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1

Uptake and metabolism of radiolabelled GM1-ganglioside in skin fibroblasts from controls and patients with GM1-gangliosidosis  

Microsoft Academic Search

Summary The uptake and metabolism of [3-3H-sphingosine]GM1-ganglioside was measured in cultured skin fibroblasts from controls and patients with infantile, juvenile and adult GM1-gangliosidosis. When dissolved in medium with phosphatidylserine, GM1-ganglioside was efficiently taken up by cultured skin fibroblasts and transferred into lysosomes. A linear increase in GM1-ganglioside endocytosis was shown with phosphatidylserine concentrations of up to 40?m\\/ml. A pulse-chase study

M. Midorikawa; K. Inui; S. Okada; H. Yabuuchi; K. Ogura; S. Handa

1991-01-01

2

Brain Proton Magnetic Resonance Spectroscopy and Neuromuscular Pathology in a Patient With GM1 Gangliosidosis  

Microsoft Academic Search

The authors report the clinical, neuroradiologic, and neuromuscular pathological findings in a patient with GM1 gangliosidosis. The proton magnetic resonance spectroscopy, previously reported in a single patient with GM1 gangliosidosis, detected a mild reduction of N-acetylaspartate, consistent with relative paucity of axons and neurons and increased levels of myoinositol suggestive of gliotic white matter changes along with the accumulation of

Nicola Brunetti-Pierri; Meenakshi B. Bhattacharjee; Zhiyue J. Wang; Zili Chu; David A. Wenger; Lorraine Potocki; Jill Hunter; Fernando Scaglia

2008-01-01

3

GM1 Gangliosidosis Type II  

Microsoft Academic Search

A patient with monosialoganglioside accumulation in the brain is described who shows a clinical onset of the disease at 1 year of age, no visceromegaly nor skeletal X-ray changes. There is no ganglioside accumulation in the liver. These observations permit a clear distinction from the generalized GM1 gangliosidosis and agree with the division in 2 types as proposed by Derry.

C. Hooft; R. F. Vlietinck; G. Dacremont; J. A. Kint

1970-01-01

4

Neuroimaging findings in infantile GM1 gangliosidosis  

Microsoft Academic Search

GM1 gangliosidosis is an autosomal recessive glycosphingolipid storage disease caused by defects in the enzyme ?-galactosidase. Three clinical forms (infantile-, juvenile-, and adult-onset) of the disease are recognized. Patients with infantile GM1 gangliosidosis present at birth or shortly thereafter with somatic and bony changes, followed by severe neurological deterioration ultimately leading to death within the first 2 years of life.

Ilknur Erol; Füsun Alehan; M. Ali Pourbagher; Oguz Canan; S. Vefa Yildirim

2006-01-01

5

Genotypic and phenotypic characterization of Brazilian patients with GM1 gangliosidosis.  

PubMed

GM1 gangliosidosis is a lysosomal disorder caused by ?-galactosidase deficiency due to mutations in the GLB1 gene. It is a rare neurodegenerative disorder with an incidence of about 1:100,000-1:200,000 live births worldwide. Here we review GLB1 mutations and clinical features from 65 Brazilian GM1 gangliosidosis patients. Molecular analysis showed 17 different mutations and c.1622-1627insG was the most frequent, accounting for 50% of the alleles. Cognitive impairment was the main clinical sign, observed in 82% of patients, followed by hepatosplenomegaly observed in 56% of patients. It was possible to establish a significant correlation between age at onset of symptoms preceding the first year of life and the presence of the mutation c.1622-1627insG (p=0.03). Overall our findings differ from literature and represent the exclusive genotypic profile found in Brazilian GM1 gangliosidosis patients. PMID:23046582

Sperb, Fernanda; Vairo, Filippo; Burin, Maira; Mayer, Fabiana Quoos; Matte, Ursula; Giugliani, Roberto

2013-01-01

6

Hyperpigmented macules and patches in a patient with GM1 type 1 gangliosidosis.  

PubMed

We report a case of a 10-month-old male infant with GM1 type 1 gangliosidosis who also had hyperpigmented macules and patches. Light and electron microscopic findings correlated with previously published reports on findings in skin biopsy specimens of patients with lipid storage disorders. The hyperpigmented macules are most likely mongolian spots. A differential diagnosis of these lesions is discussed. PMID:2497160

Selsor, L C; Lesher, J L

1989-05-01

7

[GM1-gangliosidosis knockout mouse].  

PubMed

We generated a beta-galactosidosis mouse by gene targeting in an embryonic stem cell. Clinical, pathological, and biochemical analyses revealed that this mouse is a useful animal model to study the pathogenesis and therapy of human GM1-gangliosidosis. PMID:9545780

Oshima, A

1998-03-01

8

Three novel beta-galactosidase gene mutations in Han Chinese patients with GM1 gangliosidosis are correlated with disease severity  

Microsoft Academic Search

BACKGROUND: GM1 gangliosidosis (GM1) is an autosomal recessive lysosomal storage disease caused by deficiency of acid beta-galactosidase (GLB1; EC3.2.1.23). Here, we identify three novel mutations in the GLB1 gene from two Han Chinese patients with GM1 that appear correlated with clinical phenotype. METHODS: One of the two Han Chinese patients with GM1 presented with the juvenile form, and the other

Chi-Fan Yang; Jer-Yuarn Wu; Fuu-Jen Tsai

2010-01-01

9

Phenotype determining alleles in GM1 gangliosidosis patients bearing novel GLB1 mutations.  

PubMed

GM1 gangliosidosis manifests with progressive psychomotor deterioration and dysostosis of infantile, juvenile, or adult onset, caused by alterations in the structural gene coding for lysosomal acid beta-galactosidase (GLB1). In addition, allelic variants of this gene can result in Morquio B disease (MBD), a phenotype with dysostosis multiplex and entire lack of neurologic involvement. More than 100 sequence alterations in the GLB1 gene have been identified so far, but only few could be proven to be predictive for one of the GM1 gangliosidosis subtypes or MBD. We performed genotype analyses in 16 GM1 gangliosidosis patients of all phenotypes and detected 28 different genetic lesions. Among these, p.I55FfsX16, p.W65X, p.F107L, p.H112P, p.C127Y, p.W161X, p.I181K, p.C230R, p.W273X, p.R299VfsX5, p.A301V, p.F357L, p.K359KfsX23, p.L389P, p.D448V, p.D448GfsX8, and the intronic mutation IVS6-8A>G have not been published so far. Due to their occurrence in homozygous patients, four mutations could be correlated to a distinct GM1 gangliosidosis phenotype. Furthermore, the missense mutations from heteroallelic patients and three artificial nonsense mutations were characterized by overexpression in COS-1 cells, and the subcellular localization of the mutant proteins in fibroblasts was assessed. The phenotype specificity of 10 alleles can be proposed on the basis of our results and previous data. PMID:20175788

Hofer, D; Paul, K; Fantur, K; Beck, M; Roubergue, A; Vellodi, A; Poorthuis, B J; Michelakakis, H; Plecko, B; Paschke, E

2010-09-01

10

?-Galactosidase Gene Mutations in Patients With Slowly Progressive GM1 Gangliosidosis  

Microsoft Academic Search

Three unrelated North American cases with slowly progressive forms of GM1 gangliosidosis were found to have two unique point mutations and a 9 bp insertion in the coding region of the gene encoding ?-galactosidase. Case 1 was noted to have a 9 bp insertion {CAGAATTTT} on one allele between nucleotides 730 and 731 with no other mutations identified in the

Edward M. Kaye; Christo Shalish; James Livermore; Harold A. Taylor; Roger E. Stevenson; Xandra O. Breakefield

1997-01-01

11

Phenotype determining alleles in GM1 gangliosidosis patients bearing novel GLB1 mutations  

Microsoft Academic Search

GM1 gangliosidosis manifests with progressive psychomotor deterioration and dysostosis of infantile, juvenile, or adult onset, caused by alterations in the structural gene coding for lysosomal acid ?-galactosidase (GLB1). In addition allelic variants of this gene can result in Morquio B disease, a phenotype with dysostosis multiplex and entire lack of neurologic involvement. More than 100 sequence alterations in the GLB1

D. Hofer; K. Paul; K. Fantur; M. Beck; A. Roubergue; A. Vellodi; B. J. Poorthuis; H. Michelakakis; B. Plecko; E. Paschke

2010-01-01

12

GM1 gangliosidosis type 1 in twins  

Microsoft Academic Search

This report describes 7-month-old monozygotic twin female infants with GM1 gangliosidosis type I. In addition to the usual clinical and biochemical abnormalities generalized intracutaneous telangiectasis were present in both infants.

C M Ginsburg; C G Long

1977-01-01

13

Genetics Home Reference: GM1 gangliosidosis  

MedlinePLUS

... type I, but still causes a shortened life expectancy. People with the late infantile form typically survive ... and abnormalities of the spinal bones (vertebrae). Life expectancy varies among people with GM1 gangliosidosis type III. ...

14

GM1 gangliosidosis type 1 in twins.  

PubMed Central

This report describes 7-month-old monozygotic twin female infants with GM1 gangliosidosis type I. In addition to the usual clinical and biochemical abnormalities generalized intracutaneous telangiectasis were present in both infants. Images

Ginsburg, C M; Long, C G

1977-01-01

15

Primary and Secondary Elastin-Binding Protein Defect Leads to Impaired Elastogenesis in Fibroblasts from GM1-Gangliosidosis Patients  

PubMed Central

GM1-gangliosidosis is a lysosomal storage disorder caused by acid ?-galactosidase deficiency. Aside from the lysosomal ?-galactosidase enzyme, the ?-galactosidase gene also encodes the elastin-binding protein (EBP), deficiency in which impairs elastogenesis. Using expression studies and Western blots of COS-1 cells, we identified and characterized four new and two known ?-galactosidase gene mutations detected in GM1-gangliosidosis patients with infantile, juvenile, or adult forms of disease. We then focused on impaired elastogenesis detected in fibroblasts from patients with infantile and juvenile disease. The juvenile patient showed connective-tissue abnormalities, unusual urinary keratan sulfate excretion, and an EBP reduction, despite mutations affecting only ?-galactosidase. Because galactosugar-bearing moieties may alter EBP function and impair elastogenesis, we assessed infantile and juvenile patients for the source of altered elastogenesis. We confirmed that the infantile patient’s impaired elastogenesis arose from a primary EBP defect, according to molecular analysis. We examined the juvenile’s fibroblasts by immunohistochemistry, addition of keratanase, soluble/insoluble elastin assay, and radiolabeling of tropoelastin. These experiments revealed that the juvenile’s impaired elastogenesis likely arose from secondary EBP deficiency caused by keratan sulfate accumulation. Thus, impaired elastogenesis in GM1-gangliosidosis can arise from primary or secondary EBP defects in fibroblasts from infantile and juvenile patients, respectively.

Caciotti, Anna; Donati, Maria Alice; Bardelli, Tiziana; d'Azzo, Alessandra; Massai, Graziella; Luciani, Luciana; Zammarchi, Enrico; Morrone, Amelia

2005-01-01

16

Primary and secondary elastin-binding protein defect leads to impaired elastogenesis in fibroblasts from GM1-gangliosidosis patients.  

PubMed

G(M1)-gangliosidosis is a lysosomal storage disorder caused by acid beta-galactosidase deficiency. Aside from the lysosomal beta-galactosidase enzyme, the beta-galactosidase gene also encodes the elastin-binding protein (EBP), deficiency in which impairs elastogenesis. Using expression studies and Western blots of COS-1 cells, we identified and characterized four new and two known beta-galactosidase gene mutations detected in G(M1)-gangliosidosis patients with infantile, juvenile, or adult forms of disease. We then focused on impaired elastogenesis detected in fibroblasts from patients with infantile and juvenile disease. The juvenile patient showed connective-tissue abnormalities, unusual urinary keratan sulfate excretion, and an EBP reduction, despite mutations affecting only beta-galactosidase. Because galactosugar-bearing moieties may alter EBP function and impair elastogenesis, we assessed infantile and juvenile patients for the source of altered elastogenesis. We confirmed that the infantile patient's impaired elastogenesis arose from a primary EBP defect, according to molecular analysis. We examined the juvenile's fibroblasts by immunohistochemistry, addition of keratanase, soluble/insoluble elastin assay, and radiolabeling of tropoelastin. These experiments revealed that the juvenile's impaired elastogenesis likely arose from secondary EBP deficiency caused by keratan sulfate accumulation. Thus, impaired elastogenesis in G(M1)-gangliosidosis can arise from primary or secondary EBP defects in fibroblasts from infantile and juvenile patients, respectively. PMID:16314480

Caciotti, Anna; Donati, Maria Alice; Bardelli, Tiziana; d'Azzo, Alessandra; Massai, Graziella; Luciani, Luciana; Zammarchi, Enrico; Morrone, Amelia

2005-12-01

17

Genetic heterogeneity in GM1-gangliosidosis  

Microsoft Academic Search

GM1-GANGLIOSIDOSIS is an inherited lysosomal storage disease which is due to a deficiency of the acid hydrolase GM1-beta-galactosidase1. During the past few years several clinical variants have been described2-6 that differ in time of onset of symptoms, involvement of visceral organs or skeletal tissue and in the degree of neuronal and mental deterioration. Some of these variants have been related

H. Galjaard; A. Hoogeveen; W. Keijzer; H. A. de Wit-Verbeek; A. J. J. Reuser; MAE WAN HO; D. ROBINSON

1975-01-01

18

Ocular pathology of bovine GM 1 gangliosidosis  

Microsoft Academic Search

Late-onset of disturbed vision is a clinical feature of bovine GM1 gangliosidosis. Studies on eight affected calves showed that ocular lesions were confined to the retinae and optic nerves. Myriad tiny white spots were visible by ophthalmic examination of the fundus. These spots were related to protuberances on the vitreal surface caused by distended retinal ganglion cells. The perikaryons of

B. J. Sheahan; W. J. C. Donnelly; T. D. Grimes

1978-01-01

19

GM1-generalized gangliosidosis variant with cardiomegaly  

Microsoft Academic Search

A female infant with generalized GM1-gangliosidosis differing in several aspects from previously reported cases is described. Clinically she is the first case to have cardiomegaly, unilateral congenitial dislocation of the hip and normal facial appearance. She had a higher residual leucocyte ?-galactosidase activity towards two synthetic substrates, namely p-nitrophenyl-?-D-galactoside (PNP-?-gal) and 4-methylumbelliferyl-?-D-galactoside (MU-?-gal) than in previously reported cases. Total ?-hexosaminidase

P. F. Benson; S. P. Brown; A. Babarik; T. P. Mann

1976-01-01

20

GM1gangliosidosis: Clinical and radiological clue to diagnosis  

PubMed Central

GM1gangliosidosis is a rare autosomal recessive lysosomal storage disorder caused by deficiency of enzyme ?-galactosidase, resulting in progressive neural and visceral accumulation of GM1gangliosides. Coarse facial features, bilateral cherry red spots, and dysostosis multiplex are important clue to diagnose this condition. We describe a case of GM1gangliosidosis with dysostosis multiplex and characteristic magnetic resonance imaging findings.

Suthar, Renu; Sahu, Jitendra K.; Singhi, Pratibha

2012-01-01

21

A homozygous missense arginine to histidine substitution at position 482 of the ?-galactosidase in an Italian infantile GM1-gangliosidosis patient  

Microsoft Academic Search

We have studied, by the polymerase chain reaction, the ß-galactosidase cDNA from several Italian patients with infantile GM1-gangliosidosis. One homozygote for a previously undiscovered G > A mutation at position 1479, causing an arginine to histidine change, was detected. The same mutation, in heterozygosis, was identified in 6 unrelated patients, but not in 100 normal chromosomes.

G. Mosna; S. Fattore; G. Tubiello; S. Brocca; M. Trubia; E. Gianazza; R. Gatti; C. Danesino; A. Minelli; M. Piantanida

1992-01-01

22

GM1 gangliosidosis type 3 with severe jaw-closing impairment  

Microsoft Academic Search

The patient had adult GM1 gangliosidosis (type 3) with severe impairment of mastication caused by dystonia of anterior digastric muscles (jaw-opener) on clenching. This is the first report on jaw dystonia severe enough to cause the masticatory impairment in adult GM1 gangliosidosis. The discordance of closing and opening muscles during mastication might be caused by a basal ganglia lesion in

Mikio Hirayama; Yoshimasa Kitagawa; Sachiko Yamamoto; Akira Tokuda; Tatsuro Mutoh; Tadanori Hamano; Takashi Aita; Masaru Kuriyama

1997-01-01

23

Angiokeratoma corporis diffusum in GM1 gangliosidosis, type 1.  

PubMed

A patient with severe deficiency of beta-galactosidase, who developed skin lesions of angiokeratoma corporis diffusum between the 3rd and 10th month of life, is described. The activity of other lysosomal enzymes, including alpha-neuraminidase, was normal. The first signs of the disease were noticed during the first month of life. By 3 months coarseness of the face and psychomotor retardation were present. In addition to angiokeratoma, he had large mongolian spots and several scattered slate-blue spots of pigmentation over his body. With the exception of the skin lesions, the other clinical signs and the course of the psychomotor deterioration were within the clinical picture of GM1 gangliosidosis, Type 1. Angiokeratoma, a manifestation of several lysosomal disorders, may appear in GM1 gangliosidosis during the first year of life. PMID:2504516

Beratis, N G; Varvarigou-Frimas, A; Beratis, S; Sklower, S L

1989-07-01

24

Expression and characterization of 14 GLB1 mutant alleles found in GM1-gangliosidosis and Morquio B patients  

Microsoft Academic Search

GM1-gangliosidosis and Morquio B disease are lysosomal storage disorders caused by b-galactosidase de- ficiency attributable to mutations in the GLB1 gene. On reaching the endosomal-lysosomal compartment, the b- galactosidase protein associates with the protective protein\\/ cathepsin A (PPCA) and neuraminidase proteins to form the lysosomal multienzyme complex (LMC). The correct inter- action of these proteins in the complex is essential

Raul Santamaria; Amparo Chabas; John W. Callahan; Daniel Grinberg; L. Vilageliu

2007-01-01

25

GM1 gangliosidosis and Morquio B disease: An update on genetic alterations and clinical findings  

Microsoft Academic Search

GM1 gangliosidosis and Morquio B syndrome, both arising from beta-galactosidase (GLB1) deficiency, are very rare lysosomal storage diseases with an incidence of about 1:100,000–1:200,000 live births worldwide. Here we report the beta-galactosidase gene (GLB1) mutation analysis of 21 unrelated GM1 gangliosidosis patients, and of 4 Morquio B patients, of whom two are brothers. Clinical features of the patients were collected

Anna Caciotti; Scott C. Garman; Yadilette Rivera-Colón; Elena Procopio; Serena Catarzi; Lorenzo Ferri; Carmen Guido; Paola Martelli; Rossella Parini; Daniela Antuzzi; Roberta Battini; Michela Sibilio; Alessandro Simonati; Elena Fontana; Alessandro Salviati; Gulcin Akinci; Cristina Cereda; Carlo Dionisi-Vici; Francesca Deodato; Adele d'Amico; Alessandra d'Azzo; Enrico Bertini; Mirella Filocamo; Maurizio Scarpa; Maja di Rocco; Cynthia J. Tifft; Federica Ciani; Serena Gasperini; Elisabetta Pasquini; Renzo Guerrini; Maria Alice Donati; Amelia Morrone

2011-01-01

26

Gm1 gangliosidosis and galactosialidosis : pathogenesis and therapy  

Microsoft Academic Search

GM1 gangliosidosis and galactosialidosis belong to the large group of\\u000ametabolic disorders collectively known as Iysosomal storage diseaSE!S (lSDs). lSDs\\u000aare caused by a single or combined deficiency of specific hydr,olytic enzymes\\u000aresulting in progressive accumulation of undigested substrates in Iysosomes of\\u000amany cells, and ultimately in cellular and organ dysfunction. In general, the patients\\u000aexhibit multi-systemic symptoms mostly involving

Martin del Pilar M

2003-01-01

27

Intrauterine growth retardation and placental vacuolization as presenting features in a case of GM 1 gangliosidosis  

Microsoft Academic Search

Summary  Diagnosis of GM1 gangliosidosis (OMIM 230500) is usually based on the presence of physical signs of storage such as coarse facial features,\\u000a corneal clouding, cherry red macula, hepatosplenomegaly and skeletal dysostosis. More rarely it can present as nonimmune hydrops.\\u000a We describe a male patient with GM1 gangliosidosis born to healthy first-cousin parents of Indian Asian descent. The disease was recognized

Nicola Brunetti-Pierri; Asad Mian; Rebecca Luetchke; Brett H. Graham

2007-01-01

28

GM1 gangliosidosis type 3 with severe jaw-closing impairment.  

PubMed

The patient had adult GM1 gangliosidosis (type 3) with severe impairment of mastication caused by dystonia of anterior digastric muscles (jaw-opener) on clenching. This is the first report on jaw dystonia severe enough to cause the masticatory impairment in adult GM1 gangliosidosis. The discordance of closing and opening muscles during mastication might be caused by a basal ganglia lesion in this disease. PMID:9395131

Hirayama, M; Kitagawa, Y; Yamamoto, S; Tokuda, A; Mutoh, T; Hamano, T; Aita, T; Kuriyama, M

1997-11-01

29

Bovine GM 1 gangliosidosis: An inborn lysosomal disease  

Microsoft Academic Search

The results of studies on GM1 gangliosidosis of Friesian calves are reviewed in the light of present knowledge about inborn lysosomal diseases. Affected calves have poor growth rates and develop signs of incoordination and blindness at about three months of age. The disease is progressive resulting in death at six to nine months of age. Storage of GM1 ganglioside in

W. J. C. Donnelly; B. J. Sheahan

1977-01-01

30

GM 1 gangliosidosis: Review of clinical, molecular, and therapeutic aspects  

Microsoft Academic Search

GM1 gangliosidosis is a lysosomal storage disorder due to deficiency of the ?-galactosidase enzyme. This deficiency results in accumulation of GM1 gangliosides and related glycoconjugates in the lysosomes leading to lysosomal swelling, cellular damage, and organ dysfunction. The disease is lethal in the infantile and juvenile forms. To date, up to 102 mutations distributed along the ?-galactosidase gene (GLB1) have

Nicola Brunetti-Pierri; Fernando Scaglia

2008-01-01

31

GM1 gangliosidosis: molecular analysis of nine patients and development of an RT-PCR assay for GLB1 gene expression profiling.  

PubMed

The human GLB1 gene produces two alternatively spliced transcripts that encode the lysosomal enzyme beta-galactosidase (GLB1) and the elastin binding protein (EBP). Mutations at the GLB1 locus, which are responsible for the storage disorder GM1 gangliosidosis, may affect either both proteins or GLB1 only. The EBP, when affected, contributes to specific features of GM1 gangliosidosis patients, such as cardiomyopathy and connective-tissue abnormalities. Here we report the development of reliable and quantitative assays based on real-time PCR for assessing the levels of GLB1 and EBP transcripts in patients' samples. We also report the characterisation of GLB1 gene mutations in nine GM1 gangliosidosis patients in order to correlate the genetic lesions with mRNA levels and phenotypes. Mutation analysis identified four new (c.1835_1836delCC; p.Arg148Cys; c.1068+1G>T; and p.Pro549Leu), five known (p.Arg59His; p.Arg201His; p.Gly123Arg; c.245+1G>A; and c.75+2insT) mutations and one new polymorphism (c.1233+8T>C). Comparative analysis of the patients' phenotypes enabled a more thorough correlation between GLB1 mutations and specific clinical manifestations. GLB1 and EBP mRNA levels were both reduced in three patients carrying the splicing defects. The accurate and fast method for the detection of alternatively spliced transcripts of the GLB1 gene could be applied to other disease-causing lysosomal genes that encode multiple mRNAs. PMID:17221873

Caciotti, Anna; Donati, Maria Alice; Procopio, Elena; Filocamo, Mirella; Kleijer, Wim; Wuyts, Wim; Blaumeiser, Bettina; d'Azzo, Alessandra; Simi, Lisa; Orlando, Claudio; McKenzie, Fiona; Fiumara, Agata; Zammarchi, Enrico; Morrone, Amelia

2007-02-01

32

Transient high-level expression of beta-galactosidase after transfection of fibroblasts from GM1 gangliosidosis patients with plasmid DNA.  

PubMed

GM1 gangliosidosis is an autosomal recessive disorder caused by the deficiency of lysosomal acid hydrolase beta-galactosidase (beta-Gal). It is one of the most frequent lysosomal storage disorders in Brazil, with an estimated frequency of 1:17,000. The enzyme is secreted and can be captured by deficient cells and targeted to the lysosomes. There is no effective treatment for GM1 gangliosidosis. To determine the efficiency of an expression vector for correcting the genetic defect of GM1 gangliosidosis, we tested transfer of the beta-Gal gene (Glb1) to fibroblasts in culture using liposomes. Beta-Gal cDNA was cloned into the expression vectors pSCTOP and pREP9. Transfection was performed using 4 microL lipofectamine 2000 and 1.5-2.0 microg DNA. Cells (2 x 10(5)/well) were harvested 24 h, 48 h, and 7 days after transfection. Enzyme specific activity was measured in cell lysate and supernatant by fluorometric assay. Twenty-four hours after transfection, treated cells showed a higher enzyme specific activity (pREP9-beta-Gal: 621.5 +/- 323.0, pSCTOP-beta-Gal: 714.5 +/- 349.5, pREP9-beta-Gal + pSCTOP-beta-Gal: 1859.0 +/- 182.4, and pREP9-ss-Gal + pTRACER: 979.5 +/- 254.9 nmol x h-1 x mg-1 protein) compared to untreated cells (18.0 +/- 3.1 for cell and 32.2 +/- 22.2 nmol x h-1 x mg-1 protein for supernatant). However, cells maintained in culture for 7 days showed values similar to those of untreated patients. In the present study, we were able to transfect primary patients' skin fibroblasts in culture using a non-viral vector which overexpresses the beta-Gal gene for 24 h. This is the first attempt to correct fibroblasts from patients with GM1 gangliosidosis by gene therapy using a non-viral vector. PMID:18392450

Balestrin, R C; Baldo, G; Vieira, M B; Sano, R; Coelho, J C; Giugliani, R; Matte, U

2008-04-01

33

Filipin recognizes both GM1 and cholesterol in GM1 gangliosidosis mouse brain.  

