.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Mucopolysaccharidosis (MPS) IIIA (Sanfilippo syndrome type A) is a lysosomal storage disorder caused by deficiency of the enzyme sulfamidase. Information on the natural course of MPS IIIA is scarce, but is much needed in view of emerging therapies. METHODS: Clinical history and molecular defects of all 110 MPS IIIA patients identified by enzymatic studies in the Netherlands were collected and included in this study. RESULTS: First clinical signs, mainly consisting of delayed speech development and behavioral problems, were noted between the ages of 1 and 6 years. Other symptoms included sleeping and hearing problems, recurrent upper airway infections, diarrhea, and epilepsy. The clinical course varied remarkably and could be correlated with the molecular defects. The frequent pathogenic mutations p.R245H, p.Q380R, p.S66W, and c.1080delC were associated with the classical severe phenotype. Patients compound heterozygous for the p.S298P mutation in combination with 1 of the mutations associated with the classical severe phenotype had a significantly longer preservation of psychomotor functions and a longer survival. Two patients homozygous for the p.S298P mutation, and 4 patients from 3 families heterozygous for 3 missense variants not reported previously (p.T421R, p.P180L, and p.L12Q), showed a remarkably attenuated phenotype. INTERPRETATION: We report the natural history and mutational analysis in a large unbiased cohort of MPS IIIA patients. We demonstrate that the clinical spectrum of MPS IIIA is much broader than previously reported. A significant genotype-phenotype correlation was established in this cohort. 01 december 2010
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- 2010
6. Sanfilippo syndrome type C: mutation spectrum in the heparan sulfate acetyl-CoA: α-glucosaminide N-acetyltransferase (HGSNAT) gene
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James E. Wraith, Lenka Mrázová, Helen Michelakakis, Rachel Laframboise, Otto P. van Diggelen, Stanislav Kmoch, Matthew Feldhammer, Alexey V. Pshezhetsky, Stéphanie Durand, Robert Steinfeld, Martin Hřebíček, Renee Myriam Boucher, and Clinical Genetics
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Mucopolysaccharidosis ,Molecular Sequence Data ,Nonsense mutation ,N-acetyltransferase ,Biology ,medicine.disease_cause ,Mucopolysaccharidosis III ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Acetyltransferases ,Genetics ,medicine ,Humans ,Missense mutation ,Amino Acid Sequence ,Genetics (clinical) ,030304 developmental biology ,Sanfilippo syndrome ,0303 health sciences ,Mutation ,Heparan sulfate ,medicine.disease ,Molecular biology ,3. Good health ,Biochemistry ,chemistry ,030217 neurology & neurosurgery - Abstract
Mucopolysaccharidosis (MPS) type IIIC or Sanfilippo syndrome type C is a rare autosomal recessive disorder caused by the deficiency of the lysosomal membrane enzyme, heparan sulfate acetyl-CoA (AcCoA): alpha-glucosaminide N,acetyltransferase (HGSNAT; EC 2.3.1.78), which catalyzes transmembrane acetylation. of the terminal glucosamine residues of heparan sulfate prior to their hydrolysis by alpha-N-acetylglucosaminidase. Lysosomal storage of undegraded heparan sulfate in the cells of affected patients leads to neuronal death, causing neurodegeneration and severely impaired development accompanied by mild visceral and skeletal abnormalities, including mild dwarfism, coarse facies, and joint stiffness. To date, 50 HGSNAT mutations have been identified in MPS IIIC patients: 40 were previously published and 10 novel mutations are reported here. The mutations span the entire structure of the gene and include 13 splice-site mutations, I I insertions and deletions, 8 nonsense mutations, and 18 missense mutations (http://chromium.liacs.nl/LOVD2/home.php? select_db = HGSNAT). In addition, four polymorphisms result in amino acid changes that do not affect activity of the enzyme. In this work we discuss the spectrum of MPS MC mutations, their clinical presentation and distribution within the patient population, and speculate how the mutations may affect the structure and function of HGSNAT. Hum Mutat 30, 918-925, 2009. (C) 2009 Wiley-Liss, Inc.
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- 2009
7. A new large animal model of CLN5 neuronal ceroid lipofuscinosis in Borderdale sheep is caused by a nucleotide substitution at a consensus splice site (c.571+1G > A) leading to excision of exon 3
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Robert D. Jolly, David Palmer, Otto P. van Diggelen, Nadia L. Mitchell, Tony Frugier, Graham W. Kay, Donald G. Arthur, Imke Tammen, Peter J. Houweling, and Clinical Genetics
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Batten disease ,Borderdale sheep ,Genetic Linkage ,DNA Mutational Analysis ,Molecular Sequence Data ,Sheep Diseases ,Biology ,medicine.disease_cause ,mRNA splicing ,Article ,lcsh:RC321-571 ,Gene product ,Exon ,Islets of Langerhans ,Microscopy, Electron, Transmission ,Neuronal Ceroid-Lipofuscinoses ,medicine ,Lysosomal storage disease ,Leukocytes ,Animals ,Point Mutation ,Animal model ,Gene ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Sheep, Domestic ,Genetics ,Mutation ,Point mutation ,CLN5 ,Membrane Proteins ,NCL ,Exons ,medicine.disease ,Molecular biology ,Disease Models, Animal ,Neurology ,Neuronal ceroid lipofuscinosis - Abstract
Batten disease (neuronal ceroid lipofuscinoses, NCLs) are a group of inherited childhood diseases that result in severe brain atrophy, blindness and seizures, leading to premature death. To date, eight different genes have been identified, each associated with a different form. Linkage analysis indicated a CLN5 form in a colony of affected New Zealand Borderdale sheep. Sequencing. studies established the disease-causing mutation to be a substitution at a consensus splice site (c.571+1G>A), leading to the excision of exon 3 and a truncated putative protein. A molecular diagnostic test has been developed based on the excision of exon 3. Sequence alignments support the gene product being a soluble lysosomal protein. Western blotting of isolated storage bodies indicates the specific storage of subunit c of mitochondrial ATP synthase. This flock is being expanded as a large animal model for mechanistic studies and trial therapies. (C) 2007 Elsevier Inc. All rights reserved.
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- 2008
8. Increased expression of lysosomal acid phosphatase in CLN3-defective cells and mouse brain tissue
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Otto P. van Diggelen, Sandra Pohl, Alfried Kohlschütter, Hannah M. Mitchison, Stephan Storch, and Thomas Braulke
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Male ,Transcriptional Activation ,Batten disease ,Acid Phosphatase ,Biology ,Biochemistry ,Mice ,Cellular and Molecular Neuroscience ,Downregulation and upregulation ,Neuronal Ceroid-Lipofuscinoses ,Lysosomal-Associated Membrane Protein 2 ,Gene expression ,Lysosomal storage disease ,medicine ,Animals ,Humans ,Cerebral Cortex ,Mice, Knockout ,Gene knockdown ,Membrane Glycoproteins ,digestive, oral, and skin physiology ,Neurodegeneration ,Brain ,Intracellular Membranes ,Fibroblasts ,medicine.disease ,Molecular biology ,Up-Regulation ,Mice, Inbred C57BL ,Lysosomal acid phosphatase ,CLN3 ,Female ,Lysosomes ,Biomarkers ,HeLa Cells ,Molecular Chaperones - Abstract
Juvenile neuronal ceroid lipofuscinosis (Batten disease) is a neurodegenerative disorder caused by defective function of the lysosomal membrane glycoprotein CLN3. The activity of the lysosomal acid phosphatase (LAP/ACP2) was found to be significantly increased in the cerebellum and brain stem of Cln3-targeted mice during the early stages of postnatal life. Histochemical localization studies revealed an increased LAP/ACP2 staining intensity in neurons of the cerebral cortex of 48-week-old Cln3-targeted mice as compared with controls. Additionally, the expression of another lysosomal membrane protein LAMP-2 was increased in all brain areas. Knockdown of CLN3 expression in HeLa cells by RNA interference also resulted in increased LAP/ACP2 and LAMP-2 expression. Finally in fibroblasts of two juvenile neuronal ceroid lipofuscinosis patients elevated levels of LAP/ACP2 were found. Both activation of gene transcription and increased protein half-life appear to contribute to increased LAP/ACP2 protein expression in CLN3-deficient cells. The data suggest that lysosomal dysfunction and accumulation of storage material require increased biogenesis of LAP/ACP2 and LAMP-2 positive membranes which makes LAP/ACP2 suitable as biomarker of Batten disease.
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- 2007
9. Adult polyglucosan body disease: Proton magnetic resonance spectroscopy of the brain and novel mutation in theGBE1gene
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Alessandro Martorana, Antonio Federico, Otto P. van Diggelen, Nicola De Stefano, Roberto Massa, and Claudio Bruno
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Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,biology ,Physiology ,Chemistry ,Central nervous system ,Magnetic resonance imaging ,Adult polyglucosan body disease ,Cellular and Molecular Neuroscience ,Myelin ,medicine.anatomical_structure ,Physiology (medical) ,Peripheral nervous system ,medicine ,Glycogen branching enzyme ,biology.protein ,Missense mutation ,Neurology (clinical) ,Axon ,Neuroscience - Abstract
Adult polyglucosan body disease (APBD) is characterized by the accumulation of insoluble glucose polymers within the central and peripheral nervous systems. A common missense mutation in the glycogen branching enzyme (GBE1) gene has been identified in Ashkenazi patients with APBD. We report on a non-Jewish patient with APBD on whom we performed proton magnetic resonance spectroscopic imaging of the brain. GBE activity in fibroblasts was markedly reduced, and a novel heterozygous mutation was identified in the GBE1 gene. Our findings widen the spectrum of APBD genotypes, underline the importance of performing GBE analysis in all APBD patients, and suggest that brain white matter degeneration in APBD may result from tissue damage involving axons and myelin.
