178,113 research outputs found
Proton MRS of a child with Sandhoff disease reveals elevated brain hexosamine
No full textSandhoff disease (gangliosidosis type 0) is a lysosomal storage disorder with a deficiency of hexosaminidases A and B. After an initially normal development the clinical course of affected children is severe and rapidly progressive leading to spastic tetraparesis, epileptic seizures and early death. In a 10-month-old girl with enzymatically established diagnosis of Sandhoff disease MRI of the brain showed signal changes in the periventricular white matter, pyramidal tract, basal ganglia, and cerebellar hemispheres. Proton MR spectroscopy (MRS) at the age of 13 months revealed a reduction of total N-acetylaspartate (neuroaxonal marker) as well as strongly elevated inositol (glial marker) in white matter, gray matter, and basal ganglia. A new resonance at 2.07ppm was detected in all regions and ascribed to N-acetylhexosamine with highest concentrations in white matter and thalamus. While conventional MRS findings are in line with neuroaxaonal damage and pronounced astrocytosis, the observation of N-acetylhexosamine appears as a specific marker of Sandhoff disease indicating accumulation of hexosamine-containing oligosaccharides. This interpretation is supported by a recent in vitro MRS study of a Sandhoff mouse model. in conclusion, proton MRS of cerebral metabolites offers specific insights into the pathopysiologic processes of children with Sandhoff disease and may prove to represent another disease specific MRS pattern of the brain. (c) 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved
Iminosugar-based GCS inhibitors improve Sandhoff mouse function.
No full text<p>(<b>A</b>) Mice were evaluated in an open-field assay at 112 days of age. Total distance traversed (ambulatory distance) and the number of times the mice raised onto their hind legs (rearing events) over 30 min are shown. (n = 15/group. Statistics are between untreated and treated Sandhoff mice, and were determined using the Graphpad Prism software t test; ** = p<0.01, *** = p<0.001. Error bars indicate SEM). (<b>B</b>) Mice were evaluated for motor coordination using the rotarod assay. The amount of time (in secs) the mice remained on the rotarod is reported as the latency. Latency is shown for wild-type mice, Genz-529468- and <i>N</i>B-DNJ-treated Sandhoff mice and untreated Sandhoff mice. (n = 15/group). Statistics compared untreated Sandhoff to Genz-529468-treated Sandhoff mice, and were determined using the Graphpad Prism software t test; * = p<0.05, ** = p<0.01, *** = p<0.001. Error bars indicate SEM.</p
The X-ray crystal structure of human beta-hexosaminidase B provides new insights into Sandhoff disease
No full textHuman lysosomal beta-hexosaminidases are dimeric enzymes composed of alpha and beta-chains, encoded by the genes HEXA and HEXB. They occur in three isoforms, the homodimeric hexosaminidases B (betabeta) and S (alphaalpha), and the heterodimeric hexosaminidase A (alphabeta), where dimerization is required for catalytic activity. Allelic variations in the HEXA and HEXB genes cause the fatal inborn errors of metabolism Tay-Sachs disease and Sandhoff disease, respectively. Here, we present the crystal structure of a complex of human beta-hexosaminidase B with a transition state analogue inhibitor at 2.3 Angstrom resolution (pdb 1o7a). On the basis of this structure and previous studies on related enzymes, a retaining double-displacement mechanism for glycosyl hydrolysis by beta-hexosaminidase B is proposed. In the dimer structure, which is derived from an analysis of crystal packing, most of the mutations causing late-onset,Sandhoff disease reside near the dimer interface and are proposed to interfere with correct dimer formation. The structure reported here is a valid template also for the dimeric structures of beta-hexosaminidase A and S. (C) 2003 Elsevier Science Ltd. All rights reserved
Bone marrow transplantation prolongs life span and ameliorates neurologic manifestations in Sandhoff disease mice.