PubMed

Filipin is an antibiotic polyene widely used as a histochemical marker for cholesterol. We previously reported cholesterol/filipin-positive staining in brain of ?-galactosidase (?-gal) knockout ((-/-)) mice (GM1 gangliosidosis). The content and distribution of cholesterol and gangliosides was analyzed in plasma membrane (PM) and microsomal (MS) fractions from whole-brain tissue of 15 week-old control (?-gal(+/-)) and GM1 gangliosidosis (?-gal(-/-)) mice. Total ganglioside content (?g sialic acid/mg protein) was 3-fold and 7-fold greater in the PM and MS fractions, respectively, in ?gal(-/-) mice than in ?gal(+/-) mice. GM1 content was 30-fold and 50-fold greater in the PM and MS fractions, respectively. In contrast, unesterified cholesterol content (?g/mg protein) was similar in the PM and the MS fractions of the ?gal(-/-) and ?gal(+/-) mice. Filipin is known to bind to various sterol derivatives and phospholipids on thin-layer chromatograms. Biochemical evidence is presented showing that filipin also binds to GM1 with an affinity similar to that for cholesterol, with a corresponding fluorescent reaction. Our data suggest that the GM1 storage seen in the ?-gal(-/-) mouse contributes to the filipin ultraviolet fluorescence observed in GM1 gangliosidosis brain. The data indicate that in addition to cholesterol, filipin can also be useful for detecting GM1. PMID:21508255

Arthur, Julian R; Heinecke, Karie A; Seyfried, Thomas N

2011-07-01

34

Filipin recognizes both GM1 and cholesterol in GM1 gangliosidosis mouse brain  

PubMed Central

Filipin is an antibiotic polyene widely used as a histochemical marker for cholesterol. We previously reported cholesterol/filipin-positive staining in brain of ?-galactosidase (?-gal) knockout (?/?) mice (GM1 gangliosidosis). The content and distribution of cholesterol and gangliosides was analyzed in plasma membrane (PM) and microsomal (MS) fractions from whole-brain tissue of 15 week-old control (?-gal+/?) and GM1 gangliosidosis (?-gal?/?) mice. Total ganglioside content (?g sialic acid/mg protein) was 3-fold and 7-fold greater in the PM and MS fractions, respectively, in ?gal?/? mice than in ?gal+/? mice. GM1 content was 30-fold and 50-fold greater in the PM and MS fractions, respectively. In contrast, unesterified cholesterol content (?g/mg protein) was similar in the PM and the MS fractions of the ?gal?/? and ?gal+/? mice. Filipin is known to bind to various sterol derivatives and phospholipids on thin-layer chromatograms. Biochemical evidence is presented showing that filipin also binds to GM1 with an affinity similar to that for cholesterol, with a corresponding fluorescent reaction. Our data suggest that the GM1 storage seen in the ?-gal?/? mouse contributes to the filipin ultraviolet fluorescence observed in GM1 gangliosidosis brain. The data indicate that in addition to cholesterol, filipin can also be useful for detecting GM1.

Arthur, Julian R.; Heinecke, Karie A.; Seyfried, Thomas N.

2011-01-01

35

Fetal GM1-gangliosidosis: morphological and biochemical studies.  

PubMed

A 23-week fetus with GM1-gangliosidosis type 1 was studied morphologically and biochemically. The GM1-ganglioside content in the brain was approximately twice that of a control. A GM1-ganglioside comprised about 25% of the total ganglioside NANA (N-acetyl-neuraminic acid), whereas in control fetus brain the proportion was 14.3%. The storage of GM1-ganglioside in fetal GM1-ganglioside brain was confirmed by a thin-layer chromatogram immunostained with anti-GM1-ganglioside antibody. The accumulation of GM1-ganglioside in visceral organs (liver, spleen and kidney) was not detected with biochemical and immunochemical methods. However, in hepatocytes, Kupffer cells, renal tubular cells and spleen cells from the affected fetus, there were many vacuoles which could contain oligosaccharides as storage materials. These data suggest that pathochemical changes in the brain and visceral organs of an affected fetus are already evident in the second trimester of the pregnancy. Tissue specific accumulation of glycolipids or oligosaccharides in fetal GM1-gangliosidosis suggests that the biosynthesis or degradation of these compounds occurs at different periods. PMID:2618963

Ida, H; Eto, Y; Maekawa, K

1989-01-01

36

Structural bases of GM1 gangliosidosis and Morquio B disease  

Microsoft Academic Search

Allelic mutations of the lysosomal ?-galactosidase gene cause heterogeneous clinical phenotypes, such as GM1 gangliosidosis and Morquio B disease, the former being further classified into three variants, namely infantile, juvenile and adult forms; and heterogeneous biochemical phenotypes were shown in these forms. We tried to elucidate the bases of these diseases from a structural viewpoint. We first constructed a three-dimensional

Mizuki Morita; Seiji Saito; Kazuyoshi Ikeda; Kazuki Ohno; Kanako Sugawara; Toshihiro Suzuki; Tadayasu Togawa; Hitoshi Sakuraba

2009-01-01

37

GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings.  

PubMed

GM1 gangliosidosis and Morquio B syndrome, both arising from beta-galactosidase (GLB1) deficiency, are very rare lysosomal storage diseases with an incidence of about 1:100,000-1:200,000 live births worldwide. Here we report the beta-galactosidase gene (GLB1) mutation analysis of 21 unrelated GM1 gangliosidosis patients, and of 4 Morquio B patients, of whom two are brothers. Clinical features of the patients were collected and compared with those in literature. In silico analyses were performed by standard alignments tools and by an improved version of GLB1 three-dimensional models. The analysed cohort includes remarkable cases. One patient with GM1 gangliosidosis had a triple X syndrome. One patient with juvenile GM1 gangliosidosis was homozygous for a mutation previously identified in Morquio type B. A patient with infantile GM1 gangliosidosis carried a complex GLB1 allele harbouring two genetic variants leading to p.R68W and p.R109W amino acid changes, in trans with the known p.R148C mutation. Molecular analysis showed 27 mutations, 9 of which are new: 5 missense, 3 microdeletions and a nonsense mutation. We also identified four new genetic variants with a predicted polymorphic nature that was further investigated by in silico analyses. Three-dimensional structural analysis of GLB1 homology models including the new missense mutations and the p.R68W and p.R109W amino acid changes showed that all the amino acid replacements affected the resulting protein structures in different ways, from changes in polarity to folding alterations. Genetic and clinical associations led us to undertake a critical review of the classifications of late-onset GM1 gangliosidosis and Morquio B disease. PMID:21497194

Caciotti, Anna; Garman, Scott C; Rivera-Colón, Yadilette; Procopio, Elena; Catarzi, Serena; Ferri, Lorenzo; Guido, Carmen; Martelli, Paola; Parini, Rossella; Antuzzi, Daniela; Battini, Roberta; Sibilio, Michela; Simonati, Alessandro; Fontana, Elena; Salviati, Alessandro; Akinci, Gulcin; Cereda, Cristina; Dionisi-Vici, Carlo; Deodato, Francesca; d'Amico, Adele; d'Azzo, Alessandra; Bertini, Enrico; Filocamo, Mirella; Scarpa, Maurizio; di Rocco, Maja; Tifft, Cynthia J; Ciani, Federica; Gasperini, Serena; Pasquini, Elisabetta; Guerrini, Renzo; Donati, Maria Alice; Morrone, Amelia

2011-07-01

38

GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings  

PubMed Central

GM1 gangliosidosis and Morquio B syndrome, both arising from beta-galactosidase (GLB1) deficiency, are very rare lysosomal storage diseases with an incidence of about 1:100,000– 1:200,000 live births worldwide. Here we report the beta-galactosidase gene (GLB1) mutation analysis of 21 unrelated GM1 gangliosidosis patients, and of 4 Morquio B patients, of whom two are brothers. Clinical features of the patients were collected and compared with those in literature. In silico analyses were performed by standard alignments tools and by an improved version of GLB1 three-dimensional models. The analysed cohort includes remarkable cases. One patient with GM1 gangliosidosis had a triple X syndrome. One patient with juvenile GM1 gangliosidosis was homozygous for a mutation previously identified in Morquio type B. A patient with infantile GM1 gangliosidosis carried a complex GLB1 allele harbouring two genetic variants leading to p.R68W and p.R109W amino acid changes, in trans with the known p.R148C mutation. Molecular analysis showed 27 mutations, 9 of which are new: 5 missense, 3 microdeletions and a nonsense mutation. We also identified four new genetic variants with a predicted polymorphic nature that was further investigated by in silico analyses. Three-dimensional structural analysis of GLB1 homology models including the new missense mutations and the p.R68W and p.R109W amino acid changes, showed that all the amino acids replacements affected the resulting protein structures in different ways, from changes in polarity to folding alterations. Genetic and clinical associations led us to undertake a critical review of the classifications of late-onset GM1 gangliosidosis and Morquio B disease.

Caciotti, Anna; Garman, Scott C; Rivera-Colon, Yadilette; Procopio, Elena; Catarzi, Serena; Ferri, Lorenzo; Guido, Carmen; Martelli, Paola; Parini, Rossella; Antuzzi, Daniela; Battini, Roberta; Sibilio, Michela; Simonati, Alessandro; Fontana, Elena; Salviati, Alessandro; Akinci, Gulcin; Cereda, Cristina; Dionisi-Vici, Carlo; Deodato, Francesca; d'Amico, Adele; d'Azzo, Alessandra; Bertini, Enrico; Filocamo, Mirella; Scarpa, Maurizio; di Rocco, Maja; Tifft, Cynthia J; Ciani, Federica; Gasperini, Serena; Pasquini, Elisabetta; Guerrini, Renzo; Donati, Maria Alice; Morrone, Amelia

2011-01-01

39

Modulating action of the new polymorphism L436F detected in the GLB1 gene of a type-II GM1 gangliosidosis patient.  

PubMed

We report the modulating action of the L436F new polymorphism identified in the GLB1 gene of a patient affected by GM1 gangliosidosis with onset at 17 months and rapidly progressive psychomotor deterioration. Sequencing analysis and familial restriction studies revealed that the maternal allele of this patient carried the L436F polymorphism in cis with the known R201C mutation. The new mutation R68W was identified in his paternal allele. Since the GLB1 activity of the patient's leukocytes was very low and compatible with both the type-I and the type-II form of the disease, the potential impact of each mutation was investigated by expression studies in COS1 cells, and Western blots. Expression study of the R68W mutated allele resulted in no GLB1 activity. Transfection with a vector carrying the R201C mutation gave rise to a residual GLB1 activity, which, interestingly, was severely reduced in transfection with the L436F/R201C allele. These expression studies, together with co-transfection experiments, suggest that the R201C/L436F GLB1 "complex allele" leads to this patient's clinical and biochemical findings. The type-II phenotype of the disease is subdivided into late infantile and juvenile forms. The clinical and molecular characterization of this patient as late-infantile GM1 gangliosidosis is in keeping with a clear-cut division between the two sub forms of the type-II phenotype. The modulating role of the L436F polymorphism should be stressed as a cause of this patient's condition. This model suggests that the combination of missense mutations or polymorphisms should be evaluated when diagnosing inherited genetic disorders. PMID:12644936

Caciotti, Anna; Bardelli, Tiziana; Cunningham, John; D'Azzo, Alessandra; Zammarchi, Enrico; Morrone, Amelia

2003-07-01

40

GM1 gangliosidosis in shiba dogs.  

PubMed

A six-month-old shiba dog with a one-month history of progressive motor dysfunction showed clinical signs of a cerebellar disorder, including ataxia, dysmetria and intention tremor of the head. Histopathological and ultrastructural studies revealed distended neurons packed with membranous cytoplasmic bodies throughout the central nervous system. The activities of lysosomal acid beta-galactosidase in its leucocytes and liver were less than 2 per cent of the control levels, and the compound accumulated in the brain was identified as GM1 ganglioside. A sibling which died immediately after birth was shown to have a beta-galactosidase deficiency in the brain and visceral organs. A family study revealed that the sire and dam of the probands were heterozygotes with approximately half of the normal level of beta-galactosidase activity, suggesting an autosomal recessive pattern of inheritance. PMID:10887996

Yamato, O; Ochiai, K; Masuoka, Y; Hayashida, E; Tajima, M; Omae, S; Iijima, M; Umemura, T; Maede, Y

2000-04-22

41

Molecular form and subcellular distribution of acid beta-galactosidase in fibroblasts from patients with GM1 gangliosidosis, Morquio B disease and galactosialidosis.  

PubMed

The molecular form and subcellular distribution of acid beta-galactosidase in cultured fibroblasts from patients with beta-galactosidase deficiency (GM1-gangliosidosis, Morquio B disease and galactosialidosis) were studied, using antibodies against three different forms of the human enzyme: a high-molecular-weight multienzymic complex, a recombinant 84-kDa precursor, and a 64-kDa tryptic product of the precursor. The mature enzyme from normal fibroblasts was immunoprecipitated by the anti-complex and anti-64-kDa protein antibodies, but not by the anti-84-kDa precursor one. immunofluorescence staining of normal fibroblasts revealed the granular (lysosomal) distribution with anti-64-kDa protein antibody and the perinuclear reticular distribution with anti-84-kDa precursor antibody, probably representing the Golgi apparatus. Both patterns were demonstrated in Morquio B disease, but the residual enzyme activity was exclusively due to the mature enzyme. In Type 1 galactosialidosis, most of the expressed enzyme was detected as the precursor form with a perinuclear reticular distribution. In type 2 galactosialidosis, more than half of the enzyme activity was due to the mature form with a lysosomal distribution. Fibroblasts from a patient with GM1 gangliosidosis, expressing no beta-galactosidase mRNA, did not react against either anti-64-kDa protein antibody or anti-84-kDa precursor antibody. The combined use of immunoprecipitation and immunostaining was useful for analysing the pathophysiology of the intracellular processing and transport of the mutant beta-galactosidase. PMID:9105659

Takiyama, N; Itoh, K; Shimmoto, M; Nishimoto, J; Inui, K; Sakuraba, H; Suzuki, Y

1997-03-01

42

Chemical chaperone therapy for brain pathology in GM1-gangliosidosis  

Microsoft Academic Search

We synthesized a galactose derivative, N-octyl-4-epi--valienamine (NOEV), for a molecular therapy (chemical chaperone therapy) of a human neurogenetic disease, -galactosidosis (GM1-gangliosidosis and Morquio B disease). It is a potent inhibitor of lysosomal -galactosidase in vitro. Addition of NOEV in the culture medium restored mutant enzyme activity in cultured human or murine fibroblasts at low intracellular concentrations, resulting in a marked

Junichiro Matsuda; Osamu Suzuki; Akihiro Oshima; Yoshie Yamamoto; Akira Noguchi; Kazuhiro Takimoto; Masayuki Itoh; Yuji Matsuzaki; Yosuke Yasuda; Seiichiro Ogawa; Yuko Sakata; Eiji Nanba; Katsumi Higaki; Yoshimi Ogawa; Lika Tominaga; Kousaku Ohno; Hiroyuki Iwasaki; Hiroshi Watanabe; Roscoe O. Brady; Yoshiyuki Suzuki

2003-01-01

43

Rapid prenatal diagnosis of GM 1 -gangliosidosis using microchemical methods  

Microsoft Academic Search

Prenatal diagnoses were established in 3 pregnancies at risk for GM1-gangliosidosis at 9, 10, and 12 days after amniocentesis. ß-galactosidase activities in cultured amniotic fluid cells were determined by microchemical assays in cell homogenates and in isolated groups of 10–30 freeze-dried cells. The latter method requires only a few hundred cells growing in one or more clones and will usually

W. J. Kleijer; E. Van der Veer; M. F. Niermeijer

1976-01-01

44

A case of GM1 gangliosidosis type I.  

PubMed

A six-month-old female gypsy child, the daughter of second degree cousins, born after a full-term pregnancy and normal delivery, is described. There was generalized neonatal edema. Abnormalities included psychomotor retardation from birth and progressive appearance of facial dysmorphism, organ enlargement, axial hypotonia, hypertonia in limbs, myoclonic jerks, optic atrophy and bilateral cherry-red spots. The diagnosis of GM1 type 1 gangliosidosis was confirmed by biochemical, enzymatic and ultrastructural findings. PMID:2500629

Cabral, A; Portela, R; Tasso, T; Eusébio, F; Moreira, A; dos Santos, H M; Soares, J; Moura-Nunes, J F

1989-03-01

45

Anomalous eosinophil granulocytes in blood and bone marrow: a diagnostic marker for infantile GM 1 -gangliosidosis?  

Microsoft Academic Search

On routine smears of blood and bone marrow of four patients with GM1 gangliosidosis type I, eosinophil granulocytes were unusually pale and contained faintly stained, unevenly spaced granules some of which were larger than normal and had abnormal ultrastructural appearance. The anomaly may represent a hitherto overlooked but easily obtainable diagnostic marker.

R. Gitzelmann; M. A. Spycher; S. Adank; K. Baerlocher; B. Steinmann

1985-01-01

46

The leukoencephalopathy of infantile GM1 gangliosidosis: oligodendrocytic loss and axonal dysfunction  

Microsoft Academic Search

A myelin deficit in the cerebral white matter in infantile GM1 gangliosidosis is well established. Some have proposed this deficit to be secondary to axonal loss, while others argue for delayed or arrested myelination. We compared the frontal white and gray matter of two infants with GM1 gangliosidosis with four age-matched controls, using light microscopy with a quantitative analysis, immunohistochemistry,

J. Patrick van der Voorn; Wout Kamphorst; Marjo S. van der Knaap; James M. Powers

2004-01-01

47

A novel mutation in the gene for canine acid ?-galactosidase that causes GM1-gangliosidosis in Shiba dogs  

Microsoft Academic Search

A homozygous recessive mutation, causing GM1-gangliosidosis in Shiba dogs, was identified as a deletion of C nucleotide 1668 in the gene for canine acid ß-galactosidase, which was a novel mutation in canine GM1-gangliosidosis.

O. Yamato; D. Endoh; A. Kobayashi; Y. Masuoka; M. Yonemura; A. Hatakeyama; H. Satoh; M. Tajima; M. Yamasaki; Y. Maede

2002-01-01

48

A severe infantile sialidosis ( ? -galactosidase- ? -neuraminidase deficiency) mimicking GM 1 -gangliosidosis type 1  

Microsoft Academic Search

We observed a 3-month-old Japanese female infant with severe psychomotor retaration, coarse facial appearance, hepatosplenomegaly, and dysostosis multiplex. Only ß-galactosidase was found to be deficient when the routine lysosomal hydrolase assay was performed on the patient's lymphocytes at 6 months of age. At first GM1-gangliosidosis type 1 seemed the most likely diagnosis. Later, however, additional studies (hydrolase assay in cultured

S. Okada; H. Sugino; T. Kato; T. Yutaka; M. Koike; T. Dezawa; T. Yamano; H. Yabuuchi

1983-01-01

49

Candidate molecules for chemical chaperone therapy of GM1-gangliosidosis.  

PubMed

A growing body of evidence suggests that misfolding of a mutant protein followed by its aggregation or premature degradation in the endoplasmic reticulum is one of the main mechanisms that underlie inherited neurodegenerative diseases, including lysosomal storage diseases. Chemical or pharmacological chaperones are small molecules that bind to and stabilize mutant lysosomal enzyme proteins in the endoplasmic reticulum. A number of chaperone compounds for lysosomal hydrolases have been identified in the last decade. They have gained attention because they can be orally administrated, and also because they can penetrate the blood-brain barrier. In this article, we describe two chaperone candidates for the treatment of GM1-gangliosidosis. We also discuss the future direction of this strategy targeting other lysosomal storage diseases as well as protein misfolding diseases in general. PMID:24024947

Higaki, Katsumi; Ninomiya, Haruaki; Suzuki, Yoshiyuki; Nanba, Eiji

2013-09-01

50

[Three siblings with type 3 GM1-gangliosidosis--pathophysiology of dystonia and MRI findings].  

PubMed

GM1-gangliosidosis is a rare neurovisceral storage disease caused by an inherited deficiency of acid beta-galactosidase. The characteristic neurological feature of type 3 (adult or chronic) GM1-gangliosidosis is usually a slowly progressive dystonia with dysarthria due to predominant involvement of basal ganglia. About 20 adult patients with this disorder have been reported in the literature. However, there are no reports of 3 brothers with type 3 GM1-gangliosidosis, and MRI findings. Case 1 (proband): A 28-year-old man was hospitalized because of facial grimace, dysarthria, and generalized dystonia. He was born after normal pregnancy and delivery. His development was normal until 3 years of age when the difficulties of speaking and walking were noticed by his parents. These neurological abnormalities progressed slowly and facial grimace and dystonic movements occurred 7 years later. He could not walk at 22 years of age. On admission, he was bedridden with marked scoliosis and subluxation of the mandibule. The communication was possible only by pointing the words written on the board. Case 2: A 33-year-old man, elder brother of case 1, showed the similar neurological features and clinical course. Slit-lamp examination revealed corneal opacities which were located in the deep stroma. Case 3: A 33-year-old man, elder brother of case 1 or case 2. At age 10-11, he noted similar symptoms as case 1 or case 2. The severity of dystonia was milder than his brothers. A diagnosis of GM1-gangliosidosis in three patients was made on the basis of the following data.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2123760

Uyama, E; Terasaki, T; Owada, M; Naito, M; Araki, S

1990-08-01

51

?-Galactosidase-deficient mouse as an animal model for GM1-gangliosidosis  

Microsoft Academic Search

GM1-gangliosidosis is a progressive neurological disease in humans caused by deficiency of lysosomal acid ?-galactosidase,\\u000a which hydrolyses the terminal ?-galactosidic residue from ganglioside GM1 and other glycoconjugates. In this study, we generated\\u000a a mouse model for GM1-gangliosidosis by gene targeting in embryonic stem cells. The mouse homozygous for the disrupted ?-galactosidase\\u000a gene showed ?-galactosidase deficiency, presented with progressive spastic diplegia,

Junichiro Matsuda; Osamu Suzuki; Akihiro Oshima; Atsuo Ogura; Yoko Noguchi; Yoshie Yamamoto; Toshihiko Asano; Kazuhiro Takimoto; Kazuko Sukegawa; Yoshiyuki Suzuki; Masaharu Naiki

1997-01-01

52

Mechanisms of distribution of mouse ?-galactosidase in the adult GM1-gangliosidosis brain  

Microsoft Academic Search

GM1-gangliosidosis is a lysosomal storage disease (LSD) caused by an autosomal recessive deficiency of lysosomal acid ?-galactosidase (?gal). This leads to accumulation of GM1-ganglioside and its asialo derivative GA1 in the central nervous system (CNS), and progressive neurodegeneration. Therapeutic AAV-mediated gene delivery to the brain for LSDs has proven very successful in several animal models. GM1-gangliosidosis is also a prime

M L D Broekman; L A Tierney; C Benn; P Chawla; J H Cha; M Sena-Esteves

2009-01-01

53

Type 1 GM1 gangliosidosis with basal ganglia calcification: a case report.  

PubMed

This report concerns a 10-month-old boy, admitted to the Veterans General Hospital-Kaohsiung with generalized tonic convulsion and aspiration pneumonia. He was found to have had developmental regression, progressive hypotonia and hepatosplenomegaly since four months of age. Physical examination revealed a large head circumference (97th percentile), frontal bossing, depressed nasal bridge, hepatosplenomegaly, broad hands and short fingers. Neurologic examination showed poor control of eye movement, profound hypotonia, muscle weakness, brisk deep tendon reflexes and Babinski's sign. Hypoplasia of the vertebral bodies with anterior beaking, wedge-shaped metacarpals, spatulated ribs and a J-shaped sella turcica were displayed on bone radiographs. Cranial computerized tomography scans showed diffuse brain atrophy, dilated ventricles and calcification of the bilateral basal ganglia. Vacuolated lymphocytes were noted in a peripheral blood smear. Type 1 GM1 gangliosidosis was diagnosed based on a deficiency of beta-galactosidase activity. To our knowledge, basal ganglia calcification in type 1 GM1 gangliosidosis has never been reported in the literature. We suggest that type 1 GM1 gangliosidosis be considered in the differential diagnosis of patients with an early onset of neurologic decline, organomegaly and basal ganglia calcification. PMID:10063711

Chen, C C; Chiu, P C; Shieh, K S

1999-01-01

54

GM1 gangliosidosis (type 1) in a cat.  

PubMed Central

A kitten with clinical and morphological symptoms of a neurovisceral lysosomal-storage disease has been shown to have a marked deficiency of acidic beta-D-galactosidase in the brain, kidney and spleen. Chromatography on concanavalin A-Sepharose and inhibition studies with 2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine, a selective inhibitor of the neutral broad-specificity beta-D-galactosidase, have shown that the residual beta-D-galactosidase at pH 4.0 in the tissues of the affected cat is due to the neutral beta-D-galactosidase and that there is a complete deficiency of the acidic (lysosomal) beta-D-galactosidase. There is marked accumulation in all tissues and excretion in the urine of neutral oligosaccharides. Analysis of these oligosaccharides by fast-atom-bombardment mass spectrometry and g.l.c. suggests that they arise from the incomplete catabolism of N-glycans of glycoproteins. The ganglioside content of all the tissues is elevated, and it has been shown by t.l.c. that the concentration of a ganglioside fraction with a mobility similar to that of GM1 ganglioside is particularly increased. There is also some evidence of accumulation of glycosaminoglycans in the brain. The clinical symptoms, the complete deficiency of acidic beta-D-galactosidase and the storage products in visceral organs all suggest that this is a case of feline GM1-type gangliosidosis comparable with the severe infantile (Type 1) form of the disease in humans. Images Fig. 3.

Barker, C G; Blakemore, W F; Dell, A; Palmer, A C; Tiller, P R; Winchester, B G

1986-01-01

55

?-Galactosidosis in Patient with Intermediate GM1 and MBD Phenotype.  

PubMed

A 5-year-old girl with clinical and biochemical phenotypes encompassing both GM1-gangliosidosis (GM1) and Morquio B disease (MBD) is described. Mild generalized skeletal dysplasia and keratan sulfaturia were consistent with a diagnosis of MBD, while developmental delay and GM1-specific oligosacchariduria were consistent with GM1 gangliosidosis. No observable ?-galactosidase activity was detected in leukocytes, and two mutations, p.R201H (c.602G>A) and p.G311R (c.931G>A), were identified by gene sequencing. The R201H substitution has been previously reported in patients with both GM1 and MBD, and G311R is a novel mutation. Our patient represents a further example of the clinical heterogeneity that can result from mutations at the ?-galactosidase locus. PMID:23430499

Moore, Tereza; Bernstein, Jonathan A; Casson-Parkin, Sylvie; Cowan, Tina M

2013-01-01

56

[The role of ophthalmological examination in the diagnosis of gangliosidosis GM1].  

PubMed

Gangliosidosis GM1 belongs to a group of lysosomal storage diseases and results from the deficiency of acidic beta-galactosidase activity. The enzyme is essential for the degradation of ganglioside GM1 and its derivatives. The disease causes multi-organ injury, however accumulation of ganglioside GM1 mainly in the brain white and gray matter results in predomination of neurological symptoms. Based on the actual knowledge--the condition is untreatable and especially in the very severe infantile form, the duration of the survival is very short. One of the characteristic symptoms of some lysosomal storage diseases, including gangliosidosis GM1, is "cherry-red" spot found in the fundus of the eye. In the publication the clinical course of gangliosidosis GM1 in two infants is presented. The value of an ophthalmological examination in the diagnosis of this rare condition has been emphasized. PMID:22256571

Krzywi?ska-Zdeb, Elzbieta; Gizewska, Maria; Modrzejewska, Monika; Romanowska, Hanna; Stecewicz, Iwona; Paw?owska, Anna; Tuziak, Martyna; Walczak, Mieczys?aw

2011-01-01

57

Chaperone therapy update: Fabry disease, GM1-gangliosidosis and Gaucher disease.  