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- 2007
10. Null mutations and lethal congenital form of glycogen storage disease type IV
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Stefania Assereto, Margarida Maria Videira Henriques, Jildau Dilling, Isabel M. Carreira, Olinda Rebelo, Paula Garcia, Carlo Minetti, Eva Morava, Denise Cassandrini, Willem P. de Boode, Henk J. ter Laak, Luísa Diogo, Otto P. van Diggelen, Claudio Bruno, and Clinical Genetics
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DNA, Complementary ,Biopsy ,Blotting, Western ,DNA Mutational Analysis ,Molecular Sequence Data ,Biophysics ,medicine.disease_cause ,Biochemistry ,Genomic disorders and inherited multi-system disorders [IGMD 3] ,Exon ,Glycogen Storage Disease Type IV ,Fatal Outcome ,1,4-alpha-Glucan Branching Enzyme ,medicine ,Perception and Action [DCN 1] ,Humans ,Amino Acid Sequence ,Glycogen storage disease type IV ,Glycogen synthase ,Muscle, Skeletal ,Molecular Biology ,GSK3B ,Gene ,Mutation ,biology ,Base Sequence ,Intron ,Infant, Newborn ,Cell Biology ,Exons ,Glycostation disorders [IGMD 4] ,Fibroblasts ,medicine.disease ,Molecular biology ,Neuromuscular development and genetic disorders [UMCN 3.1] ,Introns ,Glycogen Branching Enzyme Deficiency ,Mitochondrial medicine [IGMD 8] ,Genetic defects of metabolism [UMCN 5.1] ,biology.protein ,Female - Abstract
Contains fulltext : 51443.pdf (Publisher’s version ) (Closed access) Glycogen branching enzyme deficiency (glycogen storage disease type IV, GSD-IV) is a rare autosomal recessive disorder of the glycogen synthesis with high mortality. Two female newborns showed severe hypotonia at birth and both died of cardiorespiratory failure, at 4 and 12 weeks, respectively. In both patients, muscle biopsies showed deposits of PAS-positive diastase-resistant material and biochemical analysis in cultured fibroblasts showed markedly reduced glycogen branching enzyme activity. Direct sequencing of GBE1 gene revealed that patient 1 was homozygous for a novel c.691+5 g>c in intron 5 (IVS5+5 g>c). RT-PCR analysis of GBE1 transcripts from fibroblasts cDNA showed that this mutation produce aberrant splicing. Patient 2 was homozygous for a novel c.1643G>A mutation leading to a stop at codon 548 in exon 13 (p.W548X). These data underscore that in GSD-IV a severe phenotype correlates with null mutations, and indicate that RNA analysis is necessary to characterize functional consequences of intronic mutations.
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- 2007
11. Autosomal Dominant Adult Neuronal Ceroid Lipofuscinosis: a Novel Form of NCL with Granular Osmiophilic Deposits without Palmitoyl Protein Thioesterase 1 Deficiency
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Raymund A.C. Roos, Jaana Tyynelä, Johannes L.J.M. Teepen, Peter C G Nijssen, Milan Elleder, Jean-Jacques Martin, Chantal Ceuterick, and Otto P. van Diggelen
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Adult ,Male ,Protein subunit ,Blotting, Western ,Cathepsin D ,Substantia nigra ,Saposins ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Neuronal Ceroid-Lipofuscinoses ,medicine ,Humans ,Palmitoyl protein thioesterase ,Glycoproteins ,030304 developmental biology ,Family Health ,Neurons ,Antiserum ,0303 health sciences ,biology ,General Neuroscience ,Skeletal muscle ,Pigments, Biological ,Middle Aged ,Mitochondrial Proton-Translocating ATPases ,Immunohistochemistry ,Lipids ,Molecular biology ,Sphingolipid ,Pedigree ,Lysosomal Storage Diseases ,Blot ,Microscopy, Electron ,medicine.anatomical_structure ,Palmitoyl-CoA Hydrolase ,Biochemistry ,biology.protein ,Electrophoresis, Polyacrylamide Gel ,Female ,Neurology (clinical) ,030217 neurology & neurosurgery ,Research Article ,Peptide Hydrolases - Abstract
We describe the neuropathological and biochemical autopsy findings in 3 patients with autosomal dominant adult neuronal ceroid lipofuscinosis (ANCL, Parry type; MIM 162350), from a family with 6 affected individuals in 3 generations. Throughout the brain of these patients, there was abundant intraneuronal lysosomal storage of autofluorescent lipopigment granules. Striking loss of neurons in the substantia nigra was found. In contrast, little neuronal cell loss occurred in other cerebral areas, despite massive neuronal inclusions. Visceral storage was present in gut, liver, cardiomyocytes, skeletal muscle, and in the skin eccrine glands. The storage material showed highly variable immunoreactivity with antiserum against subunit c of mitochondrial ATP synthase, but uniform strong immunoreactivity for saposin D (sphingolipid activating protein D). Protein electrophoresis of isolated storage material revealed a major protein band of about 14 kDa, recognized in Western blotting by saposin D antiserum (but not subunit c of mitochondrial ATPase (SCMAS) antiserum). Electron microscopy showed ample intraneuronal granular osmiophilic deposits (GRODs), as occurs in CLN1 and congenital ovine NCL. These forms of NCL are caused by the deficiencies of palmitoyl protein thioesterase 1 and cathepsin D, respectively. However, activities of these enzymes were within normal range in our patients. Thus we propose that a gene distinct from the cathepsin D and CLN1-CLN8 genes is responsible for this autosomal dominant form of ANCL.
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- 2006
12. A new diagnostic assay for glycogen storage disease type II in mixed leukocytes
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Toshika Okumiya, Nadine A. M. E. van der Beek, Arnold J. J. Reuser, Marian A. Kroos, Otto P. van Diggelen, Marijke Boer, J. L. M. Keulemans, Hiroaki Takeuchi, Clinical Genetics, and Neurology
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medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Biochemistry ,Glycogen debranching enzyme ,chemistry.chemical_compound ,Endocrinology ,Internal medicine ,Glycogen storage disease type II ,Genetics ,Lysosomal storage disease ,medicine ,Leukocytes ,Humans ,Molecular Biology ,Acarbose ,chemistry.chemical_classification ,Maltase-glucoamylase ,Glycogen ,Glycogen Storage Disease Type II ,Substrate (chemistry) ,Infant ,alpha-Glucosidases ,Hydrogen-Ion Concentration ,medicine.disease ,Enzyme ,chemistry ,Glucan 1,4-alpha-Glucosidase ,medicine.drug - Abstract
We have established a new method for the enzymatic diagnosis of glycogen storage disease type II (Pompe disease or acid maltase deficiency) using mixed leukocytes. The method employs glycogen and 4-methylumbelliferyl-alpha-D-glucopyranoside (4MU-alphaGlc) as substrates for measuring the lysosomal acid alpha-glucosidase (acid alphaGlu) activity, and incorporates acarbose to eliminate the interference of unrelated alpha-glucosidases (predominantly maltase-glucoamylase). It is shown that 3.0 micromol/L acarbose completely inhibits the maltase-glucoamylase activity at pH 4.0, but the lysosomal acid alphaGlu activity by less than 5%. With this method, we determined the acid alphaGlu activity in mixed leukocytes from 25 patients with glycogen storage disease type II (2 infantile and 23 late-onset cases), one GAA2/GAA2 homozygote and 30 healthy subjects. In the assay with glycogen as substrate, the addition of acarbose created a clear separation between the patient and the control ranges. In the assay with 4MU-alphaGlc as substrate, the two ranges were fully separated but remained very close despite the use of acarbose. The separation of the patient and normal ranges was improved considerably by taking the ratio of acarbose-inhibited over uninhibited activity. A GAA2/GAA2 homozygote was correctly diagnosed with 4MU-alphaGlc but misdiagnosed as patient when glycogen was used as substrate. We conclude that the inclusion of 3.0 micromol/L acarbose in the assays with glycogen and 4MU-alphaGlc substrates at pH 4.0 allows for the specific measurement of lysosomal acid alphaGlu activity in mixed leukocytes, thus enabling a reliable diagnosis of glycogen storage disease type II in this specimen.
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- 2006
13. A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging
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Anna-Liisa Fabritius, Janna Saarela, Helena Minye, Otto P. van Diggelen, Carina von Schantz, Leena Peltonen, Anu Jalanko, Outi Kopra, Jouni Vesa, Juhani Rapola, Tuula Manninen, and Clinical Genetics
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Pathology ,medicine.medical_specialty ,Aging ,Batten disease ,Central nervous system ,Neuropathology ,Biology ,03 medical and health sciences ,Exon ,Myelin ,Mice ,0302 clinical medicine ,Atrophy ,Neuronal Ceroid-Lipofuscinoses ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Genetics (clinical) ,gamma-Aminobutyric Acid ,030304 developmental biology ,DNA Primers ,Mice, Knockout ,0303 health sciences ,Base Sequence ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Neurodegeneration ,Brain ,Lysosome-Associated Membrane Glycoproteins ,Membrane Proteins ,General Medicine ,medicine.disease ,Immunohistochemistry ,Disease Models, Animal ,medicine.anatomical_structure ,GABAergic ,Lysosomes ,030217 neurology & neurosurgery - Abstract
Neuronal ceroid lipofuscinoses (NCL) comprise the most common group of childhood encephalopathies caused by mutations in eight genetic loci, CLN1-CLN8. Here, we have developed a novel mouse model for the human vLINCL (CLN5) by targeted deletion of exon 3 of the mouse Cln5 gene. The Cln5-/- mice showed loss of vision and accumulation of autofluorescent storage material in the central nervous system (CNS) and peripheral tissues without prominent brain atrophy. The ultrastructure of the storage material accurately replicated the abnormalities in human patients revealing mixture of lamellar profiles including fingerprint profiles as well as curvilinear and rectilinear bodies in electronmicroscopic analysis. Prominent loss of a subset of GABAergic interneurons in several brain areas was seen in the Cln5-/- mice. Transcript profiling of the brains of the Cln5-/- mice revealed altered expression in several genes involved in neurodegeneration, as well as in defense and immune response, typical of age-associated changes in the CNS. Downregulation of structural components of myelin was detected and this agrees well with the hypomyelination seen in the human vLINCL patients. In general, the progressive pathology of the Cln5-/- brain mimics the symptoms of the corresponding neurodegenerative disorder in man. Since the Cln5-/- mice do not exhibit significant brain atrophy, these mice could serve as models for studies on molecular processes associated with advanced aging.