No full textThe GM2 gangliosidoses are a group of severe, neurodegenerative conditions that include Tay-Sachs disease, Sandhoff disease, and the GM2 activator deficiency. Bone marrow transplantation (BMT) was examined as a potential treatment for these disorders using a Sandhoff disease mouse model. BMT extended the life span of these mice from approximately 4.5 mo to up to 8 mo and slowed their neurologic deterioration. BMT also corrected biochemical deficiencies in somatic tissues as indicated by decreased excretion of urinary oligosaccharides, and lower glycolipid storage and increased levels of beta-hexosaminidase activity in visceral organs. Even with neurologic improvement, neither clear reduction of brain glycolipid storage nor improvement in neuronal pathology could be detected, suggesting a complex pathogenic mechanism. Histological analysis revealed beta-hexosaminidase-positive cells in the central nervous system and visceral organs with a concomitant reduction of colloidal iron-positive macrophages. These results may be important for the design of treatment approaches for the GM2 gangliosidoses
A novel HEXB mutation and its structural effects in juvenile Sandhoff disease
No full textMutations in HEXB, encoding the β-subunit common to hexosaminidases A and B, cause the neurodegenerative condition, Sandhoff disease. A homozygous missense HEXB mutation (p. D459A) was discovered in six patients with a rare juvenile variant: we show that this disrupts a salt bridge between aspartate D459 and arginine 505 at the subunit interface; R505 mutations are reported in late-onset Sandhoff disease. Identification of D459A contributes to diagnosis and molecular understanding of attenuated Sandhoff disease variants. Crown Copyright © 2008
Neural precursor cell cultures from GM2-gangliosidosis animal models recapitulate the biochemical and molecular hallmarks of the brain pathology
No full textIn this work we showed that genotype-related patterns of hexosaminidase activity, isoenzyme composition, gene expression and ganglioside metabolism observed during embryonic and postnatal brain development are recapitulated during the progressive stages of neural precursor cell (NPC) differentiation to mature glia and neurons in vitro. Further, by comparing NPCs and their differentiated progeny established from Tay-Sachs (TS) and Sandhoff (SD) animal models with the wild-type counterparts, we studied the events linking the accumulation of undegraded substrates to hexosaminidase activity. We showed that similarly to what observed in brain tissues in TS NPCs and progeny, the stored GM2 was partially converted by sialidase to GA2, which can be then degraded in the lysosomes to its components. The latter can be used in a salvage pathway for the formation of GM3. Interestingly, results obtained from ganglioside feeding assays and from measurement of lysosomal sialidase activity suggest that a similar pathway might work also in the SD model
Iminosugar-based GCS inhibitors increase Sandhoff mouse survival.
No full text<p>Mice were monitored daily from 80 days of age and euthanized when they became moribund and were unable to right themselves from a supine position within 30 sec. Untreated mice displayed a median survival of 135 days; Sandhoff mice treated with Genz-5294468 or <i>N</i>B-DNJ had median survivals of 181 days and 191 days, respectively. Both iminosugar-based GCS inhibitors significantly (p<0.0001) increased survival relative to that of untreated Sandhoff mice. (n = 15/group).</p
Restricted ketogenic diet enhances the therapeutic action of N-butyldeoxynojirimycin towards brain GM2 accumulation in adult Sandhoff disease mice.