PubMed

Chaperone therapy is a newly developed molecular therapeutic approach to lysosomal diseases, a group of human genetic diseases causing severe brain damage. Based on early molecular studies during the last decade of the 20th century and early years of the 21st century, mainly on Fabry disease and GM1-gangliosidosis, we found some mutant enzyme proteins were unstable in the cell, and unable to express catalytic activities. Subsequently galactose and other active-site binding substrate analogs were found stabilized and enhance the mutant enzyme activity in culture cells. We concluded that the mutant misfolding enzyme protein and substrate analog competitive inhibitor (chemical chaperone) form a stable complex to be transported to the lysosome, to restore the catalytic activity of mutant enzyme after spontaneous dissociation under the acidic condition. This gene mutation-specific molecular interaction is a paradoxical phenomenon that an enzyme inhibitor in vitro serves as an enzyme stabilizer in situ. First we developed a commercially available compound 1-deoxygalactonojirimycin (DGJ) for Fabry disease, and confirmed the above molecular phenomenon. Currently DGJ has become a new candidate of oral medicine for Fabry disease, generalized vasculopathy involving the kidneys, heart and central nervous system in the middle age. This drug development has reached the phase 3 of human clinical study. Then we found two valienamine derivatives, N-octyl-4-epi-?-valienamine (NOEV) and N-octyl-?-valienamine (NOV), as promising therapeutic agents for human ?-galactosidase deficiency disorders (GM1-gangliosidosis and Morquio B disease) and ?-glucosidase deficiency disorders (phenotypic variations of Gaucher disease), respectively. Originally NOEV and NOV had been discovered as competitive inhibitors, and then their paradoxical bioactivities as chaperones were confirmed in cultured fibroblasts from patients with these disorders. Subsequently GM1-gangliosidosis model mice have been used for confirmation of clinical effectiveness, adverse effects and pharmacokinetic studies. Orally administered NOEV entered the brain through the blood-brain barrier, enhanced ?-galactosidase activity, reduced substrate storage, and improved neurological deterioration clinically. Computational analysis revealed pH-dependent enzyme-chaperone interactions. Our recent study indicated chaperone activity of a new DGJ derivative, MTD118, for ?-galactosidase complementary to NOEV. NOV also showed the chaperone effect toward several ?-glucosidase gene mutants in Gaucher disease. Furthermore a commercial expectorant drug ambroxol was found to be a chaperone for ?-glucosidase. A few Gaucher patients responded to this drug with remarkable improvement of oculomotor dysfunction and myoclonus. We hope chaperone therapy will become available for some patients with Fabry disease, GM1-gangliosidosis, Gaucher disease, and other lysosomal storage diseases particularly with central nervous system involvement. PMID:23290321

Suzuki, Yoshiyuki

2013-06-01

58

698. Gene Therapy of Murine GM1 Gangliosidosis by Genetically Modified Bone Marrow Hematopoietic Progenitor Cells  

Microsoft Academic Search

b-galactosidase (b-gal), a lysosomal enzyme involved in the removal of b-linked terminal galactosyl residues of many glycoconjugates, is deficient in the neurodegenerative lysosomal disorder GM1-gangliosidosis (GM1). GM1-\\/-mice closely mimic the most fundamental aspects of the neuropathological and neurochemical abnormalities of the human disorder. Bone marrow progenitor cells have been used as a source of corrective protein because of their ability

Renata Sano; Alessandra Tessitore; Angela Ingrassia; Alessandra d'Azzo

2004-01-01

59

N-butyldeoxygalactonojirimycin reduces neonatal brain ganglioside content in a mouse model of GM1 gangliosidosis  

Microsoft Academic Search

GM1 gangliosidosis is a glycosphingolipid (GSL) lysosomal storage disease caused by a genetic deficiency of acid b-galactosidase (b-gal), the enzyme that catabolyzes GM1 within lysosomes. Accumulation of GM1 and its asialo form (GA1) occurs primarily in the brain, leading to progressive neurodegeneration and brain dysfunction. Substrate reduction therapy aims to decrease the rate of GSL biosynthesis to counterbalance the impaired

Julie L. Kasperzyk; Mohga M. El-Abbadi; Eric C. Hauser; Alessandra d'Azzo; Frances M. Platt; Thomas N. Seyfried

2004-01-01

60

Mutation analysis of GM1 gangliosidosis in a Siamese cat from Japan in the 1960s.  

PubMed

GM1 gangliosidosis is a fatal, progressive neurodegenerative lysosomal storage disease caused by mutations of the ?-galactosidase (GLB1) gene. In feline GM1 gangliosidosis, a pathogenic mutation (c.1448G>C) of the feline GLB1 gene was identified in Siamese and Korat cats previously diagnosed with the disease in the USA and Italy, respectively. The present study demonstrated the same mutation in a Siamese cat that had been diagnosed with GM1 gangliosidosis in Japan in the 1960s. The mutation was confirmed using DNA extracted from stored paraffin-embedded brain tissue by a direct sequencing method and a polymerase chain reaction-restriction fragment length polymorphism assay. This pathogenic mutation seems to have been distributed around the world. PMID:22772479

Uddin, Mohammad M; Tanimoto, Takeshi; Yabuki, Akira; Kotani, Takao; Kuwamura, Mitsuru; Chang, Hye-Sook; Yamato, Osamu

2012-12-01

61

Manifestation of infantile GM1 gangliosidosis in the fetal eye. An electron microscopic study.  

PubMed

GM1 gangliosidosis in the infantile form is a rapidly fatal storage disease produced by deficiency of acid beta-galactosidase. Ultrastructural studies of the eyes from two fetuses affected with GM1 gangliosidosis were performed in an effort to assess tissue-specific distribution of storage inclusions in the different ocular components derived from neuroectoderm, surface ectoderm, and mesoderm. Two major configurations of inclusions were observed: electronlucent vacuoles and pleiomorphic osmiophilic membranes. Although the latter changes mainly affected the retinal neurons, they were occasionally found in cells of epithelial and mesenchymal origin. The findings indicate that the lysosomal storage process in GM1 gangliosidosis, type 1, has a wide morphologic spectrum that is already present in the early period of fetal life. PMID:3125087

Schmitt-Gräff, A

1988-01-01

62

Rapid detection of GM1 ganglioside in cerebrospinal fluid in dogs with GM1 gangliosidosis using matrix-assisted laser desorption ionization time-of-flight mass spectrometry.  

PubMed

The concentration of GM1 (monosialotetrahexosyl ganglioside) in cerebrospinal fluid (CSF) is markedly increased in dogs with GM1 gangliosidosis due to GM1 accumulation in the central nervous system and leakage to the CSF. The present study established a rapid and simple method for detection of accumulated GM1 in the CSF in dogs with GM1 gangliosidosis using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI TOF MS) and discusses the usefulness of this method for the rapid diagnosis and/or high-risk screening of this disease in domestic animals. Cerebrospinal fluid was collected from normal dogs and 4- to 11-month-old Shiba dogs with GM1 gangliosidosis. The MALDI TOF MS analysis was carried out in combination with a special sample plate and a simple desalting step on the plate. Specific signs of GM1 could be detected in the standard GM1 solutions at concentrations of 50 nmol/l or more. The signs were also clearly detected in CSF (131-618 nmol/l) in affected dogs, but not in normal canine CSF (12 ± 5 nmol/l, mean ± standard deviation). The results demonstrated that MALDI TOF MS can detect GM1 accumulated in canine CSF even in the early stage of the disease. In conclusion, the rapid detection of increased CSF GM1 using MALDI TOF MS is a useful method for diagnosis and/or screening for canine GM1 gangliosidosis. PMID:22362802

Satoh, Hiroyuki; Yamauchi, Toyofumi; Yamasaki, Masahiro; Maede, Yoshimitsu; Yabuki, Akira; Chang, Hye-Sook; Asanuma, Taketoshi; Yamato, Osamu

2011-11-01

63

Neuronal-visceral GM1 gangliosidosis in a dog with beta-galactosidase deficiency.  

PubMed

A 9-month-old dog with a history of progressive motor dysfunction was shown to have a deficiency in brain beta-galactosidase activity. The canine disease, like that of children with GM1 gangliosidosis, is characterized by accumulation of GM1 ganglioside in the brain, liver, and spleen, and membranous cytoplasmic bodies in neurons. The dog's pedigree suggests an autosomal recessive pattern of inheritance. PMID:824730

Read, D H; Harrington, D D; Keenana, T W; Hinsman, E J

1976-10-22

64

Neuronal-Visceral GM1 Gangliosidosis in a Dog with beta Galactosidase Deficiency  

Microsoft Academic Search

A 9-month-old dog with a history of progressive motor dysfunction was shown to have a deficiency in brain beta -galactosidase activity. The canine disease, like that of children with GM1 gangliosidosis, is characterized by accumulation of GM1 ganglioside in the brain, liver, and spleen, and membranous cytoplasmic bodies in neurons. The dog's pedigree suggests an autosomal recessive pattern of inheritance.

Deryck H. Read; Daniel D. Harrington; Thomas W. Keenan; Edward J. Hinsman

1976-01-01

65

Therapeutic chaperone effect of N-octyl 4-epi-?-valienamine on murine G(M1)-gangliosidosis.  

PubMed

Therapeutic chaperone effect of a valienamine derivative N-octyl 4-epi-?-valienamine (NOEV) was studied in G(M1)-gangliosidosis model mice. Phamacokinetic analysis revealed rapid intestinal absorption and renal excretion after oral administration. Intracellular accumulation was not observed after continuous treatment. NOEV was delivered to the central nervous system through the blood-brain barrier to induce high expression of the apparently deficient ?-galactosidase activity. NOEV treatment starting at the early stage of disease resulted in remarkable arrest of neurological progression within a few months. Survival time was significantly prolonged. This result suggests that NOEV chaperone therapy will be clinically effective for prevention of neuronal damage if started early in life hopefully also in human patients with G(M1)-gangliosidosis. PMID:22436580

Suzuki, Yoshiyuki; Ichinomiya, Satoshi; Kurosawa, Mieko; Matsuda, Junichiro; Ogawa, Seiichiro; Iida, Masami; Kubo, Takatoshi; Tabe, Miho; Itoh, Masayuki; Higaki, Katsumi; Nanba, Eiji; Ohno, Kousaku

2012-05-01

66

[Late infantile GM1 gangliosidosis with progressive dilatation of common bile duct and obstructive apnea--an autopsy case].  

PubMed

We report a 5-year-old autopsy case of late infantile type of GM1 gangliosidosis,which developed rare respiratory and intestinal complications. Obstructive apnea by adenoidal hypertrophy was improved by adenoidectomy, but the right bronchus was compressed by hilar lymph node swellings. The lymph nodes could not be treated surgically because of her poor general condition. There was hyperplasia showing foamy histiocyte including mucopolysaccharide which demonstrated a vacuolar formation containing irregular arranged fibrillar material on electron microscopy. Cerebral atrophy progressed gradually, and epileptic apnea developed, which was intractable to all antiepileptic drugs administered. Glycolipid accumulation, showing membranous cytoplasmic body on electron microscopy, seemed to lead to neurodegeneration. Abdominal distension due to hepatosplenomegaly, common bile duct dilatation compressed by lymph node swelling of the caput pancreatis part, and enteroparalysis was uncontrolled. These findings suggest that severe glycolipid deposition in lymphoreticular organs can induce various complications in patients with late infantile type of GM1 gangliosidosis. PMID:17228820

Kuki, Ichiro; Tomiwa, Kiyotaka; Okazaki, Shin; Ikeda, Hiroko; Kawawaki, Hisashi

2007-01-01

67

Tuning glycosidase inhibition through aglycone interactions: pharmacological chaperones for Fabry disease and GM1 gangliosidosis.  

PubMed

Competitive inhibitors of either ?-galactosidase (?-Gal) or ?-galactosidase (?-Gal) with high affinity and selectivity have been accessed by exploiting aglycone interactions with conformationally locked sp(2)-iminosugars. Selected compounds were profiled as potent pharmacological chaperones for mutant lysosomal ?- and ?-Gal associated with Fabry disease and GM(1) gangliosidosis. PMID:22618082

Aguilar-Moncayo, M; Takai, T; Higaki, K; Mena-Barragán, T; Hirano, Y; Yura, K; Li, L; Yu, Y; Ninomiya, H; García-Moreno, M I; Ishii, S; Sakakibara, Y; Ohno, K; Nanba, E; Ortiz Mellet, C; García Fernández, J M; Suzuki, Y

2012-07-01

68

GM1-gangliosidosis Types 1 and 2: Enzymatic Differences in Cultured Fibroblasts  

Microsoft Academic Search

GM1-GANGLIOSIDOSIS occurs in two clinical forms1,2. Type 1 resembles Hurler's syndrome somatically, but its psychomotor aspect is apparent from birth and progresses rapidly to cause death by 2 years of age. Type 2 presents no Hurler signs and its psychomotor course, though similar to that in type 1, is neither congenital nor is rapidly progressive; death occurs about 5 years

Leonard Pinsky; Elizabeth Powell; JOHN CALLAHAN

1970-01-01

69

Ultrastructural study on nervous system of fetus with GM 1 -gangliosidosis type 1  

Microsoft Academic Search

The nervous system of a 22-week-old fetus with GM1-gangliosidosis type 1 was studied by electron microscopy. The tissues thus examined were the cerebral cortex at the parietal region, the cerebellum, the thoracic spinal cord, the Auerbach's myenteric plexus in the large intestine and the radial nerve fibers. In the cerebral cortex, membrane-bound vacuoles, which occasionally contained stacks of fine fibrils,

T. Yamano; M. Shimada; S. Okada; T. Yutaka; T. Kato; K. Inui; H. Yabuuchi; S. Kanzaki; S. Kanda

1983-01-01

70

A bicyclic 1-deoxygalactonojirimycin derivative as a novel pharmacological chaperone for GM1 gangliosidosis.  

PubMed

Lysosomal ?-galactosidase (?-Gal) deficiency causes a group of disorders that include neuronopathic GM1 gangliosidosis and non-neuronopathic Morquio B disease. We have previously proposed the use of small molecule ligands of ?-Gal as pharmacological chaperones (PCs) for the treatment of GM1 gangliosidosis brain pathology. Although it is still under development, PC therapy has yielded promising preclinical results in several lysosomal diseases. In this study, we evaluated the effect of bicyclic 1-deoxygalactonojirimycin (DGJ) derivative of the sp(2)-iminosugar type, namely 5N,6S-(N'-butyliminomethylidene)-6-thio-1- deoxygalactonojirimycin (6S-NBI-DGJ), as a novel PC for human mutant ?-Gal. In vitro, 6S-NBI-DGJ had the ability to inhibit the activity of human ?-Gal in a competitive manner and was able to protect this enzyme from heat-induced degradation. Computational analysis supported that the rigid glycone bicyclic core of 6S-NBI-DGJ binds to the active site of the enzyme, with the aglycone N'-butyl substituent, in a precise E-orientation, located at a hydrophobic region nearby. Chaperone potential profiling indicated significant increases of enzyme activity in 24 of 88 ?-Gal mutants, including four common mutations. Finally, oral administration of 6S-NBI-DGJ ameliorated the brain pathology of GM1 gangliosidosis model mice. These results suggest that 6S-NBI-DGJ is a novel PC that may be effective on a broad range of ?-Gal mutants. PMID:23337983

Takai, Tomoko; Higaki, Katsumi; Aguilar-Moncayo, Matilde; Mena-Barragán, Teresa; Hirano, Yuki; Yura, Kei; Yu, Liang; Ninomiya, Haruaki; García-Moreno, M Isabel; Sakakibara, Yasubumi; Ohno, Kousaku; Nanba, Eiji; Ortiz Mellet, Carmen; García Fernández, José M; Suzuki, Yoshiyuki

2013-03-01

71

A Bicyclic 1-Deoxygalactonojirimycin Derivative as a Novel Pharmacological Chaperone for GM1 Gangliosidosis  

PubMed Central

Lysosomal ?-galactosidase (?-Gal) deficiency causes a group of disorders that include neuronopathic GM1 gangliosidosis and non-neuronopathic Morquio B disease. We have previously proposed the use of small molecule ligands of ?-Gal as pharmacological chaperones (PCs) for the treatment of GM1 gangliosidosis brain pathology. Although it is still under development, PC therapy has yielded promising preclinical results in several lysosomal diseases. In this study, we evaluated the effect of bicyclic 1-deoxygalactonojirimycin (DGJ) derivative of the sp2-iminosugar type, namely 5N,6S-(N?-butyliminomethylidene)-6-thio-1- deoxygalactonojirimycin (6S-NBI-DGJ), as a novel PC for human mutant ?-Gal. In vitro, 6S-NBI-DGJ had the ability to inhibit the activity of human ?-Gal in a competitive manner and was able to protect this enzyme from heat-induced degradation. Computational analysis supported that the rigid glycone bicyclic core of 6S-NBI-DGJ binds to the active site of the enzyme, with the aglycone N?-butyl substituent, in a precise E-orientation, located at a hydrophobic region nearby. Chaperone potential profiling indicated significant increases of enzyme activity in 24 of 88 ?-Gal mutants, including four common mutations. Finally, oral administration of 6S-NBI-DGJ ameliorated the brain pathology of GM1 gangliosidosis model mice. These results suggest that 6S-NBI-DGJ is a novel PC that may be effective on a broad range of ?-Gal mutants.

Takai, Tomoko; Higaki, Katsumi; Aguilar-Moncayo, Matilde; Mena-Barragan, Teresa; Hirano, Yuki; Yura, Kei; Yu, Liang; Ninomiya, Haruaki; Garcia-Moreno, M. Isabel; Sakakibara, Yasubumi; Ohno, Kousaku; Nanba, Eiji; Ortiz Mellet, Carmen; Garcia Fernandez, Jose M.; Suzuki, Yoshiyuki

2013-01-01

72

A Duplication in the Canine  Galactosidase Gene GLB1 Causes Exon Skipping and GM1Gangliosidosis in Alaskan Huskies  

Microsoft Academic Search

GM1-gangliosidosis is a lysosomal storage disease that is inherited as an autosomal recessive disorder, predominantly caused by structural defects in the -galactosidase gene (GLB1). The molecular cause of GM1-gangliosidosis in Alaskan huskies was investigated and a novel 19-bp duplication in exon 15 of the GLB1 gene was identified. The duplication comprised positions 1688-1706 of the GLB1 cDNA. It partially disrupted

Robert Kreutzer; Tosso Leeb; Gundi Müller; Andreas Moritz; Wolfgang Baumgärtner

2005-01-01

73

Intracerebral cell transplantation therapy for murine GM1 gangliosidosis.  

PubMed

We performed a cell transplantation study to treat the brain involvement in lysosomal storage diseases. We used acid beta-galactosidase knock-out mice (BKO) from C57BL/6 as recipients. To minimize immune responses, we used cells derived from transgenic mice of C57BL/6 overexpressing the normal human beta-galactosidase. Fetal brain cells (FBC), bone marrow-derived mesenchymal stem cells (MSC), and mixed FBC and MSC cells were prepared and injected into the ventricle of newborn BKO mouse brain. The mice were examined at 1, 2, 4, and 8 weeks and 6 months after injection. In each experiment, the injected cells migrated into the whole brain effectively and survived for at least 8 weeks. Decrease in ganglioside GM1 level was also observed. FBC could survive for 6 months in recipient brain. However, the number of transplanted FBC decreased. In the brains of MSC- or mixed cell-treated mice, no grafted cells could be found at 6 months. To achieve sufficient long-term effects on the brain, a method of steering the immune response away from cytotoxic responses or of inducing tolerance to the products of therapeutic genes must be developed. PMID:19118961

Sawada, Tomo; Tanaka, Akemi; Higaki, Katsumi; Takamura, Ayumi; Nanba, Eiji; Seto, Toshiyuki; Maeda, Mitsuyo; Yamaguchi, Etsuko; Matsuda, Junichiro; Yamano, Tunekazu

2009-11-01

74

GM1-gangliosidosis in American black bears: clinical, pathological, biochemical and molecular genetic characterization.  

PubMed

G(M1)-gangliosidosis is a rare progressive neurodegenerative disorder due to an autosomal recessively inherited deficiency of lysosomal ?-galactosidase. We have identified seven American black bears (Ursus americanus) found in the Northeast United States suffering from G(M1)-gangliosidosis. This report describes the clinical features, brain MRI, and morphologic, biochemical and molecular genetic findings in the affected bears. Brain lipids were compared with those in the brain of a G(M1)-mouse. The bears presented at ages 10-14 months in poor clinical condition, lethargic, tremulous and ataxic. They continued to decline and were humanely euthanized. The T(2)-weighted MR images of the brain of one bear disclosed white matter hyperintensity. Morphological studies of the brain from five of the bears revealed enlarged neurons with foamy cytoplasm containing granules. Axonal spheroids were present in white matter. Electron microscopic examination revealed lamellated membrane structures within neurons. Cytoplasmic vacuoles were found in the liver, kidneys and chondrocytes and foamy macrophages within the lungs. Acid ?-galactosidase activity in cultured skin fibroblasts was only 1-2% of control values. In the brain, ganglioside-bound sialic acid was increased more than 2-fold with G(M1)-ganglioside predominating. G(A1) content was also increased whereas cerebrosides and sulfatides were markedly decreased. The distribution of gangliosides was similar to that in the G(M1)-mouse brain, but the loss of myelin lipids was greater in the brain of the affected bear than in the brain of the G(M1) mouse. Isolated full-length cDNA of the black bear GLB1 gene revealed 86% homology to its human counterpart in nucleotide sequence and 82% in amino acid sequence. GLB1 cDNA from liver tissue of an affected bear contained a homozygous recessive T(1042) to C transition inducing a Tyr348 to His mutation (Y348H) within a highly conserved region of the GLB1 gene. The coincidence of several black bears with G(M1)-gangliosidosis in the same geographic area suggests increased frequency of a founder mutation in this animal population. PMID:24581871

Muthupalani, Sureshkumar; Torres, Paola A; Wang, Betty C; Zeng, Bai Jin; Eaton, Samuel; Erdelyi, Ildiko; Ducore, Rebecca; Maganti, Rajanikarath; Keating, John; Perry, Bain J; Tseng, Florina S; Waliszewski, Nicole; Pokras, Mark; Causey, Robert; Seger, Rita; March, Philip; Tidwell, Amy; Pfannl, Rolf; Seyfried, Thomas; Kolodny, Edwin H; Alroy, Joseph

2014-04-01

75

Case series of two siblings suffering from GM1 gangliosidosis resulting in early multiple joint arthroplasties  

Microsoft Academic Search

Introduction  GM1 gangliosidosis is a rare autosomal recessive lysosomal storage disorder leading to accumulation of substrates of gangliosides\\u000a in lysosomes (Okada and O'Brien, Science 160:1002–1004, 1968; Brunetti-Pierri and Scaglia, Mol Genet Metab 94:391–396, 2008). The disease is diagnosed by a deficiency of beta-galactosidase enzyme (Brunetti-Pierri and Scaglia, Mol Genet Metab 94:391–396,\\u000a 2008). Animal studies and in vitro models have shown an

Yasmeen Khan

2010-01-01

76

Founder mutation causing infantile GM1-gangliosidosis in the Gypsy population.  

PubMed

The Gypsies are a trans-national founder population of Asian descent, whose genetic heritage is still incompletely characterized. Here, we describe the first founder mutation leading to a lysosomal storage disorder in this population: R59H in GLB1, which causes infantile GM1-gangliosidosis. The R59H carrier rate is approximately 2% in the general Gypsy population and approximately 10% in the Rudari sub-isolate. Haplotype analysis suggests that the Gypsy diaspora may have contributed to the spread of this mutation to South America. PMID:16466959

Sinigerska, Ivanka; Chandler, David; Vaghjiani, Vijesh; Hassanova, Irfet; Gooding, Rebecca; Morrone, Amelia; Kremensky, Ivo; Kalaydjieva, Luba

2006-05-01

77

Exome sequencing as a diagnostic tool in a case of undiagnosed juvenile-onset GM1-gangliosidosis  

PubMed Central

Objective: To utilize high-throughput sequencing to determine the etiology of juvenile-onset neurodegeneration in a 19-year-old woman with progressive motor and cognitive decline. Methods: Exome sequencing identified an initial list of 133,555 variants in the proband's family, which were filtered using segregation analysis, presence in dbSNP, and an empirically derived gene exclusion list. The filtered list comprised 52 genes: 21 homozygous variants and 31 compound heterozygous variants. These variants were subsequently scrutinized with predicted pathogenicity programs and for association with appropriate clinical syndromes. Results: Exome sequencing data identified 2 GLB1 variants (c.602G>A, p.R201H; c.785G>T, p.G262V). ?-Galactosidase enzyme analysis prior to our evaluation was reported as normal; however, subsequent testing was consistent with juvenile-onset GM1-gangliosidosis. Urine oligosaccharide analysis was positive for multiple oligosaccharides with terminal galactose residues. Conclusions: We describe a patient with juvenile-onset neurodegeneration that had eluded diagnosis for over a decade. GM1-gangliosidosis had previously been excluded from consideration, but was subsequently identified as the correct diagnosis using exome sequencing. Exome sequencing can evaluate genes not previously associated with neurodegeneration, as well as most known neurodegeneration-associated genes. Our results demonstrate the utility of “agnostic” exome sequencing to evaluate patients with undiagnosed disorders, without prejudice from prior testing results.

Adams, David A.; Markello, Thomas; Golas, Gretchen; Yang, Sandra; Sincan, Murat; Simeonov, Dimitre R.; Fuentes Fajardo, Karin; Hansen, Nancy F.; Cherukuri, Praveen F.; Cruz, Pedro; Teer, Jamie K.; Mullikin, James C.; Boerkoel, Cornelius F.; Gahl, William A.; Tifft, Cynthia J.

2012-01-01

78

Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1 gangliosidosis mice.  

PubMed

II3NeuAc-GgOse4Cer (GM1) gangliosidosis is an incurable lysosomal storage disease caused by a deficiency in acid beta-galactosidase (beta-gal), resulting in the accumulation of ganglioside GM1 and its asialo derivative GgOse4Cer (GA1) in the central nervous system, primarily in the brain. In this study, we investigated the effects of N-butyldeoxygalacto-nojirimycin (N B-DGJ), an imino sugar that inhibits ganglioside biosynthesis, in normal C57BL/6J mice and in beta-gal knockout (beta-gal-/-) mice from postnatal day 9 (p-9) to p-15. This is a period of active cerebellar development and central nervous system (CNS) myelinogenesis in the mouse and would be comparable to late-stage embryonic and early neonatal development in humans. N B-DGJ significantly reduced total ganglioside and GM1 content in cerebrum-brainstem (C-BS) and in cerebellum of normal and beta-gal-/- mice. N B-DGJ had no adverse effects on body weight or C-BS/cerebellar weight, water content, or thickness of the external cerebellar granule cell layer. Sphingomyelin was increased in C-BS and cerebellum, but no changes were found for cerebroside (a myelin-enriched glycosphingolipid), neutral phospholipids, or GA1 in the treated mice. Our findings indicate that the effects of N B-DGJ in the postnatal CNS are largely specific to gangliosides and suggest that N B-DGJ may be an effective early intervention therapy for GM1 gangliosidosis and other ganglioside storage disorders. PMID:15687347

Kasperzyk, J L; d'Azzo, A; Platt, F M; Alroy, J; Seyfried, T N

2005-04-01

79

Hepatic storage of oligosaccharides and glycolipids in a cat affected with GM1 gangliosidosis.  