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- 2004
14. Adult neuronal ceroid lipofuscinosis with palmitoyl-protein thioesterase deficiency: first adult-onset patients of a childhood disease
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Monique Losekoot, Peter E.M. Taschner, Yakov V. Voznyi, Caroline Tilikete, Marie‐Thérèse Zabot, Otto P. van Diggelen, Stéphane Thobois, Patrick A. van Bunderen, J. L. M. Keulemans, and Clinical Genetics
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Adult ,medicine.medical_specialty ,Infantile neuronal ceroid lipofuscinosis ,Neuronal Ceroid-Lipofuscinoses ,Internal medicine ,medicine ,Humans ,Missense mutation ,Fluorometry ,Palmitoyl protein thioesterase ,Age of Onset ,biology ,Cerebellar ataxia ,PPT1 ,Middle Aged ,medicine.disease ,Palmitoyl(protein) hydrolase ,Endocrinology ,Neurology ,biology.protein ,Female ,Neuronal ceroid lipofuscinosis ,Thiolester Hydrolases ,Neurology (clinical) ,Age of onset ,medicine.symptom - Abstract
The fluorogenic enzyme assay for palmitoyl-protein thioesterase (PPT) has greatly facilitated the diagnosis of infantile neuronal ceroid lipofuscinosis (Santavuori-Haltia disease) and the search for possible new variants with atypical clinical presentation. Here, we present the first cases of adult neuronal ceroid lipofuscinosis with onset in the fourth decade of life due to a profound deficiency of PPT. The causative mutations in the CLN1 gene were the known, deleterious mutation R151X and the novel missense mutation G108R. Patients presented at onset (31 and 38 years), with psychiatric symptoms only. At present (ages 56 and 54 years), visual, verbal, and cognitive losses have progressed and both patients have cerebellar ataxia and cannot walk without support.
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- 2001
15. Determination of Acid α-Glucosidase Protein: Evaluation as a Screening Marker for Pompe Disease and Other Lysosomal Storage Disorders
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Alison M. Whittle, Otto P. van Diggelen, Kandiah Umapathysivam, John J. Hopwood, Colleen A. Bindloss, Elaine M. Ravenscroft, Peter J. Meikle, Enzo Ranieri, and Clinical Genetics
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chemistry.chemical_classification ,Newborn screening ,medicine.medical_specialty ,medicine.diagnostic_test ,Biochemistry (medical) ,Clinical Biochemistry ,Prenatal diagnosis ,Biology ,medicine.disease ,Enzyme ,Endocrinology ,chemistry ,Internal medicine ,Immunoassay ,Blood plasma ,Glycogen storage disease type II ,medicine ,Lysosomal storage disease ,Whole blood - Abstract
Background: In recent years, there have been significant advances in the development of enzyme replacement and other therapies for lysosomal storage disorders (LSDs). Early diagnosis, before the onset of irreversible pathology, has been demonstrated to be critical for maximum efficacy of current and proposed therapies. In the absence of a family history, the presymptomatic detection of these disorders ideally can be achieved through a newborn screening program. One approach to the development of such a program is the identification of suitable screening markers. In this study, the acid α-glucosidase protein was evaluated as a marker protein for Pompe disease and potentially for other LSDs.Methods: Two sensitive immunoquantification assays for the measurement of total (precursor and mature) and mature forms of acid α-glucosidase protein were used to determine the concentrations in plasma and dried blood spots from control and LSD-affected individuals.Results: In the majority of LSDs, no significant increases above control values were observed. However, individuals with Pompe disease showed a marked decrease in acid α-glucosidase protein in both plasma and whole blood compared with unaffected controls. For plasma samples, this assay gave a sensitivity of 95% with a specificity of 100%. For blood spot samples, the sensitivity was 82% with a specificity of 100%.Conclusions: This study demonstrates that it is possible to screen for Pompe disease by screening the concentration of total acid α-glucosidase in plasma or dried blood spots.
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- 2000
16. Submicroscopic Xpter deletion in a boy with growth and mental retardation caused by a familial t(X;14)
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Bert B.A. de Vries, Bert H.J. Eussen, Cokkie H. Wouters, Lutgarde C.P. Govaerts, Annet van der Heide, Dick Lindhout, Wouter H. Deelen, Otto P. van Diggelen, and Jan O. Van Hemel
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Genetics ,X-linked ichthyosis ,medicine.diagnostic_test ,Ichthyosis ,Biology ,medicine.disease ,Short stature ,Contiguous gene syndrome ,X-linked recessive chondrodysplasia punctata ,medicine ,Chondrodysplasia punctata ,medicine.symptom ,Genetics (clinical) ,X chromosome ,Fluorescence in situ hybridization - Abstract
In a 3-year-old boy with short stature, developmental delay, and dry skin, steroid sulphatase deficiency and a submicroscopic terminal deletion of Xp were found. Except for the short stature, no major clinical signs of X-linked recessive chondrodysplasia punctata could be observed. His mother had lowered steroid sulphatase activity compatible with carriership for X-linked ichthyosis and a submicroscopic translocation (X;14)(p22.31;p11.1). This finding combined with a normal amplification of exons 1, 5, and 10 of the STS gene from propositus' DNA suggested a breakpoint upstream of the STS gene. The submicroscopic maternal translocation had important implications for genetic counseling. This case report illustrates that contiguous gene syndrome related to the Xpter region may have an atypical clinical presentation and the usefulness of combined clinical, biochemical, molecular, and fluorescence in situ hybridization analysis.
- Published
- 1999
17. Is the perinatal lethal form of Gaucher disease more common than classic type 2 Gaucher disease?
- Author
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Rob Willemsen, Martinus F. Niermeijer, Johannes Lj Gaillard, Ellen Sidransky, Otto P. van Diggelen, Deborah L. Stone, Nahid Tayebi, Johannis B.C. de Klerk, Clinical Genetics, and Pediatrics
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,DNA Mutational Analysis ,Disease ,Single Center ,Fatal Outcome ,Pregnancy ,Hydrops fetalis ,Genetics ,medicine ,Humans ,Genetics (clinical) ,Skin ,Gaucher Disease ,business.industry ,Incidence (epidemiology) ,Infant, Newborn ,Exons ,Fibroblasts ,medicine.disease ,Collodion baby ,Lysosomal Glucocerebrosidase ,Glucosylceramidase ,Female ,business ,Perinatal lethal - Abstract
In recent years there has been increased recognition of a severe perinatal lethal form of Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase. We previously reported a case of severe type 2 Gaucher disease which was seen in a medical center in Rotterdam and now present three new cases from two other families seen at the same center. Mutational analyses of these cases revealed two novel mutations, H311R and V398F, located in exons 8 and 9, respectively. The identification of four cases of lethal type 2 Gaucher disease in a single center seems to be a function of increased awareness of this phenotype, rather than of geographic clustering. The actual incidence of lethal type 2 Gaucher disease may be underestimated, as many cases may have been misclassified as collodion babies or hydrops of unknown cause.
- Published
- 1999
18. Autosomal Recessive Phosphorylase Kinase Deficiency in Liver, Caused by Mutations in the Gene Encoding the β Subunit (PHKB)
- Author
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Ellen A.C.M. van Beurden, Inge E.T. van den Berg, Helga E.M. Malingré, Ruud Berger, Marijke M. Boer, Johannis B.C. de Klerk, and Otto P. van Diggelen
- Subjects
Heterozygote ,Erythrocytes ,Phosphorylase Kinase ,Protein subunit ,DNA Mutational Analysis ,Biology ,medicine.disease_cause ,Compound heterozygosity ,Glycogen phosphorylase ,medicine ,Genetics ,Humans ,Genetics(clinical) ,Phosphorylase kinase ,Gene ,Genetics (clinical) ,Mutation ,Polymorphism, Genetic ,Transition (genetics) ,Molecular biology ,Stop codon ,Pedigree ,Liver ,Child, Preschool ,Female ,Carbohydrate Metabolism, Inborn Errors ,Research Article - Abstract
The association of autosomal recessive phosphorylase kinase deficiency in liver of a 3 1/2-year-old female child with mutations in the gene encoding the common part of the beta subunit of phosphorylase kinase is reported. The proband had a severe deficiency of phosphorylase kinase in liver, while the phosphorylase kinase activity in erythrocytes was only slightly diminished. She had no symptoms of muscle involvement. The complete coding sequences of the liver gamma subunit and of the beta subunit of phosphorylase kinase of the proband were analyzed for the presence of mutations, by either reverse-transcribed PCR or SSCP analysis. Three deviations from the normal sequence were found in the region encoding the common part of the beta subunit of phosphorylase kinase-namely, a 1827G-->A (W609X) transition, a 2309A-->G (Y770C) transition, and a deletion of nucleotides 2896-2911-whereas no mutations were detected in the sequence encoding the liver gamma subunit of phosphorylase kinase. The 1827G-->A mutation and the deletion both result in the formation of early stop codons. Investigation of DNA showed that the deletion is caused by a splice-acceptor site mutation (IVS30(-1),g-->t). Family analysis revealed that the 1827G-->A and IVS30(-1),g-->t substitutions are located on different parental chromosomes and that compound heterozygosity for these mutations segregates with the disease. The 2309A-->G mutation was detected in 2%-3% of the normal population. Thus, it is concluded that the deficiency of phosphorylase kinase in this proband is caused by compound heterozygosity for the 1827G-->A and the IVS30(-1),g-->t mutations and that the 2309A-->G mutation is a polymorphism. This implies that a defect in the sequence encoding the common part of the beta subunit of phosphorylase kinase may present as liver phosphorylase kinase deficiency.