No full textSandhoff disease is an autosomal recessive, neurodegenerative disease involving the storage of brain ganglioside GM2 and asialo-GM2. Previous studies showed that caloric restriction, which augments longevity, and N-butyldeoxynojirimycin (NB-DNJ, Miglustat), an imino sugar that hinders the glucosyltransferase catalyzing the first step in glycosphingolipid biosynthesis, both increase longevity and improve motor behavior in the beta-hexosaminidase (Hexb) knockout (-/-) murine model of Sandhoff disease. In this study, we used a restricted ketogenic diet (KD-R) and NB-DNJ to combat ganglioside accumulation. Adult Hexb-/- mice were placed into one of the following groups: (i) a standard diet (SD), (ii) a SD with NB-DNJ (SD + NB-DNJ), (iii) a KD-R, and (iv) a KD-R with NB-DNJ (KD-R + NB-DNJ). Forebrain GM2 content (mug sialic acid/100 mg dry wt) in the four groups was 375 +/- 15, 312 +/- 8, 340 +/- 28, and 279 +/- 26, respectively, indicating an additive interaction between NB-DNJ and the KD-R. Most interestingly, brain NB-DNJ content was 3.5-fold greater in the KD-R + NB-DNJ mice than in the SD + NB-DNJ mice. These data suggest that the KD-R and NB-DNJ may be a potential combinatorial therapy for Sandhoff disease by enhancing NB-DNJ delivery to the brain and may allow lower dosing to achieve the same degree of efficacy as high dose monotherapy
GM2-Gangliosidosis (Sandhoff and Tay Sachs disease): Diagnosis and Neuroimaging Findings (An Iranian Pediatric Case Series)
No full textHow to Cite This Article: Karimzadeh P, Jafari N, Nejad Biglari H, Jabbeh Dari S, Ahmad Abadi F, Alaee MR, Nemati H, Saket S,Tonekaboni SH, Taghdiri MM, Ghofrani M. GM2-Gangliosidosis (Sandhoff and Tay Sachs disease): Diagnosis and Neuroimaging Findings (An Iranian Pediatric Case Series) Iran J Child Neurol. 2014 Summer;8(3): 55-60. AbstractObjectiveGM2-Gangliosidosis disease is a rare autosomal recessive genetic disorder that includes two disorders (Tay–Sachs and Sandhoff disease).These disorders cause a progressive deterioration of nerve cells and inherited deficiency in creatinghexosaminidases A, B, and AB.Materials & MethodsPatients who were diagnosed withGM2-Gangliosidosis in the Neurology Department of Mofid Children’s Hospital in Tehran, Iran from October 2009 to February 2014were included in our study. The disorder was confirmed by neurometabolic and enzyme level detection of hexosaminidases A, B, and ABin reference to Wagnester Laboratory in Germany. We assessed age, gender, past medical history, developmental status, clinical manifestations, and neuroimaging findings of 9 patients with Sandhoff disease and 9 with Tay Sachs disease.Results83% of our patients were the offspring of consanguineous marriages. All of them had a developmental disorder as a chief complaint.38%of patients had a history of developmental delay or regression and 22% hadseizures. The patients with Sandhoff and Tay Sachs disease were followed for approximately 5 years and the follow-up showed all patients were bedridden or had expired due to refractory seizures, pneumonia aspiration, or swallowingdisorders.Neuro-imaging findings included bilateral thalamic involvement, brain atrophy, and hypo myelination in near half of our patients (48%). ConclusionAccording to the results of this study, we suggest that cherry-red spots, hyperacusis, refractory seizures, and relative parents in children with developmental delay and/or regression should be considered for assessment of GM2-Gangliosidosis disease. ReferencesYun YM, Lee SN. A case refort of Sandhoff disease. Korean journal of ophthalmology: KJO. 2005;19(1):68-72. Epub 2005/06/03.O’Dowd BF, Klavins MH, Willard HF, Gravel R, Lowden JA, Mahuran DJ. Molecular heterogeneity in the infantile and juvenile forms of Sandhoff disease (O-variant GM2 gangliosidosis). The Journal of biological chemistry. 