PubMed Central

1. Glycopeptides and glycolipids were isolated from normal cat liver and liver from a cat affected with GM1 gangliosidosis. 2. Bio-Gel P-6 chromatography of the crude glycopeptide fractions demonstrated three major peaks of hexose-containing compounds that were greatly increased in the mutant liver sample; these peaks contained oligosaccharides that comprised over 2% of the liver wet weight. 3. Two of the major pathological oligosaccharides, GP5 and GP6, were purified by chromatography on charcoal/Celite and Sephadex G-25. Oligosaccharides GP5 and GP6 had apparent mol.wts. of 1800 +/- 200 and 1350+/-200 respectively, and contained galactose, mannose and N-acetylglucosamine in molar proportions of 2.0:3.1:4.1 (GP5) and 1.0:2.2:2.7 (GP6). Periodate oxidation studies demonstrated the presence of galactose in a non-reducing terminal position. 4. The neutral glycolipid fraction from the mutant cat liver has a 1.3-fold increase in hexose content accompanied by an increased concentration of asialo-(ganglioside GM1). 5. There was a 2-fold increase of gangliosides in the mutant cat liver compared with normal cats. Ganglioside GM1 and a compound tentatively identified as N-glycolloyl-(ganglioside GM1) were the major glycolipids accumulated. Images Fig. 2. Fig. 5.

Holmes, E W; O'Brien, J S

1978-01-01

80

AAV-Mediated Gene Delivery in Adult GM1Gangliosidosis Mice Corrects Lysosomal Storage in CNS and Improves Survival  

Microsoft Academic Search

BackgroundGM1-gangliosidosis is a glycosphingolipid (GSL) lysosomal storage disease caused by a genetic deficiency of acid ?-galactosidase (?gal), which results in the accumulation of GM1-ganglioside and its asialo-form (GA1) primarily in the CNS. Age of onset ranges from infancy to adulthood, and excessive ganglioside accumulation produces progressive neurodegeneration and psychomotor retardation in humans. Currently, there are no effective therapies for the

Rena C. Baek; Marike L. D. Broekman; Stanley G. Leroy; Laryssa A. Tierney; Michael A. Sandberg; Alessandra D'Azzo; Thomas N. Seyfried; Miguel Sena-Esteves; Alfred Lewin

2010-01-01

81

An autopsy case of infantile GM1 gangliosidosis with adrenal calcification.  

PubMed

We describe an autopsy case of a 1-year-old male baby presenting with failure to gain milestones, floppiness, and reddish skin lesions since birth. Fundoscopic examination revealed bilateral cherry-red spots in the macula. The baby died of respiratory failure and autopsy revealed numerous ballooned neurons and astrocytes with cytoplasmic storage material seen throughout central white matter, basal ganglia, cerebellum, choroid plexus, and brain stem. There was neuronal degeneration with loss of myelin in central white matter with axonal degeneration as well. The storage material was weakly positive with PAS and oil red-O stains. Ultrastructurally, multilayered lamellated bodies were seen within the ballooned neurons. Biochemical analysis of lysosomal enzymes done in leucocytes revealed ?-galactosidase deficiency that is consistent with GM1 gangliosidosis. Extensive visceral deposition of similar material was also seen. Remarkably, both adrenals revealed extensive medullary calcification, which has not been reported in this lysosomal storage disorder, to the best of our knowledge. PMID:21800097

Nada, Ritambhra; Gupta, Kirti; Lal, Sadhna Bhasin; Vasishta, Rakesh Kumar

2011-12-01

82

Pathological features of salivary gland cysts in a Shiba dog with GM1 gangliosidosis: a possible misdiagnosis as malignancy.  

PubMed

Salivary gland cysts are often concurrent with GM1 gangliosidosis in Shiba dogs. Although the etiology is unknown, these cysts may be misdiagnosed as malignant due to the accumulation of foamy cells. The present study investigated the cytological, histopathological, immunohistochemical and electron microscopic characteristics of salivary gland cysts in a Shiba dog affected with GM1 gangliosidosis. The salivary gland masses were surgically enucleated and examined clinicopathologically and pathologically in a 7-month-old Shiba dog with GM1 gangliosidosis. Many large cells with rich cytoplasm including vacuoles of various sizes, i.e., foamy cells, were observed in stamp smears from the cut-surface of the masses and histopathologically in major parts of the cyst wall. Some of these foamy cells presented features similar to a spider-web appearance. The foamy cells were confirmed to have originated from macrophages based on marked immunohistochemical expression of vimentin, HLA-DR, lysozyme and Iba1. An ultrastructural study demonstrated electron-dense vesicular structures in the vacuolated cells. Therefore, the masses were diagnosed pathologically as benign salivary gland cysts with accumulation of foamy cells. In conclusion, the histopathological features of the salivary gland cysts in this Shiba dog were similar to those of lipoma and/or liposarcoma. In such cases, immunohistochemical and ultrastructural examinations were useful in the differential diagnosis. Practitioners, clinical pathologists and pathologists should take GM1 gangliosidosis into consideration when they encounter salivary gland cysts in Shiba dogs. PMID:22083095

Rahman, Mohammad Mahbubur; Kawaguchi, Hiroaki; Miyoshi, Noriaki; Yabuki, Akira; Nakamoto, Yuya; Ozawa, Tsuyoshi; Yamato, Osamu

2012-04-01

83

Serial MRI features of canine GM1 gangliosidosis: a possible imaging biomarker for diagnosis and progression of the disease.  

PubMed

GM1 gangliosidosis is a fatal neurodegenerative lysosomal storage disease caused by an autosomal recessively inherited deficiency of ?-galactosidase activity. Effective therapies need to be developed to treat the disease. In Shiba Inu dogs, one of the canine GM1 gangliosidosis models, neurological signs of the disease, including ataxia, start at approximately 5 months of age and progress until the terminal stage at 12 to 15 months of age. In the present study, serial MR images were taken of an affected dog from a model colony of GM1 gangliosidosis and 4 sporadic clinical cases demonstrating the same mutation in order to characterize the MRI features of this canine GM1 gangliosidosis. By 2 months of age at the latest and persisting until the terminal stage of the disease, the MR findings consistently displayed diffuse hyperintensity in the white matter of the entire cerebrum on T2-weighted images. In addition, brain atrophy manifested at 9 months of age and progressed thereafter. Although a definitive diagnosis depends on biochemical and genetic analyses, these MR characteristics could serve as a diagnostic marker in suspect animals with or without neurological signs. Furthermore, serial changes in MR images could be used as a biomarker to noninvasively monitor the efficacy of newly developed therapeutic strategies. PMID:22536126

Hasegawa, Daisuke; Yamato, Osamu; Nakamoto, Yuya; Ozawa, Tsuyoshi; Yabuki, Akira; Itamoto, Kazuhito; Kuwabara, Takayuki; Fujita, Michio; Takahashi, Kimimasa; Mizoguchi, Shunta; Orima, Hiromitsu

2012-01-01

84

The Arg482His mutation in the beta-galactosidase gene is responsible for a high frequency of GM1 gangliosidosis carriers in a Cypriot village.  

PubMed

GM1 gangliosidosis is a lysosomal storage disorder caused by deficiency of beta-galactosidase. It is mainly characterized by progressive neurodegeneration, and in its most severe infantile form, it leads to death before the age of 4. The GLB1 gene gives rise to two alternatively spliced mRNAs that encode the beta-galactosidase and the elastin binding protein (EBP). The diagnosis of two patients with the infantile form of GM1 gangliosidosis and 11 carriers in a small mountainous village in Cyprus prompted us to carry out a study in order to establish the frequency of carriers in the village and identify the mutations involved. Carrier detection was initially based on the measurement of beta-galactosidase activity in leucocytes. Among 85 random samples from the village, 10 were classified as carriers. Sequencing of the GLB1 gene in a Cypriot patient identified the missense mutation c.1445G>A (p.Arg482His) in the homozygous state. Seven of the 10 carriers identified using the enzyme assay were found to carry the same mutation by NspI restriction enzyme analysis. The three individuals who were negative for the c.1445G>A had borderline enzyme results and were probably wrongly classified as carriers. The frequency of GM1 gangliosidosis carriers in this village is approximately 8% (1:12). Western blot analysis showed a marked decrease of the 64-kDa mature form of the enzyme protein and a similar reduction of the 67-kDa EBP. Our results indicate that the c.1445G>A mutation, which appears to be responsible for all GM1 gangliosidosis alleles in this Cypriot village, affects protein conformation. PMID:15943552

Georgiou, Theodoros; Stylianidou, Goula; Anastasiadou, Violetta; Caciotti, Anna; Campos, Yvan; Zammarchi, Enrico; Morrone, Amelia; D'azzo, Alessandra; Drousiotou, Anthi

2005-01-01

85

Complete Correction of Enzymatic Deficiency and Neurochemistry in the GM1-gangliosidosis Mouse Brain by Neonatal Adeno-associated Virus–mediated Gene Delivery  

Microsoft Academic Search

GM1-gangliosidosis is a glycosphingolipid (GSL) lysosomal storage disease caused by autosomal recessive deficiency of lysosomal acid ?-galactosidase (?gal), and characterized by accumulation of GM1-ganglioside and GA1 in the brain. Here we examined the effect of neonatal intracerebroventricular (i.c.v.) injection of an adeno-associated virus (AAV) vector encoding mouse ?gal on enzyme activity and brain GSL content in GM1-gangliosidosis (?gal?\\/?) mice. Histological

M L D Broekman; R C Baek; L A Comer; J L Fernandez; T N Seyfried; M Sena-Esteves

2007-01-01

86

AAV-Mediated Gene Delivery in Adult GM1-Gangliosidosis Mice Corrects Lysosomal Storage in CNS and Improves Survival  

PubMed Central

Background GM1-gangliosidosis is a glycosphingolipid (GSL) lysosomal storage disease caused by a genetic deficiency of acid ?-galactosidase (?gal), which results in the accumulation of GM1-ganglioside and its asialo-form (GA1) primarily in the CNS. Age of onset ranges from infancy to adulthood, and excessive ganglioside accumulation produces progressive neurodegeneration and psychomotor retardation in humans. Currently, there are no effective therapies for the treatment of GM1-gangliosidosis. Methodology/Principal Findings In this study we examined the effect of thalamic infusion of AAV2/1-?gal vector in adult GM1 mice on enzyme distribution, activity, and GSL content in the CNS, motor behavior, and survival. Six to eight week-old GM1 mice received bilateral injections of AAV vector in the thalamus, or thalamus and deep cerebellar nuclei (DCN) with pre-determined endpoints at 1 and 4 months post-injection, and the humane endpoint, or 52 weeks of age. Enzyme activity was elevated throughout the CNS of AAV-treated GM1 mice and GSL storage nearly normalized in most structures analyzed, except in the spinal cord which showed ?50% reduction compared to age-matched untreated GM1 mice spinal cord. Survival was significantly longer in AAV-treated GM1 mice (52 wks) than in untreated mice. However the motor performance of AAV-treated GM1 mice declined over time at a rate similar to that observed in untreated GM1 mice. Conclusions/Significance Our studies show that the AAV-modified thalamus can be used as a ‘built-in’ central node network for widespread distribution of lysosomal enzymes in the mouse cerebrum. In addition, this study indicates that thalamic delivery of AAV vectors should be combined with additional targets to supply the cerebellum and spinal cord with therapeutic levels of enzyme necessary to achieve complete correction of the neurological phenotype in GM1 mice.

Baek, Rena C.; Broekman, Marike L. D.; Leroy, Stanley G.; Tierney, Laryssa A.; Sandberg, Michael A.; d'Azzo, Alessandra; Seyfried, Thomas N.; Sena-Esteves, Miguel

2010-01-01

87

GM1-gangliosidosis type 1 involving the cutaneous vascular endothelial cells in a black infant with multiple ectopic Mongolian spots.  

PubMed

GM1-gangliosidosis (GM1) is one of the metabolic storage diseases, of which a differential diagnosis requires an array of biochemical assays to determine the enzyme deficiency. This approach is not only time-consuming and costly but also unavailable to most hospital laboratories. However, a presumptive diagnosis of GM1 may be made on the basis of coarse facial feature, foamy endothelial cells in the cutaneous blood vessels and ectopic Mongolian spots, if present. A more definitive diagnosis of GM1 is then made on the demonstration of deficiency of GM1 beta-galactosidase in leukocytes, plasma or cultured skin fibroblasts. Thus, a battery of enzyme tests may be averted. PMID:7906450

Tang, T T; Esterly, N B; Lubinsky, M S; Oechler, H W; Harb, J M; Franciosi, R A

1993-12-01

88

Insertion of a T next to the donor splice site of intron 1 causes aberrantly spliced mRNA in a case of infantile GM1-gangliosidosis.  

PubMed

The lysosomal storage disorders GM1-gangliosidosis and Morquio B syndrome are caused by a complete or partial deficiency of acid beta-galactosidase. Here, we have characterized the mutation segregating in a family with two siblings affected by the severe infantile form of GM1-gangliosidosis. In total mRNA preparations derived from the patients' fibroblasts at least two aberrantly spliced beta-galactosidase transcripts (1 and 2) have been identified. Both transcripts contain a 20 nucleotide (nt) insertion derived from the 5' end of intron 1 of the beta-galactosidase gene. Furthermore, in transcript 2 sequences encoded by exon II are deleted during the splicing process. Comparison of the 20-nt insertion with wild-type intronic sequences indicated that in the genomic DNA of the patients an extra T nucleotide is present immediately downstream of the conserved GT splice donor dinucleotide of intron 1. Both patients are homozygous for the T nucleotide insertion. We propose that this single base insertion is the mutation responsible for aberrant splicing of beta-galactosidase pre-mRNA, giving rise to transcripts that cannot encode a normal protein. PMID:8199591

Morrone, A; Morreau, H; Zhou, X Y; Zammarchi, E; Kleijer, W J; Galjaard, H; d'Azzo, A

1994-01-01

89

Identification of Bangladeshi domestic cats with GM1 gangliosidosis caused by the c.1448G>C mutation of the feline GLB1 gene: case study.  

PubMed

GM1 gangliosidosis is a fatal, progressive neurodegenerative lysosomal storage disease caused by mutations in the ?-galactosidase (GLB1) gene. In feline GM1 gangliosidosis, a pathogenic mutation (c.1448G>C) in the feline GLB1 gene was identified in Siamese cats in the United States and Japan and in Korat cats in Western countries. The present study found the homozygous c.1448G>C mutation in 2 apparent littermate native kittens in Bangladesh that were exhibiting neurological signs. This is the first identification of GM1 gangliosidosis in native domestic cats in Southeast Asia. This pathogenic mutation seems to have been present in the domestic cat population in the Siamese region and may have been transferred to pure breeds such as Siamese and Korat cats originating in this region. PMID:23123943

Uddin, Mohammad Mejbah; Hossain, Mohammad Alamgir; Rahman, Mohammad Mahbubur; Chowdhury, Morshedul Alam; Tanimoto, Takeshi; Yabuki, Akira; Mizukami, Keijiro; Chang, Hye-Sook; Yamato, Osamu

2013-01-01

90

Evaluation of N-nonyl-deoxygalactonojirimycin as a pharmacological chaperone for human GM1 gangliosidosis leads to identification of a feline model suitable for testing enzyme enhancement therapy.  

PubMed

Deficiencies of lysosomal ?-D-galactosidase can result in GM1 gangliosidosis, a severe neurodegenerative disease characterized by massive neuronal storage of GM1 ganglioside in the brain. Currently there are no available therapies that can even slow the progression of this disease. Enzyme enhancement therapy utilizes small molecules that can often cross the blood brain barrier, but are also often competitive inhibitors of their target enzyme. It is a promising new approach for treating diseases, often caused by missense mutations, associated with dramatically reduced levels of functionally folded enzyme. Despite a number of positive reports based on assays performed with patient cells, skepticism persists that an inhibitor-based treatment can increase mutant enzyme activity in vivo. To date no appropriate animal model, i.e., one that recapitulates a responsive human genotype and clinical phenotype, has been reported that could be used to validate enzyme enhancement therapy. In this report, we identify a novel enzyme enhancement-agent, N-nonyl-deoxygalactonojirimycin, that enhances the mutant ?-galactosidase activity in the lysosomes of a number of patient cell lines containing a variety of missense mutations. We then demonstrate that treatment of cells from a previously described, naturally occurring feline model (that biochemically, clinically and molecularly closely mimics GM1 gangliosidosis in humans) with this molecule, results in a robust enhancement of their mutant lysosomal ?-galactosidase activity. These data indicate that the feline model could be used to validate this therapeutic approach and determine the relationship between the disease stage at which this therapy is initiated and the maximum clinical benefits obtainable. PMID:22784478

Rigat, Brigitte A; Tropak, Michael B; Buttner, Justin; Crushell, Ellen; Benedict, Daphne; Callahan, John W; Martin, Douglas R; Mahuran, Don J

2012-09-01

91

Evaluation of N-nonyl-deoxygalactonojirimycin as a pharmacological chaperone for human GM1 gangliosidosis leads to identification of a feline model suitable for testing enzyme enhancement therapy  

PubMed Central

Deficiencies of lysosomal ?-D-galactosidase can result in GM1 gangliosidosis, a severe neurodegenerative disease characterized by massive neuronal storage of GM1 ganglioside in the brain. Currently there are no available therapies that can even slow the progression of this disease. Enzyme enhancement therapy utilizes small molecules that can often cross the blood brain barrier, but are also often competitive inhibitors of their target enzyme. It is a promising new approach for treating diseases, often caused by missense mutations, associated with dramatically reduced levels of functionally folded enzyme. Despite a number of positive reports based on assays performed with patient cells, skepticism persists that an inhibitor-based treatment can increase mutant enzyme activity in vivo. To date no appropriate animal model, i.e., one that recapitulates a responsive human genotype and clinical phenotype, has been reported that could be used to validate enzyme enhancement therapy. In this report, we identify a novel enzyme enhancement-agent, N-nonyl-deoxygalactonojirimycin, that enhances the mutant ?-galactosidase activity in the lysosomes of a number of patient cell lines containing a variety of missense mutations. We then demonstrate that treatment of cells from a previously described, naturally occurring feline model (that biochemically, clinically and molecularly closely mimics GM1 gangliosidosis in humans) with this molecule, results in a robust enhancement of their mutant lysosomal ?-galactosidase activity. These data indicate that the feline model could be used to validate this therapeutic approach and determine the relationship between the disease stage at which this therapy is initiated and the maximum clinical benefits obtainable.

Rigat, Brigitte A.; Tropak, Michael B.; Buttner, Justin; Crushell, Ellen; Benedict, Daphne; Callahan, John W.; Martin, Douglas R.; Mahuran, Don J.

2012-01-01

92

Molecular basis of GM1 gangliosidosis and Morquio disease, type B. Structure–function studies of lysosomal ?-galactosidase and the non-lysosomal ?-galactosidase-like protein  

Microsoft Academic Search

GM1 gangliosidosis and Morquio B disease are distinct disorders both clinically and biochemically yet they arise from the same ?-galactosidase enzyme deficiency. On the other hand, galactosialidosis and sialidosis share common clinical and biochemical features, yet they arise from two separate enzyme deficiencies, namely, protective protein\\/cathepsin A and neuraminidase, respectively. However distinct, in practice these disorders overlap both clinically and

John W Callahan

1999-01-01

93

Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis.  

PubMed

Mouse models of the GM2 gangliosidoses [Tay-Sachs, late onset Tay-Sachs (LOTS), Sandhoff] and GM1 gangliosidosis have been studied to determine whether there is a common neuro-inflammatory component to these disorders. During the disease course, we have: (i) examined the expression of a number of inflammatory markers in the CNS, including MHC class II, CD68, CD11b (CR3), 7/4, F4/80, nitrotyrosine, CD4 and CD8; (ii) profiled cytokine production [tumour necrosis factor alpha (TNF alpha), transforming growth factor (TGF beta 1) and interleukin 1 beta (IL1 beta)]; and (iii) studied blood-brain barrier (BBB) integrity. The kinetics of apoptosis and the expression of Fas and TNF-R1 were also assessed. In all symptomatic mouse models, a progressive increase in local microglial activation/expansion and infiltration of inflammatory cells was noted. Altered BBB permeability was evident in Sandhoff and GM1 mice, but absent in LOTS mice. Progressive CNS inflammation coincided with the onset of clinical signs in these mouse models. Substrate reduction therapy in the Sandhoff mouse model slowed the rate of accumulation of glycosphingolipids in the CNS, thus delaying the onset of the inflammatory process and disease pathogenesis. These data suggest that inflammation may play an important role in the pathogenesis of the gangliosidoses. PMID:12615653

Jeyakumar, M; Thomas, R; Elliot-Smith, E; Smith, D A; van der Spoel, A C; d'Azzo, A; Perry, V Hugh; Butters, T D; Dwek, R A; Platt, F M

2003-04-01

94

Complete correction of enzymatic deficiency and neurochemistry in the GM1-gangliosidosis mouse brain by neonatal adeno-associated virus-mediated gene delivery.  

PubMed

GM1-gangliosidosis is a glycosphingolipid (GSL) lysosomal storage disease caused by autosomal recessive deficiency of lysosomal acid beta-galactosidase (betagal), and characterized by accumulation of GM1-ganglioside and GA1 in the brain. Here we examined the effect of neonatal intracerebroventricular (i.c.v.) injection of an adeno-associated virus (AAV) vector encoding mouse betagal on enzyme activity and brain GSL content in GM1-gangliosidosis (betagal(-/-)) mice. Histological analysis of betagal distribution in 3-month-old AAV-treated betagal(-/-) mice showed that enzyme was present at high levels throughout the brain. Biochemical quantification showed that betagal activity in AAV-treated brains was 7- to 65-fold higher than in wild-type controls and that brain GSL levels were normalized. Cerebrosides and sulfatides, which were reduced in untreated betagal(-/-) mice, were restored to normal levels by AAV treatment. In untreated betagal(-/-) brains, cholesterol was present at normal levels but showed abnormal cellular distribution consistent with endosomal/lysosomal localization. This feature was also corrected in AAV-treated mice. The biochemical and histological parameters analyzed in this study showed that normal brain neurochemistry was achieved in AAV-treated betagal(-/-) mice. Therefore we show for the first time that neonatal AAV-mediated gene delivery of lysosomal betagal to the brain may be an effective approach for treatment of GM1-gangliosidosis. PMID:17164772

Broekman, M L D; Baek, R C; Comer, L A; Fernandez, J L; Seyfried, T N; Sena-Esteves, M

2007-01-01

95

961. AAV1-Mediated Gene Delivery to the Adult GM1Gangliosidosis Mouse Hippocampus Leads to Marked Reduction in Storage in Physically and Synaptically-Connected Areas of the Brain  

Microsoft Academic Search

GM1-gangliosidosis is a lysosomal storage disease caused by an autosomal recessive deficiency of lysosomal acid beta-galactosidase (b-gal) leading to accumulation of GM1-ganglioside in the central nervous system, and often accompanied by severe mental retardation. Knock-out mouse models (GM1 KO) of this disease mimic the biochemical findings in humans, with absence of b-gal activity and extensive GM1-ganglioside storage throughout the brain.

Miguel Sena-Esteves; Marike Broekman; Fabricio F. Costa; Stanley G. LeRoy; Laryssa A. Comer

2005-01-01

96

Characterization of beta-galactosidase mutations Asp332-->Asn and Arg148-->Ser, and a polymorphism, Ser532-->Gly, in a case of GM1 gangliosidosis.  

PubMed

We have identified and characterized three missense mutations in a patient with type 1 G(M1) gangliosidosis, namely a substitution of G for A at nucleotide position 1044 (G1044-->A; in exon 10) on one allele, which converts Asp(332) into asparagine, and both a mutation (C492-->A in exon 4, leading to the amino acid change of Arg(148)-->Ser) and a polymorphism (A1644-->G in exon 15, leading to a change of Ser(532)-->Gly) on the other allele. This patient had less than 1% residual beta-galactosidase activity and minimally detectable levels of immunoreactive beta-galactosidase protein in fibroblasts. To account for the above findings, a series of expression and immunolocalization studies were undertaken to assess the impact of each mutation. Transient overexpression in COS-1 cells of cDNAs encoding Asp(332)Asn, Arg(148)Ser and Ser(532)Gly mutant beta-galactosidases produced abundant amounts of precursor beta-galactosidase, with activities of 0, 84 and 81% compared with the cDNA clone for wild-type beta-galactosidase (GP8). Since the level of vector-driven expression is much less in Chinese hamster ovary (CHO) cells than in COS-1 cells, and we knew that exogenous beta-galactosidase undergoes lysosomal processing when expressed in these cells, transient expression studies were performed of Arg(148)Ser and Ser(532)Gly, which yielded active forms of the enzyme. In this case, the Arg(148)Ser and Ser(532)Gly products gave rise to 11% and 86% of the control activity respectively. These results were not unexpected, since the Arg(148)Ser mutation introduced a major conformational change into the protein, and we anticipated that it would be degraded in the endoplasmic reticulum (ER), whereas the polymorphism was expected to produce near-normal activity. To examine the effect of the Asp(332)Asn mutation on the catalytic activity, we isolated CHO clones permanently transfected with the Asp(332)Asn and Asp(332)Glu constructs, purified the enzymes by substrate-analogue-affinity chromatography, and determined their kinetic parameters. The V(max) values of both mutant recombinant enzymes were markedly reduced (less than 0.9% of the control), and the K(m) values were unchanged compared with the corresponding wild-type enzyme isolated at the same time. Both the Arg(148)Ser beta-galactosidase in CHO cells and Asp(332)Asn beta-galactosidases (in COS-1 and CHO cells) produced abundant immunoreaction in the perinuclear area, consistent with localization in the ER. A low amount was detected in lysosomes. Incubation of patient fibroblasts in the presence of leupeptin, which reduces the rate of degradation of lysosomal beta-galactosidase by thiol proteases, had no effect on residual enzyme activity, and immunostaining was again detected largely in the perinuclear area (localized to the ER) with much lower amounts in the lysosomes. In summary, the Arg(148)Ser mutation has no effect on catalytic activity, whereas the Asp(332)Asn mutation seriously reduces catalytic activity, suggesting that Asp(332) might play a role in the active site. Immunofluorescence studies indicate the expressed mutant proteins with Arg(148)Ser and Asp(332)Asn mutations are held up in the ER, where they are probably degraded, resulting in only minimum amounts of the enzyme becoming localized in the lysosomes. These results are completely consistent with findings in the cultured fibroblasts. Our results imply that most of the missense mutations described in G(M1) gangliosidosis to date have little effect on catalytic activity, but do affect protein conformation such that the resulting protein cannot be transported out of the ER and fails to arrive in the lysosome. This accounts for the minimal amounts of enzyme protein and activity seen in most G(M1) gangliosidosis patient fibroblasts. PMID:10839995

Zhang, S; Bagshaw, R; Hilson, W; Oho, Y; Hinek, A; Clarke, J T; Callahan, J W

2000-06-15

97

A duplication in the canine beta-galactosidase gene GLB1 causes exon skipping and GM1-gangliosidosis in Alaskan huskies.  