- Published
- 1997
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19. Two extremes of the clinical spectrum of glycogen storage disease type II in one family: A matter of genotype
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Arnold J. J. Reuser, Marian A. Kroos, Wim J. Kleijer, Otto P. van Diggelen, and Magna Van der Kraan
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Delta ,Genetics ,Glycogen ,Offspring ,Biology ,Compound heterozygosity ,medicine.disease ,chemistry.chemical_compound ,chemistry ,Genotype ,Glycogen storage disease type II ,Mutation testing ,medicine ,Allele ,Genetics (clinical) - Abstract
Mutation analysis was performed in a nonconsanguineous Dutch caucasian family with a grandfather presenting the first symptoms of glycogen storage disease type II (acid alpha-glucosidase deficiency) in the sixth decade of life and a grandchild with onset of symptoms shortly after birth. The grandfather was identified as compound heterozygote having the IVS1(-13T-->G)/delta T525 combination of mutant acid alpha-glucosidase alleles, the affected third generation offspring as homozygote delta T525/delta T525. The disease phenotypes in this family are in accordance with the genotypes since the IVS1(-13T-->G) mutation reduces acid alpha-glucosidase synthesis by 60 to 80%, whereas the delta T525 mutation completely prohibits the formation of catalytically active enzyme. Four additional families were identified with patients homozygote for delta T525 and five others with an equally deleterious delta T525/delta exon 18 genotype. The nine latter patients had typically the infantile form of glycogen storage disease type II. The genotype-phenotype correlation is irrefutable.
- Published
- 1997
20. Diagnosing Lysosomal Storage Disorders: Mucopolysaccharidosis Type II
- Author
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Olaf Bodamer, Otto P. van Diggelen, Angela Dajnoki, and Britt A. Johnson
- Subjects
Male ,medicine.medical_specialty ,Pathology ,Dermatan Sulfate ,Gene mutation ,Mucopolysaccharidosis type I ,Internal medicine ,Mucopolysaccharidosis I ,Genetics ,medicine ,Humans ,Fluorometry ,Mucopolysaccharidosis type II ,Hurler syndrome ,Genetics (clinical) ,Glycoproteins ,Mucopolysaccharidosis II ,business.industry ,Hunter syndrome ,Enzyme replacement therapy ,medicine.disease ,Endocrinology ,Female ,Dried Blood Spot Testing ,Heparitin Sulfate ,Lysosomes ,Iduronidase ,business - Abstract
Mucopolysaccharidosis type II (MPS II) is an X-linked lysosomal storage disorder caused by a deficiency of iduronate 2-sulfatase (IDS). Progressive, intralysosomal accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate in almost all tissues leads to multi-organ involvement in affected males but to virtual absence of symptoms in heterozygote female carriers due to preferential inactivation of the mutant allele. Diagnosis of MPS II in males is based on IDS analysis in leukocytes, fibroblasts, plasma, or dried blood spots (DBS), whereas IDS activities may be within the normal range in heterozygote females. The advent of fluorometric and mass spectrometry methods for enzyme analysis in DBS has simplified the diagnostic approach for MPS II males. Molecular analysis of the IDS gene confirms the diagnosis of MPS II in males and is the only diagnostic test to confirm carrier status in females. This unit provides detailed analytical protocols for measurement of IDS activity in DBS and plasma using a fluorometric assay.
- Published
- 2013
21. Residual alpha-L-iduronidase activity in fibroblasts of mild to severe Mucopolysaccharidosis type I patients
- Author
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Ans T. van der Ploeg, Esmee Oussoren, Linda F. Oemardien, Remco G. M. Timmermans, George J. G. Ruijter, Otto P. van Diggelen, J. L. M. Keulemans, Pediatrics, Clinical Genetics, and Internal Medicine
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Mucopolysaccharidosis ,Mucopolysaccharidosis I ,Biochemistry ,Cell Line ,03 medical and health sciences ,Mucopolysaccharidosis type I ,Iduronidase ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Genetics ,medicine ,Humans ,skin and connective tissue diseases ,Hurler syndrome ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Newborn screening ,business.industry ,Hurler–Scheie syndrome ,Infant, Newborn ,nutritional and metabolic diseases ,Enzyme replacement therapy ,Fibroblasts ,medicine.disease ,Transplantation ,Early Diagnosis ,Mutation ,business ,Scheie syndrome ,030217 neurology & neurosurgery ,Hymecromone - Abstract
Three major clinical subgroups are usually distinguished in Mucopolysaccharidosis type I: Hurler (MPS IH, severe presentation), Hurler-Scheie (MPS IH/S, intermediate) and Scheie (MPS IS, mild). To facilitate treatment with hematopoietic stem-cell transplantation, early diagnosis is important for MPS IH patients. Although screening for MPS I in newborns would allow detection at an early age, it may be difficult to predict the phenotype on the basis of the genotype in these infants. Extra diagnostic tools are thus required. Based on the hypothesis that distinct MPS I phenotypes may result from differences in residual α-l-iduronidase (IDUA) activity, we modified the common IDUA assay using the substrate 4-methylumbelliferyl-α-l-iduronide to allow quantification of low IDUA activity in MPS I fibroblasts. Enzyme incubation was performed with high protein concentrations at different time points up to 8h. Mean residual IDUA activity was 0.18% (range 0-0.6) of the control value in MPS IH fibroblasts (n=5); against 0.27% (range 0.2-0.3) in MPS IH/S cells (n=3); and 0.79% (range 0.3-1.8) in MPS IS fibroblasts (n=5). These results suggest that residual IDUA activity and severity of the MPS I phenotype are correlated. Two MPS IS patients with rare (E276K/E276K) or indefinite (A327P/unknown) IDUA genotypes had residual IDUA activity in the MPS IS range, illustrating the usefulness of our approach. IDUA(E276K) was very unstable at 37°C, but more stable at 23°C, suggesting thermal instability. We conclude that this procedure for determining residual IDUA activity in fibroblasts of MPS I patients may be helpful to predict MPS I phenotype.
- Published
- 2013
22. Genotype-phenotype correlation in adult-onset acid maltase deficiency
- Author
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Marian A. Kroos, Frans G. I. Jennekens, Margreet G. E. M. Ausems, Marie-José H. van den Boogaard, Hans Kristian Ploos van Amstel, Otto P. van Diggelen, Elly F. Ippel, John H. J. Wokke, Marijke Boer, and Arnold J. J. Reuser
- Subjects
Adult ,Male ,Proband ,medicine.medical_specialty ,Adolescent ,Genotype ,Molecular Sequence Data ,Biology ,Compound heterozygosity ,Exon ,Internal medicine ,medicine ,Humans ,Age of Onset ,Allele ,Transversion ,Alleles ,Genetics ,Base Sequence ,Glycogen Storage Disease Type II ,Muscle weakness ,alpha-Glucosidases ,DNA ,Middle Aged ,Phenotype ,Endocrinology ,Neurology ,Mutation ,Female ,Neurology (clinical) ,Glucan 1,4-alpha-Glucosidase ,Age of onset ,medicine.symptom - Abstract
We performed a clinical, biochemical, and genetic study in 16 patients from 11 families with adult-onset acid maltase deficiency. All patients were compound heterozygotes and carried the IVS1(-13T --G) transversion on one allele; the second allele harbored either a deletion of a T at position 525 in exon 2 (7 probands, 64%) or a deletion of exon 18 (1 proband, 9%). Deterioration of handicap was related to age, and decrease in vital capacity to duration of the symptomatic stage. Respiratory insufficiency was never the first manifestation. The levels of activity of serum creatine kinase and of alpha-glucosidase in peripheral blood cells or muscle were helpful for the diagnosis, but did not have prognostic value. The adult form of acid maltase deficiency appears to be both clinically and genetically rather homogeneous; decrease of alpha-glucosidase activity is the final common pathway leading to destruction of muscle fibers and progression of muscle weakness over a period of years.