1986;261(27):12680-5. Epub 1986/09/25.Der Kaloustian VM, Khoury MJ, Hallal R, Idriss ZH, Deeb ME, Wakid NW, et al. Sandhoff disease: a prevalent form of infantile GM2 gangliosidosis in Lebanon. American journal of human genetics. 1981;33(1):85-9. Epub 1981/01/01.Cashman NR, Antel JP, Hancock LW, Dawson G, Horwitz AL, Johnson WG, et al. N-acetyl-beta-hexosaminidase beta locus defect and juvenile motor neuron disease: a case study. Annals of neurology. 1986;19(6):568-72. Epub 1986/06/01.Oonk JGW, Van der Helm HJ, Martin JJ. Spinocerebellar degeneration: hexosaminidase A and B deficiency in two adult sisters. Neurology 1979;29:380–384.Federico A, Ciacci G, D’Amore I, Pallini R, Palmeri S, Rossi A, et al. GM2 Gangliosidosis with Hexosaminidase A and B Defect: Report of a Family with Motor Neuron Disease-like Phenotype. In: Addison GM, Harkness RA, Isherwood DM, Pollitt RJ, editors. Practical Developments in Inherited Metabolic Disease: DNA Analysis, Phenylketonuria and Screening for Congenital Adrenal Hyperplasia: Springer Netherlands; 1986. p. 307-10.Gomez-Lira M, Sangalli A, Mottes M, Perusi C, Pignatti PF, Rizzuto N, et al. A common beta hexosaminidase gene mutation in adult Sandhoff disease patients. Human genetics. 1995;96(4):417-22. Epub 1995/10/01.Barbeau A, Plasse L, Cloutier T, Paris S, Roy M. Lysosomal enzymes in ataxia: discovery of two new cases of late onset hexosaminidase A and B deficiency (adult Sandhoff disease) in French Canadians. The Canadian journal of neurological sciences Le journal canadien des sciences neurologiques. 1984;11(4 Suppl):601-6. Epub 1984/11/01.Haghighi A, Masri A, Kornreich R, Desnick RJ. Tay- Sachs disease in an Arab family due to c.78G>A HEXA nonsense mutation encoding a p.W26X early truncation enzyme peptide. Molecular genetics and metabolism. 2011;104(4):700-2. Epub 2011/10/05.Tay SK, Low PS, Ong HT, Loke KY. Sandhoff disease- a case report of 3 siblings and a review of potential therapies. Annals of the Academy of Medicine, Singapore. 2000;29(4):514-7. Epub 2000/11/01.Ghosh M, Hunter WS, Wedge C. Corneal changes in Tay-Sachs disease. Canadian journal of ophthalmology Journal canadien d’ophtalmologie. 1990;25(4):190-2.Epub 1990/06/01.Hittmair K, Wimberger D, Bernert G, Mallek R, Schindler EG. MRI in a case of Sandhoff’s disease. Neuroradiology. 1996;38 Suppl 1:S178-80. Epub 1996/05/01.Koelfen W, Freund M, Jaschke W, Koenig S, Schultze C. GM-2 gangliosidosis (Sandhoff’s disease): two year follow-up by MRI. Neuroradiology. 1994;36(2):152-4.Epub 1994/01/01.Kokot W, Raczynska K, Krajka-Lauer J, Iwaszkiewicz- Bilikiewicz B, Wierzba J. [Sandhoff’s and Tay-Sachs disease--based on our own cases]. Klinika oczna. 2004;106(3 Suppl):534-6. Epub 2005/01/08. Choroba Sandhoffa oraz Tay Sachsa--w oparciu o przypadki wlasne.Barness LA, Henry K, Kling P, Laxova R, Kaback M, Gilbert-Barness E. A 7-year old white-male boy with progressive neurological deterioration. American journal of medical genetics. 1991;40(3):271-9. Epub 1991/09/01.Arisoy AE, Ozden S, Ciliv G, Ozalp I. Tay-Sachs disease: a case report. The Turkish journal of pediatrics. 1995;37(1):51-6. Epub 1995/01/01.Ozkara HA, Topcu M, Renda Y. Sandhoff disease in the Turkish population. Brain & development. 1997;19(7):469-72. Epub 1997/12/31.
Appropriate Similarity Measures for Author Cocitation Analysis
No full textWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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