PubMed

GM(1)-gangliosidosis is a lysosomal storage disease that is inherited as an autosomal recessive disorder, predominantly caused by structural defects in the beta-galactosidase gene (GLB1). The molecular cause of GM(1)-gangliosidosis in Alaskan huskies was investigated and a novel 19-bp duplication in exon 15 of the GLB1 gene was identified. The duplication comprised positions +1688-+1706 of the GLB1 cDNA. It partially disrupted a potential exon splicing enhancer (ESE), leading to exon skipping in a fraction of the transcripts. Thus, the mutation caused the expression of two different mRNAs from the mutant allele. One transcript contained the complete exon 15 with the 19-bp duplication, while the other transcript lacked exon 15. In the transcript containing exon 15 with the 19-bp duplication a premature termination codon (PTC) appeared, but due to its localization in the last exon of canine GLB1, nonsense-mediated RNA decay (NMD) did not occur. As a consequence of these molecular events two different truncated GLB1 proteins are predicted to be expressed from the mutant GLB1 allele. In heterozygous carrier animals the wild-type allele produces sufficient amounts of the active enzyme to prevent clinical signs of disease. In affected homozygous dogs no functional GLB1 is synthesized and G(M1)-gangliosidosis occurs. PMID:15944348

Kreutzer, Robert; Leeb, Tosso; Müller, Gundi; Moritz, Andreas; Baumgärtner, Wolfgang

2005-08-01

98

409. Complete Correction of Enzymatic Deficiency and Lysosomal Storage throughout the Brain in a Mouse Model of GM1-gangliosidosis after Neonatal Intracerebroventricular Injection of an AAV1 Vector Encoding Lysosomal Acid Beta galactosidase  

Microsoft Academic Search

GM1 gangliosidosis is a glycosphingolipid (GSL) lysosomal storage disease caused by autosomal recessive deficiency of lysosomal acid ?-galactosidase (?gal). This disease is characterized by accumulation of GM1-ganglioside and its asialo-form (GA1) in the CNS. In this study we examined the effect of neonatal intracerebroventricular injection of an adeno-associated virus (AAV) vector (serotype 1) encoding mouse ?gal under control of a

Marike L. D. Broekman; Rena Baek; Laryssa A. Comer; Thomas N. Seyfried; Miguel Sena-Esteves

2006-01-01

99

1-Deoxy-d-galactonojirimycins with dansyl capped N-substituents as ?-galactosidase inhibitors and potential probes for GM1 gangliosidosis affected cell lines  

PubMed Central

Two simple and reliably accessible intermediates, N-carboxypentyl- and N-aminohexyl-1-deoxy-d-galactonojirimycin were employed for the synthesis of a set of terminally N-dansyl substituted derivatives. Reaction of the terminal carboxylic acid of N-carboxypentyl-1-deoxy-d-galactonojirimycin with N-dansyl-1,6-diaminohexane provided the chain-extended fluorescent derivative. Employing bis(6-dansylaminohexyl)amine, the corresponding branched di-N-dansyl compound was obtained. Partially protected N-aminohexyl-1-deoxy-d-galactonojirimycin served as intermediate for two additional chain-extended fluorescent 1-deoxy-d-galactonojirimycin (1-DGJ) derivatives featuring terminal dansyl groups in the N-alkyl substituent. These new compounds are strong inhibitors of d-galactosidases and may serve as leads en route to pharmacological chaperones for GM1-gangliosidosis.

Frohlich, Richard F.G.; Furneaux, Richard H.; Mahuran, Don J.; Saf, Robert; Stutz, Arnold E.; Tropak, Michael B.; Wicki, Jacqueline; Withers, Stephen G.; Wrodnigg, Tanja M.

2011-01-01

100

Type 3 GM I gangliosidosis: clinical and neuroradiological findings in an 11-year-old girl  

Microsoft Academic Search

An 11-year-old Japanese girl was diagnosed as having type 3 GM1 gangliosidosis by clinical symptoms and enzyme assay. She was the youngest among the patients with type 3 GM 1 gangliosidosis whose clinical and neuroradiological findings have been documented. Clumsiness since early infancy and dystonia since early childhood which progressed slowly without mental deterioration and dysmorphism led us to the

Rieko Tanaka; Toru Momoi; Akira Yoshida; Mitsuyoshi Okumura; Shinji Yamakura; Yoshinori Takasaki; Takahiro Kiyomasu; Chutaro Yamanaka

1995-01-01

101

Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis  

Microsoft Academic Search

Summary Mouse models of the GM2 gangliosidoses (Tay-Sachs, late onset Tay-Sachs (LOTS), Sandhoff) and GM1 gang- liosidosis have been studied to determine whether there is a common neuro-inflammatory component to these disorders. During the disease course, we have: (i) exam- ined the expression of a number of inflammatory mark- ers in the CNS, including MHC class II, CD68, CD11b (CR3),

M. Jeyakumar; R. Thomas; E. Elliot-Smith; D. A. Smith; A. C. van der Spoel; A. d'Azzo; V. Hugh Perry; T. D. Butters; R. A. Dwek; F. M. Platt

2003-01-01

102

Anti-GM1 antibodies in patients with Guillain-Barré syndrome  

Microsoft Academic Search

Anti-GM1 antibodies were measured in 22 patients with the Guillain-Barré syndrome (GBS) and compared with anti-GM1 antibody activity in patients with other neurological or immunological diseases and in normal subjects. Four out of 22 patients with GBS had raised IgM, IgG, or IgA anti-GM1 antibody activities. All four patients were tetraparetic with only minimal or no sensory deficit. Three of

L H van den Berg; J Marrink; A E de Jager; H J de Jong; G W van Imhoff; N Latov; S A Sadiq

1992-01-01

103

Correction of acid beta-galactosidase deficiency in GM1 gangliosidosis human fibroblasts by retrovirus vector-mediated gene transfer: higher efficiency of release and cross-correction by the murine enzyme.  

PubMed

Mutations in the lysosomal acid beta-galactosidase (EC 3.2.1.23) underlie two different disorders: GM1 gangliosidosis, which involves the nervous system and visceral organs to varying extents, and Morquio's syndrome type B (Morquio B disease), which is a skeletal-connective tissue disease without any CNS symptoms. This article shows that transduction of human GM1 gangliosidosis fibroblasts with retrovirus vectors encoding the human acid beta-galactosidase cDNA leads to complete correction of the enzymatic deficiency. The newly synthesized enzyme is correctly processed and targeted to the lysosomes in transduced cells. Cross-correction experiments using retrovirus-modified cells as enzyme donors showed, however, that the human enzyme is transferred at low efficiencies. Experiments using a different retrovirus vector carrying the human cDNA confirmed this observation. Transduction of human GM1 fibroblasts and mouse NIH 3T3 cells with a retrovirus vector encoding the mouse beta-galactosidase cDNA resulted in high levels of enzymatic activity. Furthermore, the mouse enzyme was found to be transferred to human cells at high efficiency. Enzyme activity measurements in medium conditioned by genetically modified cells suggest that the human beta-galactosidase enzyme is less efficiently released to the extracellular space than its mouse counterpart. This study suggests that lysosomal enzymes, contrary to the generalized perception in the field of gene therapy, may differ significantly in their properties and provides insights for design of future gene therapy interventions in acid beta-galactosidase deficiency. PMID:10757351

Sena-Esteves, M; Camp, S M; Alroy, J; Breakefield, X O; Kaye, E M

2000-03-20

104

Chemokine-induced recruitment of genetically modified bone marrow cells into the CNS of GM1-gangliosidosis mice corrects neuronal pathology  

Microsoft Academic Search

Bone marrow cells (BMCs) could correct some pathologic conditions of the central nervous system (CNS) if these cells would effectively repopulate the brain. One such condition is GM1-gangliosido- sis, a neurodegenerative glycosphingo- lipidosis due to deficiency of lysosomal -galactosidase (-gal). In this disease, abnormal build up of GM1-ganglioside in the endoplasmic reticulum of brain cells results in calcium imbalance, induction

Renata Sano; Alessandra Tessitore; Angela Ingrassia; Alessandra d'Azzo

2005-01-01

105

G M1 -gangliosidosis: Accumulation of ganglioside G M1 in cultured skin fibroblasts and correlation with clinical types  

Microsoft Academic Search

Uptake of radioactivity from 14C-galactose into gangliosides by cultured skin fibroblasts was studied. GM3 was the major ganglioside in control human fibroblasts. An increase of GM1 was demonstrated in GM1-gangliosidosis fibroblasts. The degree of GM1 accumulation was correlated with the clinical types of this disease. The fibroblasts from an infantile-type patient showed a marked increase of GM1. In late-onset types

Yoshiyuki Suzuki; Norimasa Nakamura; Kazuko Fukuoka

1978-01-01

106

A fluorescent probe for GM1 gangliosidosis related ?-galactosidase: N-(dansylamino)hexylaminocarbonylpentyl-1,5-dideoxy-1,5-imino-D-galactitol.  

PubMed

N-(Dansylamino)hexylaminocarbonylpentyl-1,5-dideoxy-1,5-imino-D-galactitol, a strong competitive inhibitor of ?-galactosidase, enhances residual ?-galactosidase activities in fibroblasts and serves as lead en route to diagnostic compounds for tracking the fate of mutant ?-gal as well as aberrant GM1 gangliosides by live cell imaging. PMID:21974950

Fröhlich, Richard F G; Fantur, Katrin; Furneaux, Richard H; Paschke, Eduard; Stütz, Arnold E; Wicki, Jacqueline; Withers, Stephen G; Wrodnigg, Tanja M

2011-11-15

107

Imbalanced substrate specificity of mutant ?-galactosidase in patients with Morquio B disease  

Microsoft Academic Search

GM1-gangliosidosis and Morquio B disease are distinct in clinical and biochemical features, but both disorders are caused by genetic defects of the same enzyme, acid ?-galactosidase (?-Gal). We analyzed the kinetic properties of mutant ?-Gals from patients with GM1-gangliosidosis and Morquio B disease to examine the clinical and biochemical differences between both disorders. Five skin fibroblast lines from patients with

Toshika Okumiya; Hitoshi Sakuraba; Ryoichi Kase; Tetsuro Sugiura

2003-01-01

108

Generalized Gangliosidosis: Beta-Galactosidase Deficiency  

Microsoft Academic Search

A profound deficiency (10- to 30-fold) of beta -galactosidase activity was found in tissues (liver, spleen, kidney, and brain) from two patients with generalized gangliosidosis; this deficiency is demonstrated as a failure to cleave both p-nitrophenyl-beta -D-galactopyranoside and ganglioside GM1 labeled with C14 in the terminal galactose. We believe that this enzymic defect is responsible for the accumulation of ganglioside

Shintaro Okada; John S. O'Brien

1968-01-01

109

pH-dependent formation of membranous cytoplasmic body-like structure of ganglioside G(M1)/bis(monoacylglycero)phosphate mixed membranes.  

PubMed

Membrane structures of the mixtures of ganglioside G(M1) and endosome specific lipid, bis (monoacylglycero) phosphate (BMP, also known as lysobisphosphatidic acid) were examined at various pH conditions by freeze-fracture electron microscopy and small-angle x-ray scattering. At pH 8.5-6.5, a G(M1)/BMP (1:1 mol/mol) mixture formed small vesicular aggregates, whereas the mixture formed closely packed lamellar structures under acidic conditions (pH 5.5, 4.6) with the lamellar repeat distance of 8.06 nm. Since BMP alone exhibits a diffuse lamellar structure at a broad range of pH values and G(M1) forms a micelle, the results indicate that both G(M1) and BMP are required to produce closely stacked multilamellar vesicles. These vesicles resemble membranous cytoplasmic bodies in cells derived from patients suffering from G(M1) gangliosidosis. Similar to G(M1) gangliosidosis, cholesterol was trapped in BMP vesicles in G(M1)- and in a low pH-dependent manner. Studies employing different gangliosides and a G(M1) analog suggest the importance of sugar chains and a sialic acid of G(M1) in the pH-dependent structural change of G(M1)/BMP membranes. PMID:17056735

Hayakawa, Tomohiro; Makino, Asami; Murate, Motohide; Sugimoto, Ichiro; Hashimoto, Yasuhiro; Takahashi, Hiroshi; Ito, Kazuki; Fujisawa, Tetsuro; Matsuo, Hirotami; Kobayashi, Toshihide

2007-01-01

110

pH-dependent Formation of Membranous Cytoplasmic Body-Like Structure of Ganglioside GM1/Bis(Monoacylglycero)Phosphate Mixed Membranes  

PubMed Central

Membrane structures of the mixtures of ganglioside GM1 and endosome specific lipid, bis (monoacylglycero) phosphate (BMP, also known as lysobisphosphatidic acid) were examined at various pH conditions by freeze-fracture electron microscopy and small-angle x-ray scattering. At pH 8.5–6.5, a GM1/BMP (1:1 mol/mol) mixture formed small vesicular aggregates, whereas the mixture formed closely packed lamellar structures under acidic conditions (pH 5.5, 4.6) with the lamellar repeat distance of 8.06 nm. Since BMP alone exhibits a diffuse lamellar structure at a broad range of pH values and GM1 forms a micelle, the results indicate that both GM1 and BMP are required to produce closely stacked multilamellar vesicles. These vesicles resemble membranous cytoplasmic bodies in cells derived from patients suffering from GM1 gangliosidosis. Similar to GM1 gangliosidosis, cholesterol was trapped in BMP vesicles in GM1- and in a low pH-dependent manner. Studies employing different gangliosides and a GM1 analog suggest the importance of sugar chains and a sialic acid of GM1 in the pH-dependent structural change of GM1/BMP membranes.

Hayakawa, Tomohiro; Makino, Asami; Murate, Motohide; Sugimoto, Ichiro; Hashimoto, Yasuhiro; Takahashi, Hiroshi; Ito, Kazuki; Fujisawa, Tetsuro; Matsuo, Hirotami; Kobayashi, Toshihide

2007-01-01

111

GM1 gangliosidosis in shiba dogs  

Microsoft Academic Search

A six-month-old shiba dog with a one-month history of progressive motor dysfunction showed clinical signs of a cerebellar disorder, including ataxia, dysmetria and intention tremor of the head. Histopathological and ultrastructural studies revealed distended neurons packed with membranous cytoplasmic bodies throughout the central nervous system. The activities of lysosomal acid ?-galactosidase in its leucocytes and liver were less than 2

O. Yamato; Y. Masuoka; M. Tajima; S. Omae; Y. Maede; K. Ochiai; E. Hayashida; T. Umemura; M. lijima

2000-01-01

112

Reactivity of serum IgG anti-GM1 ganglioside antibodies with the lipopolysaccharide fractions of Campylobacter jejuni isolates from patients with Guillain–Barré syndrome (GBS)  

Microsoft Academic Search

Campylobacter jejuni (Cj) enteritis is the most frequently recognised infection preceding Guillain–Barré syndrome (GBS) and this combination is commonly associated with anti-GM1 ganglioside (anti-GM1) antibodies. We have examined the hypothesis that the anti-GM1 antibodies represent an immune response against the Cj lipopolysaccharide (LPS). We prepared the LPS fraction from 8 isolates of Cj, 3 from GBS patients with acute inflammatory

N. A Gregson; J. H Rees; R. A. C Hughes

1997-01-01

113

Increased Expression of Ganglioside GM1 in Peripheral CD4+ T Cells Correlates Soluble Form of CD30 in Systemic Lupus Erythematosus Patients  

PubMed Central

Gangliosides GM1 is a good marker of membrane microdomains (lipid rafts) with important function in cellular activation processes. In this study we found that GM1 expression on CD4+ T cells and memory T cells (CD45RO/CD4) were dramatic increased after stimulation with phytohaemagglutinin in vitro. Next, we examined the GM1 expression on peripheral blood CD4+ T cells and CD8+ T cells from 44 patients with SLE and 28 healthy controls by flow cytometry. GM1 expression was further analyzed with serum soluble CD30 (sCD30), IL-10, TNF-alpha and clinical parameters. The mean fluorescence intensity of GM1 on CD4+ T cells from patients with SLE was significantly higher than those from healthy controls, but not on CD8+ T cells. Increased expression of GM1 was more marked on CD4+/CD45RO+ memory T cells from active SLE patients. Patients with SLE showed significantly elevated serum sCD30 and IL-10, but not TNF-alpha levels. In addition, we found that enhanced GM1 expression on CD4+ T cells from patients with SLE positively correlated with high serum levels of sCD30 and IgG as well as disease activity (SLEDAI scores). Our data suggested the potential role of aberrant lipid raft/GM1 on CD4+ T cells and sCD30 in the pathogenesis of SLE.

Dong, Lingli; Hu, Shaoxian; Chen, Fang; Lei, Xiaomei; Tu, Wei; Yu, Yikai; Yang, Liu; Sun, Wei; Yamaguchi, Takuro; Masaki, Yasufumi; Umehara, Hisanori

2010-01-01

114

Increased expression of ganglioside GM1 in peripheral CD4+ T cells correlates soluble form of CD30 in Systemic Lupus Erythematosus patients.  

PubMed

Gangliosides GM1 is a good marker of membrane microdomains (lipid rafts) with important function in cellular activation processes. In this study we found that GM1 expression on CD4+ T cells and memory T cells (CD45RO/CD4) were dramatic increased after stimulation with phytohaemagglutinin in vitro. Next, we examined the GM1 expression on peripheral blood CD4+ T cells and CD8+ T cells from 44 patients with SLE and 28 healthy controls by flow cytometry. GM1 expression was further analyzed with serum soluble CD30 (sCD30), IL-10, TNF-alpha and clinical parameters. The mean fluorescence intensity of GM1 on CD4+ T cells from patients with SLE was significantly higher than those from healthy controls, but not on CD8+ T cells. Increased expression of GM1 was more marked on CD4+/CD45RO+ memory T cells from active SLE patients. Patients with SLE showed significantly elevated serum sCD30 and IL-10, but not TNF-alpha levels. In addition, we found that enhanced GM1 expression on CD4+ T cells from patients with SLE positively correlated with high serum levels of sCD30 and IgG as well as disease activity (SLEDAI scores). Our data suggested the potential role of aberrant lipid raft/GM1 on CD4+ T cells and sCD30 in the pathogenesis of SLE. PMID:20625494

Dong, Lingli; Hu, Shaoxian; Chen, Fang; Lei, Xiaomei; Tu, Wei; Yu, Yikai; Yang, Liu; Sun, Wei; Yamaguchi, Takuro; Masaki, Yasufumi; Umehara, Hisanori

2010-01-01

115

Impaired sulphated glycosaminoglycan metabolism in a patient with GM2 gangliosidosis (Tay-Sachs disease)  

Microsoft Academic Search

Summary An abnormal urinary excretion of sulphated glycosaminoglycans in a patient with GM-2 gangliosidosis (Tay-Sachs disease) is described. Besides the accumulation of GM-2 ganglioside in liver and lack of hexosaminidase A, the patient shows an abnormal urinary excretion of an iduronic acid-rich low molecular weight heparan sulphate. Also, no dermatan sulphate could be detected in the urine, whereas this compound

L. Toma; W. Pinto; V. C. Rodrigues; C. P. Dietrich; H. B. Nader

1990-01-01

116

Pharmacokinetics, safety and tolerability of miglustat in the treatment of pediatric patients with GM2 gangliosidosis  

Microsoft Academic Search

GM2 gangliosidosis (GM2g) is an inherited neurodegenerative disorder caused by deficiency of lysosomal ?-hexosaminidase A, resulting in accumulation of GM2 ganglioside, principally in the brain. Substrate reduction therapy is currently under investigation as a treatment. The study investigated the pharmacokinetics and safety of miglustat given as single and multiple doses in infantile and juvenile GM2g patients for 6- and 24-months,

Gustavo H. B. Maegawa; Paul L. M. van Giersbergen; Sandra Yang; Brenda Banwell; Christopher P. Morgan; Jasper Dingemanse; Cynthia J. Tifft; Joe T. R. Clarke

2009-01-01

117

Mutations in acid [beta]-galactosidase cause GM[sub 1]-gangliosidosis in American patients  

SciTech Connect

The authors describe four new mutations in the [beta]-galactosidase gene. These are the first mutations causing infantile and juvenile GM[sub 1]-gangliosidosis to be described in American patients. Cell lines from two patients with juvenile and from six patients with infantile GM[sub 1]-gangliosidosis were analyzed. Northern blot analysis showed the acid [beta]-galactosidase message to be of normal size and quantity in two juvenile and four infantile cases and of normal size but reduced quantity in two infantile cases. The mutations are distinct from the Japanese mutations. All are point mutations leading to amino acid substitutions: Lys[sup 577] [yields] Arg, Arg[sup 590] [yields] His, and Glu[sup 632] [yields] Gly. The fourth mutation, Arg[sup 208] [yields] Cys, accounts for 10 of 16 possible alleles. Two infantile cases from Puerto Rico of Spanish ancestry are homozygous for this mutation, suggesting that this allele may have come to South America and North America via Puerto Rico. That these mutations cause clinical disease was confirmed by marked reduction in catalytic activity of the mutant proteins in the Cos-1 cell expression system. 12 refs., 5 figs., 2 tabs.

Boustany, R.M.; Qian, W.H. (Duke Univ., Durham, NC (United States)); Suzuki, K. (Univ. of North Carolina, Chapel Hill, NC (United States))

1993-10-01

118

Infantile G M1 Gangliosidosis: Complete Morphology and Histochemistry of Two Autopsy Cases, with Particular Reference to Delayed Central Nervous System Myelination  

Microsoft Academic Search

Inborn metabolic errors causing lysosomal storage, such as #-galactosidase deficiency (GM1 gangliosidosis [GM1]), have well-recognized effects on cellular function and morphology. In some classically \\

Rebecca D. Folkerth; Joseph Alroy; Ina Bhan; Edward M. Kaye

2000-01-01

119

Intracerebral cell transplantation therapy for murine GM1 gangliosidosis  

Microsoft Academic Search

We performed a cell transplantation study to treat the brain involvement in lysosomal storage diseases. We used acid ?-galactosidase knock-out mice (BKO) from C57BL\\/6 as recipients. To minimize immune responses, we used cells derived from transgenic mice of C57BL\\/6 overexpressing the normal human ?-galactosidase. Fetal brain cells (FBC), bone marrow-derived mesenchymal stem cells (MSC), and mixed FBC and MSC cells

Tomo Sawada; Akemi Tanaka; Katsumi Higaki; Ayumi Takamura; Eiji Nanba; Toshiyuki Seto; Mitsuyo Maeda; Etsuko Yamaguchi; Junichiro Matsuda; Tunekazu Yamano

2009-01-01

120

Studies on G M1 -gangliosidosis, type II  

Microsoft Academic Search

Post-mortem studies on a 6-year old boy with GM1-gangliosidosis, Type II revealed no evidence of accumulation of residual bodies nor of gangliosides or glycoproteins in liver and spleen. In brain tissue the ganglioside GM1 accounted for 70% of the ganglioside fraction and ganglioside-NANA was increased 3.6 fold over controls. In addition, the brain tissue contained large amounts of glycoprotein, glycoprotein

Vimalkumar Patel; Hans H. Goebel; Itaru Watanabe; Wolfgang Zeman

1974-01-01

121

Pharmacokinetics, safety and tolerability of miglustat in the treatment of pediatric patients with GM2 gangliosidosis.  

PubMed

GM2 gangliosidosis (GM2g) is an inherited neurodegenerative disorder caused by deficiency of lysosomal beta-hexosaminidase A, resulting in accumulation of GM2 ganglioside, principally in the brain. Substrate reduction therapy is currently under investigation as a treatment. The study investigated the pharmacokinetics and safety of miglustat given as single and multiple doses in infantile and juvenile GM2g patients for 6- and 24-months, respectively. Eleven patients with infantile (n = 6) and juvenile (n = 5) GM2g received oral miglustat at 30-200 mg t.i.d. adjusted to the body surface area. Patients underwent pharmacokinetic assessments on day 1 and at month 3. The pharmacokinetics of miglustat were described by a 2-compartmental model with a lag time, median time to maximum concentration of 2.5 h, and terminal half-life of about 10 h. The pharmacokinetics were time-independent, and did not differ between infantile and juvenile cohorts. The accumulation index was 1.7. Among infantile GM2g patients, the major drug-related adverse events (DRAEs) were abdominal discomfort and flatulence. In the juvenile group, however, the major DRAEs observed were diarrhea and weight loss. One juvenile patient developed peripheral neuropathy, and others showed progression of already established neuropathy, which was judged to be part of the natural progression of the disease. Some mild laboratory abnormalities observed were either transient or attributable to concomitant medications. Miglustat showed similar pharmacokinetic parameters in all patients, with no specific difference between infantile and juvenile forms. Miglustat was shown to be a safe drug, with mild to moderate diarrhea, as an age-dependent DRAE, which was controlled by dietary modification. PMID:19447653

Maegawa, Gustavo H B; van Giersbergen, Paul L M; Yang, Sandra; Banwell, Brenda; Morgan, Christopher P; Dingemanse, Jasper; Tifft, Cynthia J; Clarke, Joe T R

2009-08-01

122

B1 variant of GM2 gangliosidosis in a 12-year-old patient.  

PubMed

A girl aged 12 y, 9 mo, suffered from a progressive neurodegenerative disorder marked by ataxia, extrapyramidal symptoms, and convulsions. A skin biopsy showed axonal pathology that emphasized axonal segments enlarged by mitochondria, dense bodies, and lysosomal residual bodies of the membranous cytoplasmic body type. This ultrastructural pathology suggested GM2 gangliosidosis which was shown to be a B1 variant by specific biochemical studies, although conventional techniques had failed to detect GM2 gangliosidosis. The B1 variant is marked by a deficient activity of beta-hexosaminidase A towards one substrate, and by an almost normal activity towards another. Both parents showed a diminished activity towards the sulfated substrate, suggesting a heterozygous state, and almost normal activity with the second substrate type. PMID:2521932

Goebel, H H; Stolte, G; Kustermann-Kuhn, B; Harzer, K

1989-01-01

123

Antibodies against GM1 gangliosides associated with metastatic melanoma.  