- Published
- 1995
23. Mucopolysaccharidosis Type IIID: 12 New Patients and 15 Novel Mutations
- Author
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George J G Ruijter, Friederike Bürger, D. Eckert, Feikje van den Bos-Terpstra, Martinus F. Niermeijer, Fatih Süheyl Ezgü, Ron A. Wevers, Peter Elfferich, Ayşegül Tokatlı, Ben J. H. M. Poorthuis, Marja W. Wessels, Dicky J. Halley, Emil Simeonov, Otto P. van Diggelen, Hugues Puissant, Ad N. Bosschaart, Aida M. Bertoli-Avella, Heymut Omran, Marlies J. Valstar, Roxana Kariminejad, Mirella Filocamo, Barbara Czartoryska, Renske Olmer, Patrick J. Willems, Sanne Neijs, Bianca M. de Graaf, Paediatric Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Medical Biochemistry, Pediatrics, Clinical Genetics, and Pediatric Surgery
- Subjects
Adult ,Male ,Adolescent ,DNA Mutational Analysis ,Nonsense mutation ,Neuroinformatics [DCN 3] ,Biology ,Frameshift mutation ,Mucopolysaccharidosis III ,Young Adult ,Genetics ,medicine ,Humans ,Missense mutation ,Child ,Genetics (clinical) ,Sanfilippo syndrome ,Mucopolysaccharidosis Type IIID ,Glycostation disorders [IGMD 4] ,N-acetylglucosamine-6-sulfatase ,medicine.disease ,Phenotype ,Child, Preschool ,Mutation ,Mutation testing ,Female ,Sulfatases ,Functional Neurogenomics [DCN 2] - Abstract
Contains fulltext : 89263.pdf (Publisher’s version ) (Closed access) Mucopolysaccharidosis III D (Sanfilippo disease type D, MPS IIID) is a rare autosomal recessive lysosomal storage disorder previously described in only 20 patients. MPS IIID is caused by a deficiency of N-acetylglucosamine-6-sulphate sulphatase (GNS), one of the enzymes required for the degradation of heparan sulphate. So far only seven mutations in the GNS gene have been reported. The clinical phenotype of 12 new MPS IIID patients from 10 families was studied. Mutation analysis of GNS was performed in 16 patients (14 index cases). Clinical signs and symptoms of the MPS IIID patients appeared to be similar to previously described patients with MPS III. Early development was normal with onset of behavioral problems around the age of 4 years, followed by developmental stagnation, deterioration of verbal communication and subsequent deterioration of motor functions. Sequence analysis of the coding regions of the gene encoding GNS (GNS) resulted in the identification of 15 novel mutations: 3 missense mutations, 1 nonsense mutation, 4 splice site mutations, 3 frame shift mutations, 3 large deletions and 1 in-frame small deletion. They include the first missense mutations and a relatively high proportion of large rearrangements, which warrants the inclusion of quantitative techniques in routine mutation screening of the GNS gene. 01 mei 2010
- Published
- 2010
24. WITHDRAWN: 86 Sixteen years of experience of biochemical analysis and prenatal diagnosis of lysosomal storage disease in Iran
- Author
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Bita Bozrgmehr, Fariba Afroozan, Jan G.M. Huijman, Mohammad Hasan Karimi-Nejad, Navid Almadani, Otto P. Van Diggelen, Roxana Kariminejad, Valeh Hadavi, and Wim J. Kleijer
- Subjects
Endocrinology ,Endocrinology, Diabetes and Metabolism ,Genetics ,Molecular Biology ,Biochemistry - Published
- 2007
25. Mutations in TMEM76* cause mucopolysaccharidosis IIIC (Sanfilippo C syndrome)
- Author
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Jacek Majewski, Robert Ivanek, Jérôme Ausseil, Viktor Stránecký, Volkan Seyrantepe, Kenneth Morgan, David Roquis, Jiddeke M. van de Kamp, Nicole M. Roslin, Andrei Verner, Otto P. van Diggelen, Stanislav Kmoch, Ben J. H. M. Poorthuis, Irène Maire, T. Mary Fujiwara, Clare E. Beesley, Hana Hartmannová, Ron A. Wevers, Martin Hřebíček, Stéphanie Durand, Thomas J. Hudson, Jana Uřinovská, Alexey V. Pshezhetsky, Helena Poupětová, Alena Čížková, Jiří Zeman, Lenka Nosková, Pierre Lepage, Lenka Mrázová, Jakub Sikora, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Medical Biochemistry
- Subjects
Male ,DNA, Complementary ,Energy and redox metabolism [NCMLS 4] ,Recombinant Fusion Proteins ,Mucopolysaccharidosis ,DNA Mutational Analysis ,Molecular Sequence Data ,Nonsense mutation ,Gene Expression ,Neuroinformatics [DCN 3] ,Biology ,Transfection ,medicine.disease_cause ,Polymerase Chain Reaction ,Article ,Cell Line ,Frameshift mutation ,Mice ,Mucopolysaccharidosis III ,Acetyltransferases ,Perception and Action [DCN 1] ,medicine ,Genetics ,Animals ,Humans ,Genetics(clinical) ,Amino Acid Sequence ,Cloning, Molecular ,Genetics (clinical) ,Mutation ,Base Sequence ,Sequence Homology, Amino Acid ,Mucopolysaccharidosis Type IIIC ,Chromosome Mapping ,Exons ,Glycostation disorders [IGMD 4] ,medicine.disease ,Molecular biology ,Neuromuscular development and genetic disorders [UMCN 3.1] ,Transmembrane protein ,Pedigree ,Transmembrane domain ,Genetic defects of metabolism [UMCN 5.1] ,Female ,Chromosomes, Human, Pair 8 - Abstract
Contains fulltext : 50018.pdf (Publisher’s version ) (Closed access) Mucopolysaccharidosis IIIC (MPS IIIC, or Sanfilippo C syndrome) is a lysosomal storage disorder caused by the inherited deficiency of the lysosomal membrane enzyme acetyl-coenzyme A: alpha -glucosaminide N-acetyltransferase (N-acetyltransferase), which leads to impaired degradation of heparan sulfate. We report the narrowing of the candidate region to a 2.6-cM interval between D8S1051 and D8S1831 and the identification of the transmembrane protein 76 gene (TMEM76), which encodes a 73-kDa protein with predicted multiple transmembrane domains and glycosylation sites, as the gene that causes MPS IIIC when it is mutated. Four nonsense mutations, 3 frameshift mutations due to deletions or a duplication, 6 splice-site mutations, and 14 missense mutations were identified among 30 probands with MPS IIIC. Functional expression of human TMEM76 and the mouse ortholog demonstrates that it is the gene that encodes the lysosomal N-acetyltransferase and suggests that this enzyme belongs to a new structural class of proteins that transport the activated acetyl residues across the cell membrane.
- Published
- 2006
26. The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literature
- Author
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Wim C. J. Hop, Otto P. van Diggelen, G. Peter A. Smit, B. T. Poll-The, Ans T. van der Ploeg, Jan A.M. Smeitink, Johannis B.C. de Klerk, Hannerieke Van den Hout, Henk D. Bakker, M Christa B Loonen, Arnold J. J. Reuser, Pediatrics, Epidemiology, Clinical Genetics, and Neurology
- Subjects
medicine.medical_specialty ,Pediatrics ,Heart disease ,Physical examination ,Cardiomegaly ,Child Development ,Internal medicine ,Glycogen storage disease type II ,medicine ,Humans ,Alglucosidase alfa ,Netherlands ,biology ,medicine.diagnostic_test ,business.industry ,Glycogen Storage Disease Type II ,Hypertrophic cardiomyopathy ,Infant, Newborn ,Brain ,Infant ,alpha-Glucosidases ,Enzyme replacement therapy ,medicine.disease ,Survival Analysis ,Endocrinology ,Genetic defects of metabolism [UMCN 5.1] ,Pediatrics, Perinatology and Child Health ,Mutation ,Acid alpha-glucosidase ,biology.protein ,Disease Progression ,Creatine kinase ,business ,Cellular energy metabolism [UMCN 5.3] ,Blood Chemical Analysis ,Infant, Premature ,medicine.drug - Abstract
Objective. Infantile Pompe’s disease is a lethal cardiac and muscular disorder. Current developments toward enzyme replacement therapy are promising. The aim of our study is to delineate the natural course of the disease to verify endpoints of clinical studies.Methods. A total of 20 infantile patients diagnosed by the collaborative Dutch centers and 133 cases reported in literature were included in the study. Information on clinical history, physical examination, and diagnostic parameters was collected.Results. The course of Pompe’s disease is essentially the same in the Dutch and the general patient population. Symptoms start at a median age of 1.6 months in both groups. The median age of death is 7.7 and 6 months, respectively. Five percent of the Dutch patients and 8% of all reported patients survive beyond 1 year of age. Only 2 patients from literature became older than 18 months. A progressive cardiac hypertrophy is characteristic for infantile Pompe’s disease. The diastolic thickness of the left ventricular posterior wall and cardiac weight at autopsy increase significantly with age. Motor development is severely delayed and major developmental milestones are generally not achieved. For the Dutch patient group, growth deviates significantly from normal despite start of nasogastric tube feeding. Levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine kinase, or creatine kinase-myocardial band isoenzyme are typically elevated, although aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase increase significantly with age. The patients have fully deleterious mutations. Acid α-glucosidase activity is severely deficient.Conclusions. Survival, decrease of the diastolic thickness of the left ventricular posterior wall, and achievement of major motor milestones are valid endpoints for therapeutic studies of infantile Pompe’s disease. Mutation analysis and measurement of the α-glucosidase activity should be part of the enrollment program.
- Published
- 2003
27. Palmitoyl protein thioesterase 1 is targeted to the axons in neurons
- Author
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Outi Kopra, Otto P. van Diggelen, Laura Ahtiainen, Anu Jalanko, and Clinical Genetics
- Subjects
Immunoelectron microscopy ,Blotting, Western ,Infantile neuronal ceroid lipofuscinosis ,Cell Culture Techniques ,Presynaptic Terminals ,Synaptophysin ,Nerve Tissue Proteins ,Biology ,Synaptic vesicle ,Hippocampus ,Retina ,Mice ,medicine ,Animals ,Palmitoyl protein thioesterase ,Microscopy, Immunoelectron ,Cerebral Cortex ,Neurons ,Membrane Glycoproteins ,General Neuroscience ,Colocalization ,PPT1 ,medicine.disease ,Axons ,Mice, Inbred C57BL ,Microscopy, Electron ,medicine.anatomical_structure ,nervous system ,biology.protein ,Thiolester Hydrolases ,Neuroscience ,Microtubule-Associated Proteins - Abstract
Palmitoyl protein thioesterase 1 (PPT1) is a depalmitoylating enzyme whose deficiency leads to infantile neuronal ceroid lipofuscinosis. The disease is characterized by early loss of vision and massive neuronal death. Although PPT1 is expressed in many tissues, a deficiency of PPT1 damages neurons only in the cerebral and cerebellar cortexes and retina; other cell types remain relatively unaffected. We previously demonstrated that PPT1 is present in the synaptosomes and synaptic vesicles of neurons. To understand the crucial role of PPT1 for neuronal cells, we further investigated the expression and targeting of PPT1 in retinal, hippocampal, and cortical neurons during their maturation in culture. We found that PPT1 activity increases by neuronal maturation and is highest in retinal neuron cultures. In retinal neurons the expression of PPT1 precedes that of the synaptic vesicle protein 2 and synaptophysin, indicating a significant role for PPT1 in the early development of neuronal cells. We also found by quantitative confocal immunofluorescence microscopy that PPT1 is targeted preferably to axons in mature neurons, as indicated by its colocalization with the axonal marker microtubule-associated protein 1. In axons PPT1 is targeted specifically to axonal varicosities and presynaptic terminals, as indicated by its significant colocalization with growth-associated protein 43 and synaptophysin. Axonal localization of PPT1 was confirmed by double labeling with synaptophysin and postembedding immunoelectron microscopy. The polarized axonal targeting of PPT1 may well indicate a role for PPT1 in the exocytotic pathway of neurons.
- Published
- 2002
28. Type I sialidosis: a clinical, biochemical and neuroradiological study
- Author
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Alessandro Malandrini, Danilo DeFalco, Jean G.M. Huijmans, Silvia Palmeri, Giancarlo Guazzi, Chantal Ceuterick, Jean Jacques Martin, Alessandra Rufa, Otto P. van Diggelen, G Ciacci, Marcello Villanova, and Clinical Genetics
- Subjects
Adult ,Cerebellum ,Pathology ,medicine.medical_specialty ,Disease ,Fourth ventricle ,Corpus callosum ,Atrophy ,Mucolipidoses ,Long period ,Humans ,Medicine ,Sialidosis ,Skin ,medicine.diagnostic_test ,business.industry ,Brain ,Magnetic resonance imaging ,medicine.disease ,Magnetic Resonance Imaging ,Microscopy, Electron ,medicine.anatomical_structure ,Neurology ,Female ,Neurology (clinical) ,Tomography, X-Ray Computed ,business - Abstract
We report biochemical, morphological and neuroradiological findings in a 40-year-old woman affected with type I sialidosis. The clinical symptoms, consisting of a cerebellar syndrome, were first noted at the age of 17 years. The macular cherry-red spot was first observed after 23 years of disease. A CT scan performed at 21 years of age showed enlargement of the fourth ventricle. Nuclear magnetic resonance imaging of the brain performed at the age of 40 showed severe atrophy of the cerebellum and pontine region; atrophy of cerebral hemispheres and of the corpus callosum was also observed. We emphasize the prolonged course of illness in this patient, observed over a long period of time. Of particular interest is the neuroradiological study showing our findings both at the beginning of the disease and after 20 years.
- Published
- 2000
29. An AsnLys substitution in saposin B involving a conserved amino acidic residue and leading to the loss of the single N-glycosylation site in a patient with metachromatic leukodystrophy and normal arylsulphatase A activity
- Author
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Mirella Filocamo, Stefano Regis, Fabio Corsolini, Rosanna Gatti, Otto P. van Diggelen, J. L. M. Keulemans, and Francesco Caroli
- Subjects
Male ,Sphingolipid Activator Proteins ,Glycosylation ,Molecular Sequence Data ,medicine.disease_cause ,Saposins ,Residue (chemistry) ,Genetics ,medicine ,Humans ,Amino Acid Sequence ,N-Glycosylation Site ,Genetics (clinical) ,Conserved Sequence ,Arylsulfatases ,Glycoproteins ,chemistry.chemical_classification ,Mutation ,Binding Sites ,Chemistry ,Lysine ,Leukodystrophy, Metachromatic ,medicine.disease ,Molecular biology ,Sphingolipid ,Metachromatic leukodystrophy ,Enzyme ,Biochemistry ,Amino Acid Substitution ,Child, Preschool ,Asparagine ,Glycoprotein - Abstract
Sphingolipid activator proteins are small glycoproteins required for the degradation of sphingolipids by specific lysosomal hydrolases. Four of them, called saposins, are encoded by the prosaposin gene, the product of which is proteolytically cleaved into the four mature saposin proteins (saposins A, B, C, D). One of these, saposin B, is necessary in the hydrolysis of sulphatide by arylsulphatase A where it presents the solubilised substrate to the enzyme. As an alternative to arylsulphatase A deficiency, deficiency of saposin B causes metachromatic leukodystrophy. We identified a previously undescribed mutation (N215K) in the prosaposin gene of a patient with metachromatic leukodystrophy but with normal arylsulphatase A activity and elevated sulphatide in urine. The mutation involves a highly conserved amino acidic residue and abolishes the only N-glycosylation site of saposin B.
- Published
- 1999
30. Molecular defects underlying Wolman disease appear to be more heterogeneous than those resulting in cholesteryl ester storage disease
- Author
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Pia Lohse, Peter Lohse, Otto P. van Diggelen, Adrian C. Sewell, Sylke Maas, Dietrich Seidel, and Clinical Genetics
- Subjects
chemistry.chemical_classification ,genotype ,QD415-436 ,Cell Biology ,Biology ,Compound heterozygosity ,Biochemistry ,Amino acid ,Frameshift mutation ,Exon ,chemistry.chemical_compound ,Endocrinology ,chemistry ,lipid metabolism ,lysosomal acid lipase ,Cholesteryl ester ,enzyme deficiency ,Peptide sequence ,Gene ,mutation analysis ,Lipoprotein - Abstract
Human lysosomal acid lipase/cholesteryl ester hydrolase (hLAL) is essential for the intralysosomal metabolism of cholesteryl esters and triglycerides taken up by receptor-mediated endocytosis of lipoprotein particles. The key role of the enzyme in intracellular lipid homeostasis is illustrated by two lysosomal storage diseases inherited as autosomal recessive traits. Wolman disease, associated with deficient hLAL activity, leads to massive intracellular substrate accumulation and is always fatal in early infancy. Cholesteryl ester storage disease (CESD), in contrast, is characterized by very low levels of enzymic activity sufficient to allow survival of the affected patients into adulthood. In order to elucidate the underlying molecular defects in Wolman disease, we have characterized the hLAL gene in two female Wolman patients of German and Turkish origin by SSCP and DNA sequence analysis. Our results demonstrate that the German proband was compound heterozygous for an 8-bp deletion in exon 3 and a 2-bp deletion in exon 4 of the hLAL gene. These frameshift mutations lead to protein truncation at amino acid positions 24 and 116 and to complete loss of hydrolytic activity. The Turkish proband, in contrast, was homozygous for a G1064→T substitution in exon 10 of the hLAL gene which converts the completely conserved glycine (GGG) residue at position 321 of the mature enzyme to tryptophan (TGG). In vitro expression of the hLAL(Gly321→Trp) cDNA construct revealed that the amino acid replacement results in a more than 99% reduction of neutral lipid hydrolysis. The mutations provide new insights into the molecular basis of Wolman disease which is apparently more heterogeneous at the genetic level than cholesteryl ester storage disease.—Lohse, P., S. Maas, P. Lohse, A. C. Sewell, O. P. van Diggelen, and D. Seidel. Molecular defects underlying Wolman disease appear to be more heterogeneous than those resulting in cholesteryl ester storage disease. J. Lipid Res. 1999. 40: 221–228.
- Published
- 1999
31. Two distinct deletions in the IDS gene and the gene W: a novel type of mutation associated with the Hunter syndrome
- Author
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Kristina Lagerstedt, Barbara Czartoryska, Britt-Marie Carlberg, Stanislav L. Karsten, Jacek Zaremba, Wim J. Kleijer, Ulf Pettersson, Otto P. van Diggelen, Marie-Louise Bondeson, and Clinical Genetics
- Subjects
Male ,X Chromosome ,Molecular Sequence Data ,Gene Expression ,Locus (genetics) ,Iduronate Sulfatase ,Biology ,Exon ,Genetics ,Direct repeat ,Humans ,Deletion mapping ,Mucopolysaccharidosis type II ,Child ,Gene ,Southern blot ,Mucopolysaccharidosis II ,Sequence Deletion ,Recombination, Genetic ,Base Sequence ,Iduronate-2-sulfatase ,Exons ,Sequence Analysis, DNA ,Molecular biology ,Introns ,Blotting, Southern ,Multigene Family - Abstract
A novel mutation has been identified in a patient with the Hunter syndrome (mucopolysaccharidosis type II), in whom the disorder is associated with two distinct deletions separated by 30 kb. The deletions were characterized by Southern blot and PCR analyses, and the nucleotide sequences at both junctions were determined. The first deletion, corresponding to a loss of 3152 bp of DNA, included exons 5 and 6 of the iduronate-2-sulfatase (IDS) gene. The second deletion was 3603 bp long and included exons 3 and 4 of gene W, which is located in the DXS466 locus telomeric of the IDS gene. Both deletions are the result of nonhomologous (illegitimate) recombination events between short direct repeats at the deletion breakpoints. An interesting finding was the presence of the heptamer sequence 5'-TACTCTA-3' present at both deletion junctions, suggesting that this motif might be a hot spot for recombination. We propose that the double deletion is the result of homology-associated nonhomologous recombinations caused by the presence of large duplicated regions in Xq27.3-q28.
- Published
- 1997
32. Identification of 16 Sulfamidase Gene Mutations Including the Common R74C in Patients With Mucopolysaccharidosis type IIIA (Sanfilippo A)
- Author
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Hüseyin Ince, Otto P. van Diggelen, Wim J. Kleijer, Andreas Gal, Jacek Zaremba, John J. Hopwood, Birgit Weber, Cordula Steglich, Susanna Bunge, Michael Beck, and Clinical Genetics
- Subjects
Hydrolases ,Mucopolysaccharidosis type III ,Gene mutation ,Biology ,medicine.disease_cause ,Genetic Heterogeneity ,Mucopolysaccharidosis III ,Gene Frequency ,Genetics ,medicine ,Missense mutation ,Humans ,Mucopolysaccharidosis Type IIIA ,Genetics (clinical) ,Cells, Cultured ,Polymorphism, Single-Stranded Conformational ,Mutation ,Splice site mutation ,Binding Sites ,Genetic heterogeneity ,Point mutation ,Nucleic Acid Heteroduplexes ,Fibroblasts ,Molecular biology ,Europe ,Genes - Abstract
Mucopolysaccharidosis type IIIA (MPS IIIA or Sanfilippo A disease) is a storage disorder caused by deficiency of the lysosomal enzyme sulfamidase. Mutation screening, using SSCP/heteroduplex analyses on cDNA and genomic DNA fragments, was performed in a group of 42 European patients. Sixteen of the 17 different gene mutations characterized have not been previously described. The spectrum of gene lesions consists of two 1-bp deletions (1091delC, 1093delG), an 18-bp duplication (421ins18), a splice site mutation (IVS2-2A-->G), and 13 different missense point mutations. As in other lysosomal storage disorders, the phenotypic heterogeneity is associated with a considerable genetic heterogeneity. The missense mutation R74C, which alters an evolutionary conserved amino acid in the active site of the enzyme, was found on 56% of alleles of 16 Polish patients, whereas it was less frequent among German patients (21% of disease alleles). R245H, a previously reported common mutation, represents 35% of disease alleles in German patients, but only 3% in Polish patients. As the combined frequency of the common mutations (R74C and R245H) in German and Polish populations exceeds 55%, screening for these two mutations will assist molecular genetic diagnosis of MPS IIIA and allow heterozygote testing in these populations.