PubMed

The aim was to analyze humoral immune response against GM1 ganglioside expressed on the surface of melanocytic cells, and the possible correlation between the level of antibodies against GM1 IgG and IgM class and melanoma progression. The study included 128 adult patients with malignant melanoma, without paraneoplastic neurologic disorders, 48 adults with dysplastic nevi and 48 healthy volunteers. The presence of IgM and IgG antibodies against GM1 was demonstrated by Immunodot method. Automatic evaluation of strips marked with GM1 antigen was performed by EUROLineScan software. Lactate dehydrogenase (LDH) activity was evaluated by spectrophotometry. Serum concentration of gangliosides was determined using the method with resorcinol-HCl. IgG antibodies against GM1 gangliosides were identified in six patients with melanoma (4.68%) and in none of the subjects from other groups. AntiGM1 IgM class were observed in 20 (15.63%) melanoma patients, three (6.25%) dysplastic nevi patients and one healthy volunteer. No statistically significant difference was observed when serum profile of GM1 IgM antibodies in patients with localized melanoma was compared with that of other study subjects. The levels of IgM antibodies varied with clinical stage of tumor and histopathologic features. Moreover, a statistically significant positive correlation was found between IgM antibodies and LDH (r=0.87; p=0.01; IC=95%). In conclusion, antibodies against GM1 ganglioside are frequent in patients with melanoma. Dysplastic nevi and early melanoma cannot be differentiated using the antiGM1 antibody profile. The synthesis of these antibodies is characteristic for advanced stages of melanoma. PMID:24001415

Nicolae, Corina Daniela; Nicolae, Ilinca

2013-08-01

124

Late onset GM2-gangliosidosis  

Microsoft Academic Search

Eight cases of late onset GM2-gangliosidosis are described. 4 presented before the age of 2 years and 4 between 3½ and 10 years. Gait disturbance, intellectual deterioration, and fits were prominent features. Optic atrophy was seen at a late stage in 2 patients. An exaggerated startle reaction to sound and an unusual type of cherry red spot at the macula

E. M. Brett; R. B. Ellis; L. Haas; J. U. Ikonne; B. D. Lake; A. D. Patrick; Rosemary Stephens

1973-01-01

125

Application of delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry for analysis of sphingolipids in tissues from sphingolipidosis patients  

Microsoft Academic Search

Sphingolipidosis is due to defects in enzymes involved in hydrolysis of sphingolipids. We analyzed sphingolipids in tissues from patients with sphingolipidosis, including Farber disease (FD, acid ceramidase deficiency), Gaucher disease (GD), Niemann–Pick disease type C (NPDC), and GM1-gangliosidosis (GM1G), using delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry (DE MALDI–TOF–MS). Crude lipids were extracted from about 100 mg wet

Takehisa Fujiwaki; Seiji Yamaguchi; Kazuko Sukegawa; Tamotsu Taketomi

1999-01-01

126

Application of delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry for analysis of sphingolipids in cultured skin fibroblasts from sphingolipidosis patients  

Microsoft Academic Search

Sphingolipidoses are caused by defects of enzymes involved in the hydrolysis of sphingolipids. Using delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry (DE MALDI-TOF-MS), we analyzed sphingolipids in cultured skin fibroblasts from patients with sphingolipidoses, including: (a) Farber disease (FD, acid ceramidase deficiency); (b) Gaucher disease (GD); (c) Niemann-Pick disease type C (NPDC); and (d) GM1-gangliosidosis (GM1G). Crude lipids

Takehisa Fujiwaki; Seiji Yamaguchi; Kazuko Sukegawa; Tamotsu Taketomi

2002-01-01

127

GM2 gangliosidosis variant B1  

Microsoft Academic Search

.   Variant B1 is a rare type of GM2 gangliosidosis. Clinically, it shows a wide spectrum of forms ranging from infantile to\\u000a juvenile. We report the first magnetic resonance imaging (MRI) findings from three patients affected by GM2 gangliosidosis\\u000a variant B1, two presenting with the infantile form and one with the juvenile form. The MRI appearances of the two patients

Salvatore Grosso; Maria Angela Farnetani; Rosario Berardi; Maria Margollicci; Paolo Galluzzi; Rossella Vivarelli; Guido Morgese; Paolo Ballestri

2003-01-01

128

Close association of Guillain–Barré syndrome with antibodies to minor monosialogangliosides GM1b and GM1 ?  

Microsoft Academic Search

Cumulative evidence supports the theory that anti-ganglioside antibodies function in the development of Guillain–Barré syndrome (GBS). Some patients have developed GBS after the administration of monosialoganglioside extracted from bovine brain. To clarify the pathogenesis of GBS associated with and without administration of the monosialoganglioside fraction, we investigated serum antibodies to the minor monosialogangliosides GM1b and GM1? in patients with GBS

Nobuhiro Yuki; Yumi Tagawa; Fumitoshi Irie; Yoshio Hirabayashi; Shizuo Handa

1997-01-01

129

Mutation analyses in 17 patients with deficiency in acid ß-galactosidase: three novel point mutations and high correlation of mutation W273L with Morquio disease type B  

Microsoft Academic Search

An inherited deficiency in #-galactosidase can result in GM1 gangliosidosis, with several phenotypes of generalized or chronic psychomotor deterioration, as well as in Morquio disease type B, a characteristic mucopolysaccharidosis free of neurological symptoms. We performed mutation analyses in 17 juvenile and adult patients from various European regions with a deficiency in #-galactosidase and skeletal abnormalities. Fifteen of these had

Eduard Paschke; Ivica Milos; Heidemarie Kreimer-Erlacher; Gerald Hoefler; Michael Beck; Maria Hoeltzenbein; Wim Kleijer; Thierry Levade; Helen Michelakakis; B. Radeva

2001-01-01

130

Prenatal diagnosis of G M1 -gangliosidosis: Biochemical manifestations in fetal tissues  

Microsoft Academic Search

A prenatal diagnosis of GM1-gangliosidosis was made in a pregnancy at risk, on the basis of a deficiency of ß-galactosidase activity demonstrated in cultured aminiotic fluid cells. Biochemical analyses were performed in the aborted fetus. GM1-ganglioside ß-galactosidase activity was reduced to 1% of the control value in both the brain and liver of the affected fetus. Lamellar bodies suggestive of

T. Kudoh; K. Kikuchi; F. Nakamura; S. Yokoyama; K. Karube; S. Tsugawa; R. Minami; T. Nakao

1978-01-01

131

Rapid and accurate G M1-gangliosidosis diagnosis using a parentage testing microsatellite  

Microsoft Academic Search

The GM1-gangliosidosis is an autosomal recessive lysosomal storage disease caused by structural defects of the ?-galactosidase gene (GLB1) which lead to a severe phenotypical impairment in homozygous individuals, whereas heterozygous carriers remain clinically normal. Currently employed DNA parentage tests include the analysis of microsatellites, which also have a diagnostic predictive value. The aim of this study was to provide a

Robert Kreutzer; Mihaela Kreutzer; Tosso Leeb; Wolfgang Baumgärtner

2008-01-01

132

Infantile G M1 Gangliosidosis: Complete Morphology and Histochemistry of Two Autopsy Cases, with Particular Reference to Delayed Central Nervous System Myelination  

Microsoft Academic Search

Inborn metabolic errors causing lysosomal storage, such as ?-galactosidase deficiency (GM1 gangliosidosis [GM1]), have well-recognized effects on cellular function and morphology. In some classically “neuronal” storage diseases, including\\u000a GM1, neuroradiologic observations of infants have suggested a delay in myelination on the basis of persistently “immature” signal\\u000a intensities monitored over time. We sought to evaluate in a semiquantitative fashion the pattern

Rebecca D. Folkerth; Joseph Alroy; Ina Bhan; Edward M. Kaye

2000-01-01

133

Molecular analysis of a GM2-activator deficiency in two patients with GM2-gangliosidosis AB variant  

SciTech Connect

Lysosomal degradation of ganglioside GM2 by {beta}-hexosaminidase A (hex A) requires the presence of the GM2 activator protein (GM2AP) as an essential cofactor. A deficiency of the GM2 activator causes the AB variant of GM2 gangliosidosis, a recessively inherited disorder characterized by excessive neuronal accumulation of GM2 and related glycolipids. Two novel mutations in the GM2 activator gene (GM2A) have been identified by the reverse-transcriptase-PCR method - a three-base deletion, AAG{sup 262-264}, resulting in a deletion of Lys{sup 88}, and a single-base deletion, A{sup 410}, that causes a frameshift. The latter results in substitution of 33 amino acids and the loss of another 24 amino acid residues. Both patients are homoallelic for their respective mutations inherited from their parents, who are heteroallelic at the GM2A locus. Although the cultured fibroblasts of both patients produce normal levels of activator mRNA, they lack a lysosomal form of GM2AP. Pulse/chase labeling of cultured fibroblasts of the patients, in presence and absence of brefeldin A, indicates a premature degradation of both-mutant and truncated-GM2APs in the endoplasmic reticulum or Golgi. These results were supported by in vitro translation experiments and expression of the mutated proteins. When the mutated GM2APs were expressed in Escherichia coli, both mature GM2AP forms turned proved to exhibit only residual activities in an in vitro assay. 26 refs., 7 figs.

Schepers, U.; Glombitza, G.; Lemm, T. [Institut fuer Organische Chemie und Biochemie der Universitaet, Bonn (Germany)] [and others

1996-11-01

134

Two new human {beta}-galactosidase gene mutations in American patients with slowly progressive G{sub M1} gangliosidosis  

SciTech Connect

Two cases with slowly progressive forms of G{sub M1} gangliosidosis were each found to have a novel mutation for the {beta}-galactosidase gene. AS (died at 4 yr) began with symptoms at 8 months ({beta}-galactosidase activity 10% normal) and HS (59 yr) developed dystronic hand movements at age 3 yr ({beta}-galactosidase activity < 2% of normal controls). The entire 2.4 coding region was sequenced in both directions for each patient using RT-PCR. First strand cDNA was synthesized from fibroblast RNA and double stranded PCR fragments spanning the coding region were made with oligonucleotide primers. Sequencing was performed using asymmetric PCR products made from each double stranded product. Case AS was found to have a nine base-pair insertion [CAGAATTTT] on one allele beginning at nucleotide position 730, which did not result in a frameshift and is predicted to cause the insertion of three amino acids (Glu-Phe-Ser) between amino acids 44-45. No other mutations in the coding region were identified on this or the other allele in this individual. Case HS had a unique point mutation identified in one allele. This mutation was an A{r_arrow}G transition at nucleotide 797 which results in a Asn{r_arrow}Ser amino acid substitution in codon 266 (mutation N266S) with no other mutations found in the expressed RNA sequences. SSCP was performed on a 200 bp region surrounding codon 266 using genomic DNA from over 50 controls to look for changes in nucleotide sequence. Only case HS demonstrated a shift indicating that the base pair change did not represent a normal polymorphism.

Shalish, C.; Breakefield, X.O. [Massachusetts General Hospital, Boston, MA (United States); Kaye, E.M. [Tufts Univ. School of Medicine, Boston, MA (United States)] [and others

1994-09-01

135

Lysosomal accumulation of Trk protein in brain of GM? -gangliosidosis mouse and its restoration by chemical chaperone.  

PubMed

G(M1) -gangliosidosis is a fatal neurodegenerative disorder caused by deficiency of lysosomal acid ?-galactosidase (?-gal). Accumulation of its substrate ganglioside G(M1) (G(M1) ) in lysosomes and other parts of the cell leads to progressive neurodegeneration, but underlying mechanisms remain unclear. Previous studies demonstrated an essential role for interaction of G(M1) with tropomyosin receptor kinase (Trk) receptors in neuronal growth, survival and differentiation. In this study we demonstrate accumulation of G(M1) in the cell-surface rafts and lysosomes of the ?-gal knockout (?-gal-/-) mouse brain association with accumulation of Trk receptors and enhancement of its downstream signaling. Immunofluorescence and subcellular fractionation analysis revealed accumulation of Trk receptors in the late endosomes/lysosomes of the ?-gal-/- mouse brain and their association with ubiquitin and p62. Administration of a chemical chaperone to ?-gal-/- mouse expressing human mutant R201C protein resulted in a marked reduction of intracellular storage of G(M1) and phosphorylated Trk. These findings indicate that G(M1) accumulation in rafts causes activation of Trk signaling, which may participate in the pathogenesis of G(M1) -gangliosidosis. PMID:21574998

Takamura, Ayumi; Higaki, Katsumi; Ninomiya, Haruaki; Takai, Tomoko; Matsuda, Junichiro; Iida, Masami; Ohno, Kousaku; Suzuki, Yoshiyuki; Nanba, Eiji

2011-08-01

136

Retarded bone formation in G M1 -gangliosidosis: a study of the infantile form and comparison with two canine models  

Microsoft Academic Search

The development of skeletal lesions in two canine models of GM1-gangliosidosis, English springer spaniels and Portuguese water dogs, has been studied and compared to osseous abnormalities in a child with the infantile form of the disease. In the canine models, skeletal dysplasia was progressive. Lesions were noted at 2 months of age and characterized by retarded endochondral ossification and osteoporosis.

J. Alroy; K. Knowles; S. H. Schelling; E. M. Kaye; A. E. Rosenberg

1995-01-01

137

IgG Antibody against GM1, GD1b and Asialo-GM1 in Chronic Polyneuropathy following Mycoplasma pneumoniae Infection  

Microsoft Academic Search

Serum IgG in a patient with chronic polyneuropathy after Mycoplasma pneumoniae infection reacted with ganglioside GM1, GD1b and asialo-GM1 on thin-layer chromatograms using an immunostaining technique as well as an enzyme-linked immunosorbent assay, suggesting that the galactosyl (?1-3)N-acetylgalactosaminyl moiety could be a target antigen in this patient. Serum IgG reacting with these glycolipids may be involved in the pathogenesis of

Hüde Yoshino; Takashi Inuzuka; Tadashi Miyatake

1992-01-01

138

Lower motor neuron syndrome associated with IgG anti-GM1 antibodies revisited.  

PubMed

A patient, who developed an amyotrophic lateral sclerosis-like disorder subsequent to ganglioside treatment, had IgM antibodies to GM2 as well as to minor gangliosides X1 and X2 containing GM2 epitope. These gangliosides as well as GM1 were tested in 655 sera obtained from patients who were suspected of having amyotrophic lateral sclerosis or motor neuron disease to find a treatable condition. Three patients had high titers of IgG anti-GM1 antibodies, but no IgM anti-GM1 antibodies. One of the patients also had IgG anti-X2 antibodies. The patients, being diagnosed with having lower motor neuron syndrome, had neither upper motor neuron signs nor multifocal conduction block. Both IgM and IgG anti-GM1 antibodies should be tested in patients who have lower motor neuron syndrome. PMID:24841627

Yuki, Nobuhiro; Yanaka, Chiaki; Sudo, Makoto; Funakoshi, Miyuki; Ishida, Hideharu; Mori, Masahiro; Kanda, Fumio; Hirata, Koichi

2014-07-15

139

G M1 -gangliosidosis in a cross-bred dog confirmed by detection of G M1 -ganglioside using electrospray ionisation-tandem mass spectrometry  

Microsoft Academic Search

The post-mortem diagnosis of lysosomal storage diseases can be confounded by the unavailability of suitable material. Here\\u000a we report the diagnosis of GM1-gangliosidosis in a cross-bred dog, from which only formalin-fixed brain was available, by a combination of electron microscopy\\u000a and the detection of elevated levels of GM1-ganglioside within the tissue using the novel technique of electrospray ionisation tandem mass

Phillip Whitfield; Andrew W. Johnson; Karen A. Dunn; Agnes J. N. Delauche; Bryan G. Winchester; Robin J. M. Franklin

2000-01-01

140

G M2 Gangliosidosis, AB variant  

Microsoft Academic Search

Clinical and neuropathological studies of a case of AB variant GM2-gangliosidosis have been presented. The patient was a 14 months old black female infant who had “black cherry spot” in the retinas. The total activities of ß-galactosidase and N-acetyl-ß-hexosaminidase, as well as the proportion of hexosaminidase A and B components in her serum and leukocytes were normal when the assays

Cecile M. Baecque; Kinuko Suzuki; Isabelle Rapin; Anne B. Johnson; Doris L. Whethers; Kunihiko Suzuki

1975-01-01

141

An open-label Phase I\\/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 gangliosidosis (Tay–Sachs or Sandhoff variants)  

Microsoft Academic Search

Late-onset GM2 gangliosidosis is an autosomal recessive, neurodegenerative, lysosomal storage disease, caused by deficiency of ß-hexosaminidase A (Hex A), resulting from mutations in the HEXA (Tay–Sachs variant) or the HEXB (Sandhoff variant) genes. The enzyme deficiency in many patients with juvenile or adult onset forms of the disease results from the production of an unstable protein, which becomes targeted for

Joe T. R. Clarke; Don J. Mahuran; Swati Sathe; Edwin H. Kolodny; Brigitte A. Rigat; Julian A. Raiman; Michael B. Tropak

2011-01-01

142

Heritability and biochemistry of gangliosidosis in emus (Dromaius novaehollandiae).  

PubMed

The progeny of two emu breeder pairs, which had a history of producing offspring with gangliosidosis, were monitored for 15 mo. DNA fingerprinting revealed that individuals in each breeder pair were not related to each other. One breeder pair had 13 progeny that reached or exceeded the age of 1 mo, and six of these progeny developed gangliosidosis. The mean age at which these affected emus were euthanatized, with distinct neurologic disease, or died was 5.7 mo. The second emu pair had 13 progeny, seven of which developed gangliosidosis, with a mean age of euthanasia/death of 4.6 mo. Affected emus died or were euthanatized from 2 to 8 mo of age. The primary clinical sign in the affected emus was mild to severe ataxia. Severe hemorrhage into the body cavity or the muscles of the thigh was noted in 8 of 13 of the affected emus. Brain ganglioside levels were evaluated in six of the affected emus and six controls. Significant increases (P < 0.05) in gangliosides GM1 and GM3 were noted, with 2.3- and 4.9-fold increases in these two gangliosides, respectively, in affected emus. Furthermore, the diseased emu brains contained ganglioside GM2, whereas this monosialoganglioside was undetectable in the brains of normal controls. Total mean brain ganglioside sialic acid in affected emus was increased 3.3-fold in comparison with controls. Serum chemistries revealed elevated cholesterol and decreased uric acid levels in affected emus. Gangliosidosis in emus is an inherited disease process that, in the current study, caused 50% mortality in the progeny of two emu breeder pairs. The elimination of this lethal gene from emu breeder stock is essential for the long-term economic viability of the United States emu industry. PMID:9454917

Bermudez, A J; Freischütz, B; Yu, R K; Nonneman, D; Johnson, G S; Boon, G D; Stogsdill, P L; Ledoux, D R

1997-01-01

143

Natural History of Infantile GM2 Gangliosidosis  

PubMed Central

OBJECTIVE: GM2 gangliosidoses are caused by an inherited deficiency of lysosomal ?-hexosaminidase and result in ganglioside accumulation in the brain. Onset during infancy leads to rapid neurodegeneration and death before 4 years of age. We set out to quantify the rate of functional decline in infantile GM2 gangliosidosis on the basis of patient surveys and a comprehensive review of existing literature. METHODS: Patients with infantile GM2 gangliosidosis (N = 237) were surveyed via questionnaire by the National Tay Sachs & Allied Diseases Association (NTSAD). These data were supplemented by survival data from the NTSAD database and a literature survey. Detailed retrospective surveys from 97 patients were available. Five patients who had received hematopoietic stem cell transplantation were evaluated separately. The mortality rate of the remaining 92 patients was comparable to that of the 103 patients from the NTSAD database and 121 patients reported in the literature. RESULTS: Common symptoms at onset were developmental arrest (83%), startling (65%), and hypotonia (60%). All 55 patients who had learned to sit without support lost that ability within 1 year. Individual functional measures correlated with each other but not with survival. Gastric tube placement was associated with prolonged survival. Tay Sachs and Sandhoff variants did not differ. Hematopoietic stem cell transplantation was not associated with prolonged survival. CONCLUSIONS: We studied the timing of regression in 97 cases of infantile GM2 gangliosidosis and conclude that clinical disease progression does not correlate with survival, likely because of the impact of improved supportive care over time. However, functional measures are quantifiable and can inform power calculations and study design of future interventions.

Bley, Annette E.; Giannikopoulos, Ourania A.; Hayden, Doug; Kubilus, Kim; Tifft, Cynthia J.

2011-01-01

144

NSOM/QD-based visualization of GM1 serving as platforms for TCR/CD3 mediated T-cell activation.  

PubMed

Direct molecular imaging of nanoscale relationship between T-cell receptor complexes (TCR/CD3) and gangliosidosis GM1 before and after T-cell activation has not been reported. In this study, we made use of our expertise of near-field scanning optical microscopy(NSOM)/immune-labeling quantum dots- (QD-)based dual-color imaging system to visualize nanoscale profiles for distribution and organization of TCR/CD3, GM1, as well as their nanospatial relationship and their correlation with PKC ? signaling cascade during T-cell activation. Interestingly, after anti-CD3/anti-CD28 Ab co-stimulation, both TCR/CD3 and GM1 were clustered to form nanodomains; moreover, all of TCR/CD3 nanodomains were colocalized with GM1 nanodomains, indicating that the formation of GM1 nanodomains was greatly correlated with TCR/CD3 mediated signaling. Specially, while T-cells were pretreated with PKC ? signaling inhibitor rottlerin to suppress IL-2 cytokine production, no visible TCR/CD3 nanodomains appeared while a lot of GM1 nanodomains were still observed. However, while T-cells are pretreated with PKC? ? signaling inhibitor GÖ6976 to suppress calcium-dependent manner, all of TCR/CD3 nanodomains were still colocalized with GM1 nanodomains. These findings possibly support the notion that the formation of GM1 nanodomains indeed serves as platforms for the recruitment of TCR/CD3 nanodomains, and TCR/CD3 nanodomains are required for PKC? signaling cascades and T-cell activation. PMID:24288672

Zhong, Liyun; Zhang, Zhun; Lu, Xiaoxu; Liu, Shengde; Chen, Crystal Y; Chen, Zheng W

2013-01-01

145

NSOM/QD-Based Visualization of GM1 Serving as Platforms for TCR/CD3 Mediated T-Cell Activation  

PubMed Central

Direct molecular imaging of nanoscale relationship between T-cell receptor complexes (TCR/CD3) and gangliosidosis GM1 before and after T-cell activation has not been reported. In this study, we made use of our expertise of near-field scanning optical microscopy(NSOM)/immune-labeling quantum dots- (QD-)based dual-color imaging system to visualize nanoscale profiles for distribution and organization of TCR/CD3, GM1, as well as their nanospatial relationship and their correlation with PKC? signaling cascade during T-cell activation. Interestingly, after anti-CD3/anti-CD28 Ab co-stimulation, both TCR/CD3 and GM1 were clustered to form nanodomains; moreover, all of TCR/CD3 nanodomains were colocalized with GM1 nanodomains, indicating that the formation of GM1 nanodomains was greatly correlated with TCR/CD3 mediated signaling. Specially, while T-cells were pretreated with PKC? signaling inhibitor rottlerin to suppress IL-2 cytokine production, no visible TCR/CD3 nanodomains appeared while a lot of GM1 nanodomains were still observed. However, while T-cells are pretreated with PKC?? signaling inhibitor GÖ6976 to suppress calcium-dependent manner, all of TCR/CD3 nanodomains were still colocalized with GM1 nanodomains. These findings possibly support the notion that the formation of GM1 nanodomains indeed serves as platforms for the recruitment of TCR/CD3 nanodomains, and TCR/CD3 nanodomains are required for PKC? signaling cascades and T-cell activation

Zhang, Zhun; Lu, Xiaoxu; Liu, Shengde; Chen, Crystal Y.; Chen, Zheng W.

2013-01-01

146

GM1-ganglioside accumulation at the mitochondria-associated ER membranes links ER stress to Ca2+-dependent mitochondrial apoptosis  

PubMed Central

Summary Mitochondria-associated ER membranes or MAMs define the sites of endoplasmic reticulum/mitochondria juxtaposition that control Ca2+ flux between these organelles. We found that in a mouse model of the human lysosomal storage disease GM1-gangliosidosis, GM1-ganglioside accumulates in the glycosphingolipid-enriched microdomain (GEM) fractions of MAMs, where it interacts with the phosphorylated form of IP3 receptor-1, influencing the activity of this channel. Ca2+ depleted from the ER is then taken up by the mitochondria, leading to Ca2+ overload in this organelle. The latter induces mitochondrial membrane permeabilization (MMP), opening of the permeability transition pore and activation of the mitochondrial apoptotic pathway. This study identifies the GEMs as the sites of Ca2+ diffusion between the ER and the mitochondria. We propose a new mechanism of Ca2+-mediated apoptotic signalling, whereby GM1 accumulation at the GEMs alters Ca2+ dynamics and acts as a molecular effector of both ER stress–induced and mitochondria-mediated apoptosis of neuronal cells.

Sano, Renata; Annunziata, Ida; Patterson, Annette; Moshiach, Simon; Gomero, Elida; Opferman, Joseph; Forte, Michael; d'Azzo, Alessandra

2009-01-01

147

Concentrations of an activator protein for sphingolipid hydrolysis in liver and brain samples from patients with lysosomal storage diseases.  

PubMed Central

The hydrolysis of sphingolipids by lysosomal enzymes requires the presence of additional proteins, which have been called activator proteins. The number of activator proteins, their specificity, exact mechanism of action, and response to a storage process all remain to be determined. In this study, antibodies to an activator protein known to bind sphingolipids and activate the enzymatic hydrolysis of GM1 ganglioside and sulfatide were used to estimate the concentration of this activator protein in small samples of liver and brain from patients with lysosomal storage diseases. By using rocket immunoelectrophoresis, the concentration of cross-reacting material (CRM) was determined. Control livers had an average of 0.95 +/- 0.18 (mean +/- 1 SD) microgram CRM/mg protein in the extracts, and control brains had an average of 0.25 +/- 0.14 microgram CRM/mg protein. Extremely high levels of CRM were found in extracts of livers from patients with type 1 GM1 gangliosidosis (15.1 and 16.9), and type A Niemann-Pick disease (10.7). Extracts of brain samples revealed a large amount of CRM in type 1 GM1 gangliosidosis (14.8), Tay-Sachs disease (5.3 and 8.7), and Sandhoff disease (13.5). Significantly elevated CRM was also measured in brain samples from patients with type 2 GM1 gangliosidosis, type A Niemann-Pick disease, metachromatic leukodystrophy, and Krabbe disease. The highest levels are found in those genetic diseases where the lipids stored, primarily or secondarily to the genetic defect, bind to this activator protein. This activator protein may have an important function in regulating intralysosomal lipid catabolism, and changes in its concentration in certain genetic diseases may be the cause of clinical, biochemical, and pathological heterogeneity found in the patients. Images

Inui, K; Wenger, D A

1983-01-01

148

Gene Transfer to Human Cells: Transducing Phage lambda plac Gene Expression in GMI-gangliosidosis Fibroblasts  

Microsoft Academic Search

Genetic information from the bacterium Escherichia coli was transferred to human cells by means of the specialized transducing phage lambda plac carrying the bacterial z gene for the enzyme beta -galactosidase (beta -D-galactoside galactohydrolase, EC 3.2.1.23). As recipient cells, cultured skin fibroblasts from a patient with generalized gangliosidosis (GMI-gangliosidosis Type I) characterized by a severe deficiency of beta -galactosidase activity

Jurgen Horst; Friedrich Kluge; Konrad Beyreuther; Wolfgang Gerok

1975-01-01

149

Molecular genetics of GM2-gangliosidosis AB variant: a novel mutation and expression in BHK cells  

Microsoft Academic Search

The GM2 activator is a hexosaminidase A-specific glycolipid-binding protein required for the lysosomal degradation of ganglioside GM2. Genetic deficiency of GM2 activator leads to a neurological disorder, an atypical form of Tay-Sachs disease (GM2 gangliosidosis variant AB). Here, we describe a G506 to C transversion (Arg169 to Pro) in the mRNA of an infantile patient suffering from GM2-gangliosidosis variant AB.