- Published
- 1997
33. A fatal, systemic mitochondrial disease with decreased mitochondrial enzyme activities, abnormal ultrastructure of the mitochondria and deficiency of heat shock protein 60
- Author
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Kari Skullerud, Richard Hallberg, Hans R. Scholte, Otto P. van Diggelen, Marten Veenhuis, Ola H. Skjeldal, Marcel H. J. Ruiters, Radhey S. Gupta, Klaziena Niezen-Koning, Anke Huckriede, E Agsteribbe, Groningen Biomolecular Sciences and Biotechnology, Translational Immunology Groningen (TRIGR), Vascular Ageing Programme (VAP), Center for Liver, Digestive and Metabolic Diseases (CLDM), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
- Subjects
medicine.medical_specialty ,ACYL-COA ,Mitochondrial disease ,Biophysics ,Oxidative phosphorylation ,Vacuole ,Mitochondrion ,Biology ,Biochemistry ,Mitochondrial Encephalomyopathies ,Internal medicine ,Heat shock protein ,Organelle ,Pyruvic Acid ,medicine ,Humans ,Lactic Acid ,Pyruvates ,Molecular Biology ,Cells, Cultured ,Heat-Shock Proteins ,Infant, Newborn ,Metabolic acidosis ,Cell Biology ,Fibroblasts ,medicine.disease ,LEUKOCYTES ,Mitochondria ,Microscopy, Electron ,Endocrinology ,Glucose ,Lactates ,SKELETAL-MUSCLE ,HSP60 ,Female - Abstract
We report on a girl presenting with facial dysmorphic features and breathing difficulties upon birth. She was hypotonic, developed a metabolic acidosis, and died two days old of heart failure. Post-mortem examination revealed abnormalities of brain, lungs, heart and liver. In cultured skin fibroblasts activities of enzymes of oxidative phosphorylation, pyruvate metabolism, beta-oxidation and other mitochondrial (mt) metabolic pathways were markedly decreased. Activities of enzymes localized in the mt outer membrane or in other cell organelles were found to be normal. The mitochondria appeared swollen and were located mainly around the nucleus. Electron micrographs showed locally disintegrated mt inner membranes and large mt vacuoles. The amount of mt heat shock protein 60 (hsp60) was about one fifth of that in controls. We conclude that this mt disorder is most likely caused by defective synthesis and maintenance of mitochondria, possibly due to a defect in mt protein import or enzyme assembly resulting from deficiency of hsp60.
- Published
- 1993
34. 54. Sanfilippo syndrome type C: Novel mutations in the HGSNAT gene
- Author
-
Matthew Feldhammer, Lenka Mrázová, Alexey V. Pshezhetsky, Stéphanie Durand, Stanislav Kmoch, M. Hrebicek, and Otto P. van Diggelen
- Subjects
Genetics ,Endocrinology ,Endocrinology, Diabetes and Metabolism ,medicine ,Biology ,medicine.disease ,Molecular Biology ,Biochemistry ,Sanfilippo syndrome ,HGSNAT gene - Published
- 2009
35. Enzyme replacement therapy in late‐onset Pompe's disease: A three‐year follow‐up.
- Author
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Léon P. F. Winkel, Johanna M. P. Van den Hout, Joep H. J. Kamphoven, Janus A. M. Disseldorp, Maaike Remmerswaal, Willem F. M. Arts, M. Christa B. Loonen, Arnold G. Vulto, Pieter A. Van Doorn, Gerard De Jong, Wim Hop, G. Peter A. Smit, Stuart K. Shapira, Marijke A. Boer, Arnold J. J. Reuser, Ans T. Van der Ploeg, and Otto P. van Diggelen
- Published
- 2004
36. Storage of sialic acid-containing carbohydrates in the placenta of a human galactosialidosis fetus
- Author
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Hans Galjaard, Johannes van Pelt, Otto P. van Diggelen, Johannes F.G. Vliegenthart, Johannis P. Kamerling, and J. Albert van Kuik
- Subjects
chemistry.chemical_classification ,Fetus ,Chromatography ,biology ,Oligosaccharide ,medicine.disease ,Biochemistry ,High-performance liquid chromatography ,Sialic acid ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Placenta ,medicine ,biology.protein ,Sugar ,Galactosialidosis ,Neuraminidase - Abstract
From the placenta of a human fetus with galactosialidosis, detected by prenatal diagnosis, sialyloligosaccharides were isolated by successively gel-permeation chromatography on Bio-Gel P-6, anion-exchange chromatography on Mono Q and high-performance liquid chromatography on Lichrosorb-NH2. 16 sialic acid-containing N-glycosidic N-acetyllactosamine type of structures were identified by sugar analysis and 500-MHz 1H-NMR spectroscopy. The fully sialylated oligosaccharides differ from each other in the type of branching (mono-, di-, tri-, tri'-, and tetra-antennary) or sialic acid linkage types (alpha2-3/alpha2-6). The isolated carbohydrates, including six novel structures, can be presented as follows (the numerals in a column represent one compound).
- Published
- 1988
37. Morquio B syndrome: A primary defect in β-galactosidase
- Author
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Gijsbertus T. J. van der Horst, W. Blom, Wim J. Kleijer, Otto P. van Diggelen, J. G. M. Huijmans, and André T. Hoogeveen
- Subjects
Neuraminidase ,Oligosaccharides ,Hybrid Cells ,medicine.disease_cause ,Glycosaminoglycan ,Lactose Intolerance ,medicine ,Humans ,Beta-galactosidase ,Fibroblast ,Genetics (clinical) ,Glycosaminoglycans ,chemistry.chemical_classification ,Mutation ,Galactosidases ,biology ,Structural gene ,Mucopolysaccharidosis IV ,Fibroblasts ,beta-Galactosidase ,Molecular biology ,Enzyme ,medicine.anatomical_structure ,chemistry ,Biochemistry ,biology.protein - Abstract
Fibroblasts from patients with Morquio B syndrome contain normal numbers of beta-galactosidase molecules with normal turnover but strongly reduced activity per enzyme molecule. Various substrate affinities are abnormal: the Km for methylum belliferyl (MU)-beta-galactoside is 4-10-fold elevated and affinity for keratan sulphate and oligosaccharides, isolated from Morquio B urine, was not detectable. In contrast, these substrate affinities are normal for beta-galactosidase in adult type GM1-gangliosidosis fibroblasts. Cell hybridization studies demonstrate that Morquio B syndrome and infantile and adult type GM1-gangliosidosis belong to the same complementation group. From these results we conclude that Morquio B syndrome is caused by a mutation in the structural gene for beta-galactosidase, which is allelic to the mutations in infantile and adult type GM1-gangliosidosis. Urinary excretion of keratan sulphate and oligosaccharides is abnormal in Morquio B syndrome but normal in adult type GM1-gangliosidosis. The catalytic properties of beta-galactosidase in Morquio B syndrome and GM1-gangliosidosis provide a possible explanation for the distinct clinical manifestations in these disorders.
- Published
- 1983
38. Electrophoretic Separation of Escherichia coli Ribosomal Particles on Polyacrylamide Gels
- Author
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Menno Brongers, Otto P. van Diggelen, Anneke Talens, Leendert Bosch, and Liviu M. Popa
- Subjects
Sucrose ,Macromolecular Substances ,Polyacrylamide ,Biology ,medicine.disease_cause ,Biochemistry ,Ribosome ,chemistry.chemical_compound ,Centrifugation, Density Gradient ,Escherichia coli ,Methods ,medicine ,Peptide bond ,Magnesium ,Chromatography ,Ribosomal RNA ,Electrophoresis ,chemistry ,RNA, Ribosomal ,Protein Biosynthesis ,Acrylamide ,Agarose ,Electrophoresis, Polyacrylamide Gel ,Gels ,Ribosomes - Abstract
Escherichia coli ribosomes display a remarkable heterogeneity when submitted to polyacrylamide-gel electrophoresis (4% acrylamide). Both the 70-S ribosomes and 50-S ribosomal subunits are resolved into at least four and the 30-S ribosomal subunits into three particle subclasses. After reversal of the current, all particles refocus into one single band at the origin. Ribosomes recovered from the gel after electrophoresis have retained some 40–100% of their capacity to synthesize peptide bonds. Their sedimentation behaviour has remained unaltered. Upon reelectrophoresis, no new peaks are detectable although the relative proportions of the various subclasses are frequently changed. The ratio in the occurrence of these subclasses is readily affected by a variety of factors, however, some of which are not directly related to the electrophoretic technique itself. The three classes of ribosomes and subunits (70-S, 50-S and 30-S) display approximately equal electrophoretic mobilities when the sieving action is reduced to a minimum. This conclusion follows from experiments in which the ribosomes are submitted to electrophoresis in a sucrose gradient or in 0.4% agarose gels. In contrast, electrophoresis in polyacrylamide gels with a gradient in pore size reveals the same ribosomal diversity as noted in gels with a fixed acrylamide concentration of 4%. In these pore-gradient gels (3-8% acrylamide), the migration rate of each ribosomal subclass decreases continuosly when the time of electrophoresis is prolonged. After about 30 h, further penetration seems to be blocked. All three classes consist of particles with low electrophoretic mobility (designated I particles) and those which move faster (designated II particles). The I particles are partially converted to II particles by incubation at 37 °C and/or pelleting prior to electrophoresis. The II particles are converted to I particles upon raising the ribosome concentration. The electrophoretic profiles displayed by the various 50-S subclasses are not strongly affected by variations in Mg2+ concentration in the range 0.5-10.0 mM. The electropherograms of 30-S subunits become more diffuse when the Mg2+ concentration is raised. The possible occurrence of ribosomal dimers and/or conformation changes is discussed.
- Published
- 1973
39. Diagnosing mucopolysaccharidosis IVA
- Author
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Yin-Hsiu Chien, Otto P. van Diggelen, Katie Harvey, Roberto Giugliani, Vânia D'Almeida, Zoltan Lukacs, Jerry N. Thompson, Paul Harmatz, Marzia Pasquali, Maira Graeff Burin, Sara M. Hawley, Nicole Miller, David Ketteridge, Heather J. Church, Chunli Yu, Tim Wood, Wuh-Liang Hwu, Andrea Schenone, Karen Tylee, Christian J. Hendriksz, Michael Fietz, and Michael Beck
- Subjects
Pathology ,medicine.medical_specialty ,Morquio syndrome ,Multiple Sulfatase Deficiency Disease ,Mucopolysaccharidosis ,Clinical Sciences ,Biology ,Gene mutation ,Bioinformatics ,Mucopolysaccharidosis Type IVA ,Multiple sulfatase deficiency ,Mucolipidoses ,medicine ,Leukocytes ,Genetics ,Humans ,Genetics(clinical) ,Pathology, Molecular ,Genetics (clinical) ,Glycosaminoglycans ,Genetics & Heredity ,Molecular ,Mucopolysaccharidosis IV ,Hunter syndrome ,Fibroblasts ,medicine.disease ,Mutation ,Original Article ,sense organs ,Algorithms - Abstract
Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is an autosomal recessive lysosomal storage disorder resulting from a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) activity. Diagnosis can be challenging and requires agreement of clinical, radiographic, and laboratory findings. A group of biochemical genetics laboratory directors and clinicians involved in the diagnosis of MPS IVA, convened by BioMarin Pharmaceutical Inc., met to develop recommendations for diagnosis. The following conclusions were reached. Due to the wide variation and subtleties of radiographic findings, imaging of multiple body regions is recommended. Urinary glycosaminoglycan analysis is particularly problematic for MPS IVA and it is strongly recommended to proceed to enzyme activity testing even if urine appears normal when there is clinical suspicion of MPS IVA. Enzyme activity testing of GALNS is essential in diagnosing MPS IVA. Additional analyses to confirm sample integrity and rule out MPS IVB, multiple sulfatase deficiency, and mucolipidoses types II/III are critical as part of enzyme activity testing. Leukocytes or cultured dermal fibroblasts are strongly recommended for enzyme activity testing to confirm screening results. Molecular testing may also be used to confirm the diagnosis in many patients. However, two known or probable causative mutations may not be identified in all cases of MPS IVA. A diagnostic testing algorithm is presented which attempts to streamline this complex testing process.
- Full Text
- View/download PDF
40. A rapid fluorescence technique for electrophoretic identification of hypoxanthine phosphoribosyltransferase allozymes
- Author
-
Seung-il Shin and Otto P. van Diggelen
- Subjects
Electrophoresis ,Erythrocytes ,Mutant ,Hamster ,Dehydrogenase ,Biology ,Biochemistry ,Chinese hamster ,IMP dehydrogenase ,Genetics ,medicine ,Methods ,Humans ,Pentosyltransferases ,Inosine ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Cells, Cultured ,General Medicine ,Fibroblasts ,Hydrogen-Ion Concentration ,biology.organism_classification ,Molecular biology ,Diploidy ,Isoenzymes ,Spectrometry, Fluorescence ,Hypoxanthines ,biology.protein ,Phosphoribosyltransferase ,medicine.drug ,Hypoxanthine Phosphoribosyltransferase - Abstract
A method for the rapid identification of hypoxanthine phosphoribosyltransferase allozymes is described. It involves electrophoresis on cellulose acetate gel, followed by detection of the phosphoribosyltransferase activity through a fluorescent end product formed in a specific coupled reaction with inosine 5′-monophosphate dehydrogenase. This method has been used successfully to distinguish from each other the allozymes of man, mouse, Chinese hamster, Syrian hamster, and chicken, and should be useful for the biochemical characterization of cellular mutants and somatic cell hybrids utilizing hypoxanthine phosphoribosyltransferase as a selective marker.
- Published
- 1974
41. The association of ribosomal subunits of Escherichia coli. 1. Two types of association products differing in their apparent sedimentation coefficient
- Author
-
Leendert Bosch and Otto P. van Diggelen
- Subjects
Time Factors ,Protein subunit ,Biology ,medicine.disease_cause ,Biochemistry ,Ribosome ,Bacterial Proteins ,RNA, Transfer ,Peptide Initiation Factors ,Polysome ,medicine ,Centrifugation, Density Gradient ,Escherichia coli ,Magnesium ,Carbon Radioisotopes ,Binding site ,Amino Acids ,Peptide Chain Initiation, Translational ,Mercaptoethanol ,Binding Sites ,Ribosomal RNA ,Centrifugation, Zonal ,Sedimentation coefficient ,Kinetics ,RNA, Bacterial ,Isotope Labeling ,Polyribosomes ,Transfer RNA ,Electrophoresis, Polyacrylamide Gel ,Spectrophotometry, Ultraviolet ,Ribosomes ,Protein Binding - Abstract
Association between ribosomal subunits of Escherichia coli can lead to the formation of two classes of 30-S · 50-S couples. The first class sedimenting between 50 S and 70 S, arises when native subunits associate, the second sedimenting at 70 S upon coupling of so-called derived subunits. From cross experiments it is concluded that it is the 50-S subunit which determines the nature of the association product, whereas the 30-S subunit determines whether an association product can be formed. Native and derived 50-S subunits are indistinguishable by sucrose gradient centrifugation and do not differ qualitatively in their ability to form polypeptides under the directions of bacteriophage RNA. Native 30-S subunits lose a factor during isolation, probably IF-3. They are therefore able to associate at 0° and 37 °C. On the other hand derived 30-S subunits are unable to associate at 0 °C but they do so at 37 °C in the presence of 10 mM Mg2+. A number of trivial factors have been excluded to explain the difference between the two types of 50-S subunits. The preparation method is not responsible for the difference. Nor do the derived subunits contain peptidyl-tRNA, known to influence subunit association. The content of tRNA and aminoacyl-tRNA has been determined quantitatively by polyacrylamide-gel electrophoresis. None of the subunits nor the 70-S ribosomes from which the derived subunits are prepared contain a tRNA species.
- Published
- 1973
42. Phenotypic Alterations in Mammalian Cell Lines After Mycoplasma Infection
- Author
-
Seung-il Shin and Otto P. van Diggelen
- Subjects
Agar plate ,Cellular metabolism ,Cell culture ,Mycoplasma hyorhinis ,Mammalian cell ,medicine ,Mycoplasma ,Biology ,Hayflick limit ,medicine.disease_cause ,biology.organism_classification ,Phenotype ,Virology - Abstract
Contamination of cell cultures by mycoplasma can result in subtle or profound changes in cellular metabolism and function, and thereby produce serious experimental artifacts in studies of cellular biochemistry and physiology if the contamination remains undetected. Since many species of mycoplasmas do not cause overt cytopathic effects on the animal cells, and sometimes escape detection by the usual agar plate cultivation technique described by Hayflick (1), it is often difficult to state positively that a given cell culture is absolutely free of contaminating mycoplasmas. Particularly noteworthy in this regard are the “noncultivable” strains of Mycoplasma hyorhinis which cannot be cultured in the absence of animal cells they parasitize. These host-dependent, cryptic strains of mycoplasma have recently emerged as frequent contaminants in cell cultures.{See, for example, the contributions by Barile, DelGuidice and McGarrity in this volume.}
- Published
- 1978
43. Prenatal detection of cystic fibrosis; comparative study of maltase and alkaline phosphatase activities in amniotic fluid
- Author
-
H. J. Sips, Otto P. van Diggelen, Eveline Van Der Veer, Andreas H. W. Claass, and Wim J. Kleijer
- Subjects
Fetus ,medicine.medical_specialty ,Amniotic fluid ,Cystic Fibrosis ,Obstetrics and Gynecology ,Phenylalanine ,Prenatal diagnosis ,alpha-Glucosidases ,Biology ,medicine.disease ,Alkaline Phosphatase ,Amniotic Fluid ,Cystic fibrosis ,Endocrinology ,In utero ,Pregnancy ,Internal medicine ,medicine ,Amniocentesis ,Alkaline phosphatase ,Humans ,Female ,Maltase ,Genetics (clinical) - Abstract
The potential value of microvillar enzymes in the prenatal diagnosis of cystic fibrosis (CF) has previously been demonstrated and is corroborated in the present comparative study. Maltase and alkaline phosphatase (ALP) activities were studied in the amniotic fluids of 57 pregnancies with a 1 in 4 risk for CF or with a known CF outcome and in 489 controls. A simple assay for maltase activity (MU-maltase) with the fluorogenic substate 4-methylumbelliferyl α-glucoside, offers great technical advantages and an at least equal detection rate of CF, when compared to the previously used test with maltose as substrate. Intestinal ALP was estimated either as phenylalanine inhibitable activity (PI-ALP) or as the proportions of residual activity in the presence of the inhibitors phenylalanine or homoarginine. MU-maltase and PI-ALP appeared the most successful methods: both tests were able to detect 14 of the 16 (88 per cent) pregnancies with fetal CF. Each of the two tests alone also allowed a correct prediction in 24 of the 25 pregnancies at risk but with normal outcome; however all 25 cases could be correctly predicted by a combined evaluation. It is suggested that more than one intestinal enzyme activity should be evaluated to allow optimal results in the prenatal monitoring of pregnancies at high risk for CF.
- Published
- 1986
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