Maria Schrtider; Doris Schnabel; Robert Hurwitz; Elisabeth Young; Kunihiko Suzuki; Konrad Sandhoff

1993-01-01

150

Mutations in the lysosomal [beta]-galactosidase gene that cause the adult form of GMI gangliosidosis  

SciTech Connect

Three adult patients with acid-galactosidase deficiency/GM1 gangliosidosis who were from two unrelated families of Scandinavian descent were found to share a common point mutation in the coding region of the corresponding gene. The patients share common clinical features, including early dysarthria, mild ataxia, and bone abnormalities. When cDNA from the two patients in family 1 was PCR amplified and sequenced, most (39/41) of the clones showed a C-to-T transition (C[yields]T) at nucleotide 245 (counting from the initiation codon). This mutation changes the codon for the Thr(ACG) to Met(ATG). Mutant and normal sequences were also found in that position in genomic DNA, indicating the presence of another mutant allele. Genomic DNA from the patient in family 2 revealed the same point mutation in one allele. It was determined that in each family only the father carried the C[yields]T mutation. Expression studies showed that this mutation produced 3%-4% of [beta]-galactosidase activity, confirming its deleterious effects. The cDNA clones from the patients in family 1 that did not contain the C[yields]T revealed a 20-bp insertion of intronic sequence between nucleotides 75 and 76, the location of the first intron. Further analysis showed the insertion of a T near the 5[prime] splice donor site which led to the use of a cryptic splice site. It appears that the C[yields]T mutation results in enough functional enzyme to produce a mild adult form of the disease, even in the presence of a second mutation that likely produces nonfunctional enzyme. 31 refs., 7 figs., 1 tab.

Chakraborty, S.; Rafi, M.A.; Wenger, D.A. (Thomas Jefferson Univ., Philadelphia, PA (United States))

1994-06-01

151

An open-label Phase I/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 gangliosidosis (Tay-Sachs or Sandhoff variants)  

PubMed Central

Late-onset GM2 gangliosidosis is an autosomal recessive, neurodegenerative, lysosomal storage disease, caused by deficiency of ?-hexosaminidase A (Hex A), resulting from mutations in the HEXA (Tay–Sachs variant) or the HEXB (Sandhoff variant) genes. The enzyme deficiency in many patients with juvenile or adult onset forms of the disease results from the production of an unstable protein, which becomes targeted for premature degradation by the quality control system of the smooth endoplasmic reticulum and is not transported to lysosomes. In vitro studies have shown that many mutations in either the ? or ? subunit of Hex A can be partially rescued, i.e. enhanced levels of both enzyme protein and activity in lysosomes, following the growth of patient cells in the presence of the drug, pyrimethamine. The objectives of the present clinical trial were to establish the tolerability and efficacy of the treatment of late-onset GM2 gangliosidosis patients with escalating doses of pyrimethamine, to a maximum of 100 mg per day, administered orally in a single daily dose, over a 16-week period. The primary objective, tolerability, was assessed by regular clinical examinations, along with a panel of hematologic and biochemical studies. Although clinical efficacy could not be assessed in this short trial, treatment efficacy was evaluated by repeated measurements of leukocyte Hex A activity, expressed relative to the activity of lysosomal ?-glucuronidase. A total of 11 patients were enrolled, 8 males and 3 females, aged 23 to 50 years. One subject failed the initial screen, another was omitted from analysis because of the large number of protocol violations, and a third was withdrawn very early as a result of adverse events which were not drug-related. For the remaining 8 subjects, up to a 4-fold enhancement of Hex A activity at doses of 50 mg per day or less was observed. Additionally marked individual variations in the pharmacokinetics of the drug among the patients were noted. However, the study also found that significant side effects were experienced by most patients at or above 75 mg pyrimethamine per day. We concluded that pyrimethamine treatment enhances leukocyte Hex A activity in patients with late-onset GM2 gangliosidosis at doses lower than those associated with unacceptable side effects. Further plans are underway to extend these trials and to develop methods to assess clinical efficacy.

Clarke, Joe T.R.; Mahuran, Don J.; Sathe, Swati; Kolodny, Edwin H.; Rigat, Brigitte A.; Raiman, Julian A.; Tropak, Michael B.

2010-01-01

152

An open-label Phase I/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 gangliosidosis (Tay-Sachs or Sandhoff variants).  

PubMed

Late-onset GM2 gangliosidosis is an autosomal recessive, neurodegenerative, lysosomal storage disease, caused by deficiency of ß-hexosaminidase A (Hex A), resulting from mutations in the HEXA (Tay-Sachs variant) or the HEXB (Sandhoff variant) genes. The enzyme deficiency in many patients with juvenile or adult onset forms of the disease results from the production of an unstable protein, which becomes targeted for premature degradation by the quality control system of the smooth endoplasmic reticulum and is not transported to lysosomes. In vitro studies have shown that many mutations in either the ? or ? subunit of Hex A can be partially rescued, i.e. enhanced levels of both enzyme protein and activity in lysosomes, following the growth of patient cells in the presence of the drug, pyrimethamine. The objectives of the present clinical trial were to establish the tolerability and efficacy of the treatment of late-onset GM2 gangliosidosis patients with escalating doses of pyrimethamine, to a maximum of 100 mg per day, administered orally in a single daily dose, over a 16-week period . The primary objective, tolerability, was assessed by regular clinical examinations, along with a panel of hematologic and biochemical studies. Although clinical efficacy could not be assessed in this short trial, treatment efficacy was evaluated by repeated measurements of leukocyte Hex A activity, expressed relative to the activity of lysosomal ß-glucuronidase. A total of 11 patients were enrolled, 8 males and 3 females, aged 23 to 50 years. One subject failed the initial screen, another was omitted from analysis because of the large number of protocol violations, and a third was withdrawn very early as a result of adverse events which were not drug-related. For the remaining 8 subjects, up to a 4-fold enhancement of Hex A activity at doses of 50 mg per day or less was observed. Additionally marked individual variations in the pharmacokinetics of the drug among the patients were noted. However, the study also found that significant side effects were experienced by most patients at or above 75 mg pyrimethamine per day. We concluded that pyrimethamine treatment enhances leukocyte Hex A activity in patients with late-onset GM2 gangliosidosis at doses lower than those associated with unacceptable side effects. Further plans are underway to extend these trials and to develop methods to assess clinical efficacy. PMID:20926324

Clarke, Joe T R; Mahuran, Don J; Sathe, Swati; Kolodny, Edwin H; Rigat, Brigitte A; Raiman, Julian A; Tropak, Michael B

2011-01-01

153

The AB-variant of G M2 -gangliosidosis  

Microsoft Academic Search

Clinical, neuropathological, and biochemical studies are reported in two children with the aB-variant of GM2-gangliosidosis. One patient had become symptomatic by 1–1.5 years, initially showing cerebellar signs, and then progressive psychomotor retardation, with hypotonia, spasticity, dementia, and macular cherry red spots, until death at the age of 4.5 years. The second patient showed an earlier onset of retardation and a

James E. Goldman; Tatsuhiro Yamanaka; Isabelle Rapin; Masazumi Adachi; Kinuko Suzuki; Kunihiko Suzuki

1980-01-01

154

Properties of ganglioside GM1 in phosphatidylcholine bilayer membranes.  

PubMed Central

Gangliosides have been shown to function as cell surface receptors, as well as participating in cell growth, differentiation, and transformation. In spite of their multiple biological functions, relatively little is known about their structure and physical properties in membrane systems. The thermotropic and structural properties of ganglioside GM1 alone and in a binary system with 1,2-dipalmitoyl phosphatidylcholine (DPPC) have been investigated by differential scanning calorimetry (DSC) and x-ray diffraction. By DSC hydrated GM1 undergoes a broad endothermic transition TM = 26 degrees C (delta H = 1.7 kcal/mol GM1). X-ray diffraction below (-2 degrees C) and above (51 degrees C) this transition indicates a micellar structure with changes occurring only in the wide angle region of the diffraction pattern (relatively sharp reflection at 1/4.12 A-1 at -2 degrees C; more diffuse reflection at 1/4.41 A-1 at 51 degrees C). In hydrated binary mixtures with DPPC, incorporation of GM1 (0-30 mol%; zone 1) decreases the enthalpy of the DPPC pretransition at low molar compositions while increasing the TM of both the pre- and main transitions (limiting values, 39 and 44 degrees C, respectively). X-ray diffraction studies indicate the presence of a single bilayer gel phase in zone 1 that can undergo chain melting to an L alpha bilayer phase. A detailed hydration study of GM1 (5.7 mol %)/DPPC indicated a conversion of the DPPC bilayer gel phase to an infinite swelling system in zone 1 due to the presence of the negatively charged sialic acid moiety of GM1. At 30-61 mol % GM1 (zone 2), two calorimetric transitions are observed at 44 and 47 degrees C, suggesting the presence of two phases. The lower transition reflects the bilayer gel --> L alpha transition (zone 1), whereas the upper transition appears to be a consequence of the formation of a nonbilayer, micellar or hexagonal phase, although the structure of this phase has not been defined by x-ray diffraction. At > 61 mol % GM1 (zone 3) the calorimetric and phase behavior is dominated by the micelle-forming properties of GM1; the presence of mixed GM1/DPPC micellar phases is predicted. Images FIGURE 2 FIGURE 4

Reed, R A; Shipley, G G

1996-01-01

155

?-Cyclodextrin decreases cholera toxin binding to GM1-gangliosides  

PubMed Central

Cholera toxin (CT), the principal virulence factor secreted by Vibrio cholerae, is an A-B5 type exotoxin that binds to host cell GM1-gangliosides and is responsible for cholera diarrhoea. We tested the hypothesis that the cyclic hexasaccharide ?-cyclodextrin (?-CD), but not the cyclic heptasaccharides methyl-?-cyclodextrin (MD-?-CD) and hydroxypropyl-?-cyclodextrin (HP-?-CD) inhibit binding of CT to GM1-gangliosides. We report that ?-CD decreases CT binding to GM1-ganglioside-coated microtitre plate wells and on the surface of fixed HeLa cells in a concentration-dependent manner, suggesting that this may be a promising lead for the development of compounds with therapeutic properties.

Ermolinsky, Boris; Peredelchuk, Michael

2013-01-01

156

GM2 gangliosidosis variant B1 neuroradiological findings.  

PubMed

Variant B1 is a rare type of GM2 gangliosidosis. Clinically, it shows a wide spectrum of forms ranging from infantile to juvenile. We report the first magnetic resonance imaging (MRI) findings from three patients affected by GM2 gangliosidosis variant B1, two presenting with the infantile form and one with the juvenile form. The MRI appearances of the two patients with the infantile form disease are congruent with those reported for the early-onset type of both Tay-Sachs and Sandhoff diseases, and are characterized by early involvement of the basal ganglia and thalamus with cortical atrophy appearing later. In contrast, the patient with the juvenile form of variant B1 showed progressive cortical and white-matter atrophy of the supratentorial structures and, to a lesser extent, the infratentorial structures. No basal ganglia or thalamic anomalies were observed. Because in the adult forms of both Tay-Sachs and Sandhoff diseases a progressive cerebellar atrophy represents the only abnormality detectable, it appears that an MRI pattern peculiar to GM2 gangliosidosis can be defined. This pattern ranges from the basal ganglia injury associated with the early and severe demyelination process noted in the infantile form of the disease, to cerebellar atrophy with no supratentorial anomalies in the adult form. An "intermediate" MRI picture, with cortical atrophy and mild cerebellar atrophy, but without basal ganglia impairment, can be observed in the juvenile form. In addition, our investigations suggest that MRI abnormalities in GM2 gangliosidosis correlate with the clinical form of the disease rather than with the biochemical variant of the enzymatic defect. PMID:12527987

Grosso, Salvatore; Farnetani, Maria Angela; Berardi, Rosario; Margollicci, Maria; Galluzzi, Paolo; Vivarelli, Rossella; Morgese, Guido; Ballestri, Paolo

2003-01-01

157

Hyperreflexia in Guillain-Barr? syndrome: relation with acute motor axonal neuropathy and anti-GM1 antibody  

PubMed Central

OBJECTIVES—To investigate the incidence of hyperreflexia in patients with Guillain-Barré syndrome (GBS), and its relation with electrodiagnosis of acute motor axonal neuropathy (AMAN), antiganglioside GM1 antibody, and Campylobacter jejuni infection. It was reported that patients with AMAN in northern China often had hyperreflexia in the recovery phase.?METHODS—In 54 consecutive Japanese patients with GBS, sequential findings of tendon reflexes were reviewed. By electrodiagnostic criteria, patients were classified as having AMAN or acute inflammatory demyelinating polyneuropathy (AIDP). Anti-GM1 and anti-C jejuni antibodies were measured by enzyme linked immunosorbent assays.?RESULTS—Seven (13%) patients developed hyperreflexia with the spread of the myotatic reflex to other segments in the early recovery phase, one of whom already had hyperreflexia in the acute progressive phase. Of the seven patients, six had AMAN and all seven had anti-GM1 antibodies, whereas only two had anti-C jejuni antibodies. Hyperreflexia was more often found in patients with AMAN than AIDP (6/23 v 1/18, p=0.002), and in patients with anti-GM1 antibodies than without them (7/26 v 0/28, p=0.01). Hyperreflexic patients had milder peak disabilities than patients without hyperreflexia (p=0.03). Increased motor neuron excitability in the hyperreflexic patients was supported by increased soleus H-reflex amplitudes and the appearance of H-reflexes in the small hand or foot muscles.?CONCLUSIONS—Hyperreflexia often occurs in patients with GBS especially with AMAN, anti-GM1 antibodies, and milder disease. Increased motor neuron excitability further characterises the subgroup of patients with GBS with AMAN and anti-GM1 antibodies.??

Kuwabara, S.; Ogawara, K.; Koga, M.; Mori, M.; Hattori, T.; Yuki, N.

1999-01-01

158

The Natural History of Juvenile or Subacute GM2 Gangliosidosis: 21 New Cases and Literature Review of 134 Previously Reported  

Microsoft Academic Search

ABSTRACT OBJECTIVE.Juvenile GM2 gangliosidosis is a group,of inherited neurodegenerative diseases caused by deficiency of lysosomal,-hexosaminidase,resulting in GM2 ganglioside accumulation,in brain. The purpose,of this study was to delineate the natural history of the condition and identify genotype-phenotype correlations that might be helpful in predicting the course of the disease in individual patients. METHODS.A cohort of 21 patients with juvenile GM2 gangliosidosis,

Gustavo H. B. Maegawa; Tracy Stockley; Michael Tropak; Brenda Banwell; Susan Blaser; Fernando Kok; Roberto Giugliani; Don Mahuran; Joe T. R. Clarke

2010-01-01

159

Isolation and characterization of the normal canine ?-galactosidase gene and its mutation in a dog model of GM1-gangliosidosis  

Microsoft Academic Search

The acid ß-galactosidase cDNA of Portuguese Water dogs was isolated and sequenced. The entire coding region of the gene consists of 2004 nucleotides encoding a protein of 668 amino acids. Its encoding sequence indicates approximately 86.5% identity at the nucleotide level and about 81% identity at the amino acid level with the encoding region of the human acid ß-galactosidase gene.

Z. H. Wang; B. Zeng; H. Shibuya; G. S. Johnson; J. Alroy; G. M. Pastores; S. Raghavan; E. H. Kolodny

2000-01-01

160

Lo/Ld phase coexistence modulation induced by GM1.  

PubMed

Lipid rafts are assumed to undergo biologically important size-modulations from nanorafts to microrafts. Due to the complexity of cellular membranes, model systems become important tools, especially for the investigation of the factors affecting "raft-like" Lo domain size and the search for Lo nanodomains as precursors in Lo microdomain formation. Because lipid compositional change is the primary mechanism by which a cell can alter membrane phase behavior, we studied the effect of the ganglioside GM1 concentration on the Lo/Ld lateral phase separation in PC/SM/Chol/GM1 bilayers. GM1 above 1mol % abolishes the formation of the micrometer-scale Lo domains observed in GUVs. However, the apparently homogeneous phase observed in optical microscopy corresponds in fact, within a certain temperature range, to a Lo/Ld lateral phase separation taking place below the optical resolution. This nanoscale phase separation is revealed by fluorescence spectroscopy, including C12NBD-PC self-quenching and Laurdan GP measurements, and is supported by Gaussian spectral decomposition analysis. The temperature of formation of nanoscale Lo phase domains over an Ld phase is determined, and is shifted to higher values when the GM1 content increases. A "morphological" phase diagram could be made, and it displays three regions corresponding respectively to Lo/Ld micrometric phase separation, Lo/Ld nanometric phase separation, and a homogeneous Ld phase. We therefore show that a lipid only-based mechanism is able to control the existence and the sizes of phase-separated membrane domains. GM1 could act on the line tension, "arresting" domain growth and thereby stabilizing Lo nanodomains. PMID:24835016

Puff, Nicolas; Watanabe, Chiho; Seigneuret, Michel; Angelova, Miglena I; Staneva, Galya

2014-08-01

161

Cholera toxin assault on lipid monolayers containing ganglioside GM1.  

PubMed

Many bacterial toxins bind to and gain entrance to target cells through specific interactions with membrane components. Using neutron reflectivity, we have characterized the structure of mixed DPPE:GM(1) lipid monolayers before and during the binding of cholera toxin (CTAB(5)) or its B-subunit (CTB(5)). Structural parameters such as the density and thickness of the lipid layer, extension of the GM(1) oligosaccharide headgroup, and orientation and position of the protein upon binding are reported. The density of the lipid layer was found to decrease slightly upon protein binding. However, the A-subunit of the whole toxin is clearly located below the B-pentameric ring, away from the monolayer, and does not penetrate into the lipid layer before enzymatic cleavage. Using Monte Carlo simulations, the observed monolayer expansion was found to be consistent with geometrical constraints imposed on DPPE by multivalent binding of GM(1) by the toxin. Our findings suggest that the mechanism of membrane translocation by the protein may be aided by alterations in lipid packing. PMID:15189866

Miller, C E; Majewski, J; Faller, R; Satija, S; Kuhl, T L

2004-06-01

162

First case of anti-ganglioside GM1-positive Guillain-Barré syndrome due to hepatitis E virus infection.  

PubMed

A 51-year-old previously healthy woman presented with Guillain-Barré syndrome (GBS) and elevated liver enzymes. Further diagnostic investigations showed the presence of an acute hepatitis E infection associated with anti-ganglioside GM1 antibodies. After treatment with intravenous immunoglobulins, the patient made a rapid recovery. Here, we report the first case of GBS due to acute hepatitis E virus (HEV) infection associated with the presence of anti-ganglioside GM1 antibodies. We also review available literature on the association between acute HEV infection and GBS. PMID:21877179

Maurissen, I; Jeurissen, A; Strauven, T; Sprengers, D; De Schepper, B

2012-06-01

163

Nanomolar cholera toxin inhibitors based on symmetrical pentavalent ganglioside GM1os-sym-corannulenes.  

PubMed

Eight symmetric and pentavalent corannulene derivatives were functionalized with galactose and the ganglioside GM1-oligosaccharide (GM1os) via copper-catalyzed alkyne-azide cycloaddition (CuAAC) reactions. The compounds were evaluated for their ability to inhibit the binding of the pentavalent cholera toxin to its natural ligand, ganglioside GM1. In this assay, all ganglioside GM1os-sym-corannulenes proved to be highly potent nanomolar inhibitors of cholera toxin. PMID:23736158

Mattarella, Martin; Garcia-Hartjes, Jaime; Wennekes, Tom; Zuilhof, Han; Siegel, Jay S

2013-07-14

164

The application of GM (1,1) — Connection improved genetic algorithm in power load forecasting  

Microsoft Academic Search

In this paper, a GM (1, 1)-connection improved genetic algorithm (GM (1, 1)-IGA) is put forward to solve the problem of short-term load forecasting (STLF) in power system. While Traditional GM (1, 1) forecasting model is not accurate and the value of parameter OC is constant, the proposed algorithm could overcome these disadvantages. In order to construct optimal grey model

Wei Li; Zhu-hua Han

2007-01-01

165

GM 2 gangliosidosis in a Japanese Spaniel  

Microsoft Academic Search

A storage disease in a 2-year-old Japanese Spaniel resembled a GM2 gangliosidosis previously identified in a now extinct line of German Shorthaired Pointers. Despite a later appearance of signs in the Japanese Spaniel, the distribution, staining, and ultrastructure of the stored material were similar in the two breeds. Golgi studies of cerebral cortical neurons revealed the formation of spiny and

J. F. Cummings; P. A. Wood; S. U. Walkley; A. de Lahunta; M. E. DeForest

1985-01-01

166

GM1 ganglioside induces vasodilation and increases catalase content in the brain.  

PubMed

Monosialoganglioside (GM1) is a glycosphingolipid present in most cell membranes that displays antioxidant and neuroprotective properties. GM1 increases catalase activity in cerebral cortices in vivo, but the mechanisms underlying this effect of GM1 are not known. In the current study we investigated the effect of GM1 (50 mg/kg, ip) on the content of hemoglobin and catalase activity of hippocampus, cortex, and striatum of rats. GM1 administration increased catalase activity and hemoglobin content in brain samples after 30 min, but had no effect on blood catalase activity. GM1-induced increase in catalase activity was abolished by brain perfusion with heparinized saline. Brain catalase activity in the absence of blood, estimated by regression analysis of data from perfused and nonperfused animals, was not altered by the systemic injection of GM1. Moreover, the addition of GM1 (30 or 100 microM) did not increase catalase activity in slices of cerebral cortex in situ, further suggesting that blood circulation is required for this effect. The GM1-induced vasodilation was confirmed in vivo, because the systemic injection of GM1 (50 mg/kg, ip) increased (1.2-1.6 times) the width of pial vessels. PMID:17697937

Furian, Ana Flávia; Oliveira, Mauro Schneider; Royes, Luiz Fernando Freire; Fiorenza, Natália Gindri; Fighera, Michele Rechia; Myskiw, Jociane Carvalho; Weiblen, Rudi; Rubin, Maribel Antonello; Frussa-Filho, Roberto; Mello, Carlos Fernando

2007-09-15

167

Picomolar inhibition of cholera toxin by a pentavalent ganglioside GM1os-calix[5]arene.  

PubMed

Cholera toxin (CT), the causative agent of cholera, displays a pentavalent binding domain that targets the oligosaccharide of ganglioside GM1 (GM1os) on the periphery of human abdominal epithelial cells. Here, we report the first GM1os-based CT inhibitor that matches the valency of the CT binding domain (CTB). This pentavalent inhibitor contains five GM1os moieties linked to a calix[5]arene scaffold. When evaluated by an inhibition assay, it achieved a picomolar inhibition potency (IC50 = 450 pM) for CTB. This represents a significant multivalency effect, with a relative inhibitory potency of 100,000 compared to a monovalent GM1os derivative, making GM1os-calix[5]arene one of the most potent known CTB inhibitors. PMID:23689250

Garcia-Hartjes, Jaime; Bernardi, Silvia; Weijers, Carel A G M; Wennekes, Tom; Gilbert, Michel; Sansone, Francesco; Casnati, Alessandro; Zuilhof, Han

2013-07-14

168

A Korean patient with Morquio B disease with a novel c.13_14insA mutation in the GLB1 gene.  

PubMed

Mutations in the GLB1 gene, which encodes acid ?-galactosidase, can result in two disease phenotypes: GM1-gangliosidosis (MIM #230500) and Morquio B disease (Mucopolysaccharidosis type IVB, MIM #253010). Morquio B disease occurs much more infrequently than GM1-gangliodosis and is characterized by severe skeletal manifestations (dysostosis multiplex) without central nervous system involvement. Here, we report the first known Korean patient with Morquio B disease. A 7-year-old boy presented with severe progressive skeletal dysplasia including scoliosis, contractures of the elbows, xenu valgum, funnel chest, and trigger thumb requiring surgical intervention. The patient had normal neurological functions and mental status when evaluated by pediatric neurologists. The patient's urinary glycosaminoglycans, measured by the cetylpyridinium chloride (CPC) precipitation test, were 252.8 CPC unit/g creatinine (reference range < 175). Thin layer chromatography of urine showed a keratan sulfate band. Enzyme activity of ?-galactosidase in leukocytes was 1.15 nmol/hr/mg protein (reference range 78.1-117.7; 1-1.5% of normal). The patient had compound heterozygous mutations of the GLB1 gene: c.13_14insA (p.L5HfsX29), which was reported in a patient with infantile GM1 gangliosidosis with the near-complete absence of enzyme activity, and c.367G>A (p.G123R), which is a novel frame-shift mutation. In summary, we report the first known Korean patient with Morquio B disease and a novel mutation (c.13_14insA of GLB1). PMID:22371915

Sohn, Young Bae; Park, Hyung-Doo; Park, Sung Won; Kim, Se-Hwa; Cho, Sung-Yoon; Ko, Ah-Ra; Ki, Chang-Seok; Yeau, Sunghee; Jin, Dong-Kyu

2012-01-01

169

GM 1 monosialoganglioside pretreatment protects against soman-induced seizure-related brain damage  

Microsoft Academic Search

The effects of GM1 monosialoganglioside pretreatment on brain damage resulting from soman-induced seizure activity were examined in this study.\\u000a Male Sprague-Dawley rats were infused with GM1 via an osmotic minipump connected through a permanent cannula implanted intracerebroventricularly and challenged with soman\\u000a (83 ?g\\/kg, i.e., 1.25 × LD50) 4 d after initiation of GM1 infusion. Electrocorticographic recordings were monitored via indwelling

Gerald P. H. Ballough; Frank J. Cann; Catherine D. Smith; Jeffry S. Forster; Cathleen E. Kling; Margaret G. Filbert

1998-01-01

170

Lewis rats immunized with GM1 ganglioside do not develop peripheral neuropathy  

PubMed Central

Elevated levels of anti-GM1 antibodies are associated with motor nerve syndromes. Although there is a lot of circumstantial evidence that anti-GM1 antibodies may be causing the disease, their precise role remains unclear. In order to study the role of anti-GM1 antibodies in the pathogenesis of peripheral neuropathy, eight Lewis rats were injected with GM1 ganglioside mixed with keyhole limpet hemocyanin (KLH) and emulsified with Freund’s adjuvant and three rats were immunized with GM1 in liposomes. Although IgM class anti-GM1 antibodies were detected in all animals immunized with GM1, none of the animals exhibited overt signs of neuropathy during six months after initial immunization. IgG antibody to GM1 was not produced in any of the animals. There was no pathological evidence of nerve damage. These studies suggest that elevated levels of IgM anti-GM1 antibodies by themselves do not cause nerve damage in rats.

Ilyas, Amjad A.; Chen, Zi-Wei

2009-01-01

171

Lewis rats immunized with GM1 ganglioside do not develop peripheral neuropathy.  

PubMed

Elevated levels of anti-GM1 antibodies are associated with motor nerve syndromes. Although there is a lot of circumstantial evidence that anti-GM1 antibodies may be causing the disease, their precise role remains unclear. In order to study the role of anti-GM1 antibodies in the pathogenesis of peripheral neuropathy, eight Lewis rats were injected with GM1 ganglioside mixed with keyhole limpet hemocyanin (KLH) and emulsified with Freund's adjuvant and three rats were immunized with GM1 in liposomes. Although IgM class anti-GM1 antibodies were detected in all animals immunized with GM1, none of the animals exhibited overt signs of neuropathy during 6 months after initial immunization. IgG antibody to GM1 was not produced in any of the animals. There was no pathological evidence of nerve damage. These studies suggest that elevated levels of IgM anti-GM1 antibodies by themselves do not cause nerve damage in rats. PMID:17559947

Ilyas, Amjad A; Chen, Zi-Wei

2007-08-01

172

Ganglioside GM1 mimicry in Campylobacter strains from sporadic infections in the United States.  

PubMed

To determine whether GM1-like epitopes in Campylobacter species are specific to O serotypes associated with Guillain-Barré syndrome (GBS) or whether they are frequent among random Campylobacter isolates causing enteritis, 275 random enteritis-associated isolates of Campylobacter jejuni were analyzed. To determine whether GM1-like epitopes in Campylobacter species are specific to O serotypes associated with Guillan-Barre syndrome (GBS) or whether they are frequent among random Campylobacter isolates causing enteritis, 275 enteritis-associated isolates, randomly collected in the United States, were analyzed using a cholera-toxin binding assay [corrected]. Overall, 26.2% of the isolates were positive for the GM1-like epitope. Of the 36 different O serotypes in the sample, 21 (58.3%) contained no strains positive for GM1, whereas in 6 serotypes (16.7%), >50% of isolates were positive for GM1. GBS-associated serotypes were more likely to contain strains positive for GM1 than were non-GBS-associated serotypes (37.8% vs. 15.1%, P=.0116). The results suggest that humans are frequently exposed to strains exhibiting GM1-like mimicry and, while certain serotypes may be more likely to possess GM1-like epitopes, the presence of GM1-like epitopes on Campylobacter strains does not itself trigger GBS. PMID:10191221

Nachamkin, I; Ung, H; Moran, A P; Yoo, D; Prendergast, M M; Nicholson, M A; Sheikh, K; Ho, T; Asbury, A K; McKhann, G M; Griffin, J W

1999-05-01

173

MR Imaging and Proton Spectroscopy of Neuronal Injury in Late-Onset GM2 Gangliosidosis  

Microsoft Academic Search

BACKGROUND AND PURPOSE: Despite the ubiquity of GM2 gangliosides accumulation in patients with late-onset GM2 gangliosidosis (GM2G), the only clinical MR imaging-apparent brain abnormality is profound cerebellar atrophy. The goal of this study was to detect the presence and assess the extent of neuroaxonal injury in the normal-appearing gray and white matter (NAGM and NAWM) of these patients. METHODS: During

Matilde Inglese; Annette O. Nusbaum; Gregory M. Pastores; John Gianutsos; Edwin H. Kolodny; Oded Gonen

174

Substrate reduction therapy with miglustat in chronic GM2 gangliosidosis type Sandhoff: results of a 3-year follow-up  

Microsoft Academic Search

GM2 gangliosidosis type Sandhoff is caused by a defect of beta-hexosaminidase, an enzyme involved in the catabolism of gangliosides.\\u000a It has been proposed that substrate reduction therapy using N-butyl-deoxynojirimycin (miglustat) may delay neurological progression,\\u000a at least in late-onset forms of GM2 gangliosidosis. We report the results of a 3-year treatment with miglustat (100 mg t.i.d)\\u000a in a patient with chronic Sandhoff

Marcella Masciullo; Massimo Santoro; Anna Modoni; Enzo Ricci; Jerome Guitton; Pietro Tonali; Gabriella Silvestri

175

Condensing and Fluidizing Effects of Ganglioside GM1 on Phospholipid Films  

PubMed Central

Mixed monolayers of the ganglioside GM1 and the lipid dipalmitoylphosphatidlycholine (DPPC) at air-water and solid-air interfaces were investigated using various biophysical techniques to ascertain the location and phase behavior of the ganglioside molecules in a mixed membrane. The effects induced by GM1 on the mean molecular area of the binary mixtures and the phase behavior of DPPC were followed for GM1 concentrations ranging from 5 to 70 mol %. Surface pressure isotherms and fluorescence microscopy imaging of domain formation indicate that at low concentrations of GM1 (<25 mol %), the monolayer becomes continually more condensed than DPPC upon further addition of ganglioside. At higher GM1 concentrations (>25 mol %), the mixed monolayer becomes more expanded or fluid-like. After deposition onto a solid substrate, atomic force microscopy imaging of these lipid monolayers showed that GM1 and DPPC pack cooperatively in the condensed phase domain to form geometrically packed complexes that are more ordered than either individual component as evidenced by a more extended total height of the complex arising from a well-packed hydrocarbon tail region. Grazing incidence x-ray diffraction on the DPPC/GM1 binary mixture provides evidence that ordering can emerge when two otherwise fluid components are mixed together. The addition of GM1 to DPPC gives rise to a unit cell that differs from that of a pure DPPC monolayer. To determine the region of the GM1 molecule that interacts with the DPPC molecule and causes condensation and subsequent expansion of the monolayer, surface pressure isotherms were obtained with molecules modeling the backbone or headgroup portions of the GM1 molecule. The observed concentration-dependent condensing and fluidizing effects are specific to the rigid, sugar headgroup portion of the GM1 molecule.

Frey, Shelli L.; Chi, Eva Y.; Arratia, Cristobal; Majewski, Jaroslaw; Kjaer, Kristian; Lee, Ka Yee C.

2008-01-01

176

Late-onset GM2 gangliosidosis presenting as burning dysesthesias.  

PubMed

Two brothers with a painful neuropathy as a component of late-onset GM2 gangliosidosis of the Sandhoff type are presented. A dramatic response of the severe dysesthesias to amitriptyline and gabapentin is described. Symptomatic sensory neuropathy may be a component of late-onset GM2 gangliosidosis. PMID:11483398

Chow, G C; Clarke, J T; Banwell, B L

2001-07-01

177

Endocytosis of exogenous GM1 ganglioside and cholera toxin by neuroblastoma cells.  

PubMed Central

Cholera toxin (CT) covalently linked to horseradish peroxidase (HRP) is a specific cytochemical marker for its receptor, the monosialoganglioside GM1. The binding and endocytosis of exogenous [3H]GM1 by cultured murine neuroblastoma cells (line 2A [CCl-131] ), which contain predominantly GM3, was examined by quantitative electron microscope autoradiography. The relationship between exogenous receptor, [3H]GM1, and CT HRP was studied in double labeling experiments consisting of autoradiographic demonstration of [3H]GM1 and cytochemical visualization of HRP. Exogenous [3H]GM1 was not degraded after its endocytosis by cells for 2 h at 37 degrees C. Quantitative studies showed similar grain density distributions in cells treated with [3H]GM1 alone and in cells treated with [3H]GM1 followed by CT-HRP. Qualitative studies conducted in double labeling experiments showed autoradiographic grains over the peroxidase-stained plasma membrane, lysosomes, and vesicles at the trans aspect of the Golgi apparatus. The findings indicate that exogenous glycolipid is associated with the plasmid membrane of deficient cells and undergoes endocytosis. The quantitative ultra-structural autoradiographic studies are consistent with the hypothesis that the spontaneous endocytosis of exogenous [3H]GM1 controls the subsequent uptake of CT-HRP. Images

Gonatas, N K; Stieber, A; Gonatas, J; Mommoi, T; Fishman, P H

1983-01-01

178

Neurophysiological study in chronic GM2 gangliosidosis (hexosaminidase A and B deficiency), with motor neuron disease phenotype  

Microsoft Academic Search

We report the electrophysiological investigation of two adult cases with GM 2 gangliosidosis with hexosaminidase A and B deficiency. Superficial peroneal biopsy was obtained from one patient. The electrophysiological alterations of the peripheral nervous system were fasciculations, signs of collateral reinnervation and loss of motor units, decrease in sensory potential amplitude and increase in distal motor latency. Increase in N9-N13

M. Mondelli; A. Rossi; S. Palmeri; N. Rizzuto; A. Federico

1989-01-01

179

Condensing and fluidizing effects of ganglioside GM1 on phospholipid films.  

PubMed

Mixed monolayers of the ganglioside G(M1) and the lipid dipalmitoylphosphatidlycholine (DPPC) at air-water and solid-air interfaces were investigated using various biophysical techniques to ascertain the location and phase behavior of the ganglioside molecules in a mixed membrane. The effects induced by G(M1) on the mean molecular area of the binary mixtures and the phase behavior of DPPC were followed for G(M1) concentrations ranging from 5 to 70 mol %. Surface pressure isotherms and fluorescence microscopy imaging of domain formation indicate that at low concentrations of G(M1) (<25 mol %), the monolayer becomes continually more condensed than DPPC upon further addition of ganglioside. At higher G(M1) concentrations (>25 mol %), the mixed monolayer becomes more expanded or fluid-like. After deposition onto a solid substrate, atomic force microscopy imaging of these lipid monolayers showed that G(M1) and DPPC pack cooperatively in the condensed phase domain to form geometrically packed complexes that are more ordered than either individual component as evidenced by a more extended total height of the complex arising from a well-packed hydrocarbon tail region. Grazing incidence x-ray diffraction on the DPPC/G(M1) binary mixture provides evidence that ordering can emerge when two otherwise fluid components are mixed together. The addition of G(M1) to DPPC gives rise to a unit cell that differs from that of a pure DPPC monolayer. To determine the region of the G(M1) molecule that interacts with the DPPC molecule and causes condensation and subsequent expansion of the monolayer, surface pressure isotherms were obtained with molecules modeling the backbone or headgroup portions of the G(M1) molecule. The observed concentration-dependent condensing and fluidizing effects are specific to the rigid, sugar headgroup portion of the G(M1) molecule. PMID:18192361

Frey, Shelli L; Chi, Eva Y; Arratia, Cristóbal; Majewski, Jaroslaw; Kjaer, Kristian; Lee, Ka Yee C

2008-04-15

180

Intravenous immunoglobulin treatment on anti-GM1 antibodies associated neuropathies inhibits cholera toxin and galectin-1 binding to ganglioside GM1.  

PubMed

Intravenous immunoglobulin (IVIg) therapy is efficacious in some peripheral nervous autoimmune diseases associated with anti-GM1 antibodies. Numerous mechanisms of action have been proposed to account for the immunomodulatory effects of IVIg in immune-mediated diseases. Up to now, the mechanisms of action of IVIg in pathology associated with anti-GM1 antibodies have not been well documented. In the present study, we discovered that IVIg did not inhibit the binding of anti-GM1 antibodies to its antigen and IVIg perfusions did not reduce anti-GM1 antibodies titers. In this observation, we have the result different from the hypothesis of presence of anti-idiotypic antibodies in different IVIg preparations, and show that IVIg inhibits the binding of cholera toxin and galectin-1 to GM1-expressing cells using flow cytometry. Our results suggest that the correct ratio galactosyl/agalactosyl IgG in IVIg interact with macrophages receptors to down-regulate inflammatory function of macrophages and autoimmune diseases in peripheral nerve system. PMID:22289946

Peng, Wei

2012-04-30

181

Effects of Methylprednisolone And Ganglioside GM-1 on a Spinal Lesion: A Functional Analysis  

PubMed Central

OBJECTIVES The pharmacological effects of methylprednisolone (MP) and ganglioside GM-1 on spinal injuries have been thoroughly investigated, but only a few studies have evaluated the interaction between these two drugs. METHODS Twenty-four Wistar rats were subjected to contusive injury of the spinal cord produced by the NYU system. These animals were divided into four groups: group I was injected with MP; group II was injected with GM-1; group III was injected with MP together with GM-1; and group control received physiological serum. The animals were evaluated with regard to their recovery of locomotive function by means of the BBB test on the second, seventh and fourteenth days after receiving the contusive injury to the spinal cord. They were sacrificed on the fourteenth day. RESULTS This study demonstrated that the MP and GM-1 groups presented functional results that were better than those of the control group, although the enhanced recovery of group II (GM-1) relative to the control group was not statistically significant (p>0.05). The most notable recovery of locomotive function was observed in the group that received MP alone (p<0.05). The group that received MP together with GM-1 presented results that were better than those of the control group (p<0.05). CONCLUSION Administration of methylprednisolone alone or with GM-1 was shown to be effective for recovery of locomotive function. Combined administration of these drugs resulted in better outcomes than administration of methylprednisolone alone.

Carvalho, Marcio Oliveira Penna; de Barros Filho, Tarcisio Eloy Pessoa; Tebet, Marcos Antonio

2008-01-01

182

Ganglioside GM1 binds to the Trk protein and regulates receptor function.  

PubMed Central

Several lines of evidence have suggested that ganglioside GM1 stimulates neuronal sprouting and enhances the action of nerve growth factor (NGF), but its precise mechanism is yet to be elucidated. We report here that GM1 directly and tightly associates with Trk, the high-affinity tyrosine kinase-type receptor for NGF, and strongly enhances neurite outgrowth and neurofilament expression in rat PC12 cells elicited by a low dose of NGF that alone is insufficient to induce neuronal differentiation. The potentiation of NGF activity by GM1 appears to involve tyrosine-autophosphorylation of Trk, which contains intrinsic tyrosine kinase activity that has been localized to the cytoplasmic domain. In the presence of GM1 in culture medium, there is a > 3-fold increase in NGF-induced autophosphorylation of Trk as compared with NGF alone. We also found that GM1 could directly enhance NGF-activated autophosphorylation of immunoprecipitated Trk in vitro. Monosialoganglioside GM1, but not polysialogangliosides, is tightly associated with immunoprecipitated Trk. Furthermore, such tight association of GM1 with Trk appears to be specific, since a similar association was not observed with other growth factor receptors, such as low-affinity NGF receptor (p75NGR) and epidermal growth factor receptor (EGFR). Thus, these results strongly suggest that GM1 functions as a specific endogenous activator of NGF receptor function, and these enhanced effects appear to be due, at least in part, to tight association of GM1 with Trk. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4

Mutoh, T; Tokuda, A; Miyadai, T; Hamaguchi, M; Fujiki, N

1995-01-01

183

Ameliorating GM (1, 1) Model Based on the Structure of the Area under Trapezium  

NASA Astrophysics Data System (ADS)

According to the research on the structure of background value in the GM(1,1) model, the structure method of background value, a exact formula about the background value of ? (1)(t) in the region [k,k + 1],which is used when establishing GM(1,1), is established by integrating ? (1)(t) from k to k + 1 .The modeling precision and prediction precision of the ameliorating background value can be advanced. Moreover, the application area of GM(1,1) model can be enlarged. At last, the model of Chinese per-power is set up. Simulation examples show the effectiveness of the proposed approach.

Li, Cuifeng

184

Taurine-induced neuronal differentiation: the influence of calcium and the ganglioside GM1.  

PubMed

Taurine-induced differentiation was examined in the murine neuroblastoma Neuro-2a cell line in the presence or absence of the monosialoganglioside GM1 and under conditions in which Ca2+ levels were manipulated. Taurine (4 mM), GM1 (200 micrograms/ml), or taurine with GM1 were applied to culture media that contained either various concentrations of Ca2+ or the Ca2+ ionophore A23187. Taurine or GM1 and taurine with GM1 increased the number of cells emitting neurites above that found for controls. A significant interaction was found between treatment (taurine, GM1 or taurine + GM1) and the manipulations of Ca2+ levels, affecting the number of neurites and producing changes on the neuritic and perikaryal surfaces. Treatment with both taurine and taurine + GM1 and the various concentrations of Ca2+ resulted in a significant increase in neurite elongation. The Ca2+ ionophore A23187 in the presence of taurine or taurine + GM1 caused neurites to grow longer than observed in media containing Ca2+, either in a low concentration (about 125 microM) or at 1-2 mM. Taurine-treated cultures in the presence of extracellular Ca2+ or A23187 were characterized by surfaces with numerous microvillar, spine-like projections. This effect was enhanced with GM1 and was less pronounced in the medium containing low levels of Ca2+. Transmission electron microscopy of the taurine-stimulated neurons revealed an excessive number of clear-core vesicles (40-200 nm in diameter) in perikarya, neurites and neuritic varicosities and growth cones. In addition, numerous aggregates of intermediate filaments were seen. They were most abundant in the taurine + GM1 treated cultures. The taurine + A23187 cultures also exhibited numerous microtubules within the elongated processes. The different neuritic patterns induced by taurine under conditions in which Ca2+ levels were manipulated and/or when cells were exposed to exogenous GM1 suggest that taurine's actions depend in part on Ca2+ flux. PMID:2251936

Spoerri, P E; Caple, C G; Roisen, F J

1990-01-01

185

HPLC analysis of oligosaccharides in urine from oligosaccharidosis patients.  

PubMed

Analysis of urinary oligosaccharides by thin-layer chromatography (TLC) is used as screening procedure for 10 different lysosomal diseases. We tested the usefulness of HPLC in screening, using a CarboPac PA1 column (Dionex), pulsed amperometric detection (PAD), and post-column derivatization (PCD). Patterns from six types of oligosaccharidoses were compared with normal urinary patterns and with the TLC patterns. PAD appeared to be nonspecific and therefore is applicable only to desalted urine samples. PCD was more specific and applicable to nondesalted urine samples, albeit with a lower resolving power. Peaks in urines from oligosaccharidoses patients were identified on the basis of retention times of commercially available oligosaccharides or TLC bands after isolation and HPLC of the corresponding oligosaccharides. Abnormal oligosaccharide peaks were seen in urines from patients with alpha-mannosidosis, GM1-gangliosidosis (juvenile), GM2-gangliosidosis (Sandhoff disease), Pompe disease, and beta-mannosidosis. HPLC detected no abnormal oligosaccharides in urine from patients with fucosidosis. Although TLC is a simple and reliable screening procedure for detecting classical lysosomal diseases with oligosaccharide excretion, HPLC, by its higher resolution and possibility of quantification, can more generally be used for recognition of abnormal oligosaccharides or detection of increased excretion or content for known oligosaccharides in urine, other body fluids, and cells. PMID:8087986

Peelen, G O; de Jong, J G; Wevers, R A

1994-06-01

186

Enzymological diagnosis of a group of lysosomal storage diseases. Review of 5-year experience of 1600 patient-sample referrals.  

PubMed

Lysosomal acid hydrolase activities have been measured in extracts of peripheral blood leucocytes of approximately 1600 patients referred from throughout Australia, each of whom was suspected of having a neurolipidosis. Assays for 12 different lysosomal enzymes were performed on each patient as a routine; ten assay systems were based on commercially available substrates, and four used radiolabelled glycosphingolipids prepared in our own laboratory. Of the 85 patients with positive results, 81 were diagnosed as being homozygous-deficient for a particular lysosomal enzyme. These patients comprised nine with GM1-gangliosidosis, 12 with GM2-gangliosidosis (11 of Tay-Sachs' disease and one of Sandhoff's disease), 18 with trihexosylceramide lipidosis (Fabry's disease), eight with beta-galactosylceramide lipidosis (Krabbe's disease), 14 with beta-glucosylceramide lipidosis (Gaucher's disease), two with sphingomyelin lipidosis (Niemann-Pick disease), 13 with metachromatic leucodystrophy and five with alpha-mannosidosis. In addition, four patients were diagnosed as being affected with mucolipidosis Type II (I-cell disease), based on elevated plasma lysosomal enzyme activities, making a total of 85 homozygous-affected patients. Clinically the patients showed wide phenotypic variability within each of the enzyme-deficient states, which did not appear to correlate with the level of "residual" enzyme activity in their leucocyte extracts. PMID:6780772

Pollard, A C; Carey, W F; Nelson, P V; Poulos, A; Hill, G N

1980-11-15

187

Late onset GM2 gangliosidosis presenting with motor neuron disease: An autopsy case.  

PubMed

Adult-onset GM2 gangliosidosis is very rare and only three autopsy cases have been reported up to now. We report herein an autopsy case of adult-onset GM2 gangliosidosis. The patient developed slowly progressive motor neuron disease-like symptoms after longstanding mood disorder and cognitive dysfunction. He developed gait disturbance and weakness of lower limbs at age 52 years. Because of progressive muscle weakness and atrophy, he became bed-ridden at age 65. At age of 68, he died. His neurological findings presented slight cognitive disturbance, slight manic state, severe muscle weakness, atrophy of four limbs and no extrapyramidal signs and symptoms, and cerebellar ataxia. Neuropathologically, mild neuronal loss and abundant lipid deposits were noted in the neuronal cytoplasm throughout the nervous system, including peripheral autonomic neurons. The most outstanding findings were marked neuronal loss and distended neurons in the anterior horn of the spinal cord, which supports his clinical symptomatology of lower motor neuron disease in this case. The presence of lipofuscin, zebra bodies and membranous cytoplasmic bodies (MCB) and the increase of GM2 ganglioside by biochemistry led to diagnosis of GM2 gangliosidosis. PMID:24354582

Yokoyama, Teruo; Nakamura, Seigo; Horiuchi, Emiko; Ishiyama, Miyako; Kawashima, Rei; Nakamura, Kazuo; Hasegawa, Kazuko; Yagishita, Saburo

2014-06-01

188

Clostridium perfringens Alpha-toxin Recognizes the GM1a-TrkA Complex*  

PubMed Central

Clostridium perfringens alpha-toxin is the major virulence factor in the pathogenesis of gas gangrene. Alpha-toxin is a 43-kDa protein with two structural domains; the N-domain contains the catalytic site and coordinates the divalent metal ions, and the C-domain is a membrane-binding site. The role of the exposed loop region (72–93 residues) in the N-domain, however, has been unclear. Here we show that this loop contains a ganglioside binding motif (H … SXWY … G) that is the same motif seen in botulinum neurotoxin and directly binds to a specific conformation of the ganglioside Neu5Ac?2-3(Gal?1-3GalNAc?1-4)Gal?1-4Glc?1Cer (GM1a) through a carbohydrate moiety. Confocal microscopy analysis using fluorescently labeled BODIPY-GM1a revealed that the toxin colocalized with GM1a and induced clustering of GM1a on the cell membranes. Alpha-toxin was only slightly toxic in ?1,4-N-acetylgalactosaminyltransferase knock-out mice, which lack the a-series gangliosides that contain GM1a, but was highly toxic in ?2,8-sialyltransferase knock-out mice, which lack both b-series and c-series gangliosides, similar to the control mice. Moreover, experiments with site-directed mutants indicated that Trp-84 and Tyr-85 in the exposed alpha-toxin loop play an important role in the interaction with GM1a and subsequent activation of TrkA. These results suggest that binding of alpha-toxin to GM1a facilitates the activation of the TrkA receptor and induces a signal transduction cascade that promotes the release of chemokines. Therefore, we conclude that GM1a is the primary cellular receptor for alpha-toxin, which can be a potential target for drug developed against this pathogen.

Oda, Masataka; Kabura, Michiko; Takagishi, Teruhisa; Suzue, Ayaka; Tominaga, Kaori; Urano, Shiori; Nagahama, Masahiro; Kobayashi, Keiko; Furukawa, Keiko; Furukawa, Koichi; Sakurai, Jun

2012-01-01

189

Amyloid-? induced toxicity involves ganglioside expression and is sensitive to GM1 neuroprotective action.  

PubMed

The effect of A?25-35 peptide, in its fibrillar and non-fibrillar forms, on ganglioside expression in organotypic hippocampal slice cultures was investigated. Gangliosides were endogenously labeled with D-[1-C(14)] galactose and results showed that A?25-35 affected ganglioside expression, depending on the peptide aggregation state, that is, fibrillar A?25-35 caused an increase in GM3 labeling and a reduction in GD1b labeling, whereas the non-fibrillar form was able to enhance GM1 expression. Interestingly, GM1 exhibited a neuroprotective effect in this organotypic model, since pre-treatment of the hippocampal slices with GM1 10 ?M was able to prevent the toxicity triggered by the fibrillar A?25-35, when measured by propidium iodide uptake protocol. With the purpose of further investigating a possible mechanism of action, we analyzed the effect of GM1 treatment (1, 6, 12 and 24h) upon the A?-induced alterations on GSK3? dephosphorylation/activation state. Results demonstrated an important effect after 24-h incubation, with GM1 preventing the A?-induced dephosphorylation (activation) of GSK3?, a signaling pathway involved in apoptosis triggering and neuronal death in models of Alzheimer's disease. Taken together, present results provide a new and important support for ganglioside participation in development of Alzheimer's disease experimental models and suggest a protective role for GM1 in A?-induced toxicity. This may be useful for designing new therapeutic strategies for Alzheimer's treatment. PMID:21723896

Kreutz, Fernando; Frozza, Rudimar L; Breier, Ana Carolina; de Oliveira, Valeska A; Horn, Ana Paula; Pettenuzzo, Letícia F; Netto, Carlos Alexandre; Salbego, Christianne Gazzana; Trindade, Vera Maria Treis

2011-10-01

190

Presence of sodium-calcium exchanger/GM1 complex in the nuclear envelope of non-neural cells: nature of exchanger-GM1 interaction.  

PubMed

Previous studies have revealed the presence of Na+ / Ca2+ exchanger (NCX) activity associated with GM1 ganglioside in the nuclear envelope (NE) of neurons and glia as well as various neural cell lines. The nuclear NCX1 exchanger, unlike that in the plasma membrane, was shown to be tightly associated with GM1 and potentiated by the latter. One non-neural cell line, Jurkat, was found to contain no Na+ / Ca2+ exchanger of the NCX1, NCX2, or NCX3 types in either nuclear or plasma membrane. To determine whether such absence in the NE is generally characteristic of non-neural cells we have examined two more such cell lines in addition to human lymphocytes. RT-PCR showed NCX1 expression in both HeLa and NCTC cell lines and also NCX2 in the latter; NCX3, a subtype previously observed in NG108-15 cells, was not expressed in either. Immunocytochemical and immunoblot studies indicated NCX1 on the cell surface and nuclear envelope of both cell types. Some alternatively spliced isoforms of NCX1 in the nuclear envelope of both cell types were tightly associated with ganglioside GM1. Human lymphocytes, a mixed population of T and B cells, showed similar evidence for plasma membrane and nuclear expression in some but not all cells. The high affinity association between NCX1 and GM1, explored by reaction with base, acid, and proteases, was found to involve charge-charge interaction with a requirement for a positively charged moiety in NCX. PMID:15662848

Xie, Xin; Wu, Gusheng; Lu, Zi-Hua; Rohowsky-Kochan, Christine; Ledeen, Robert W

2004-11-01

191

Interaction of bee venom toxin melittin with ganglioside GM1 bicelle.  

PubMed

Melittin is a bee venom toxin that can act as antimicrobial peptide. Gangliosides are glycosphingolipids that help maintain membrane structure and organization as well as act as anchors for lectins, toxins, pathogens and antimicrobial peptides. Here we investigate interaction of melittin with fast tumbling isotropic control DMPC/CHAPS bicelles and ganglioside doped DMPC/CHAPS/GM1 bicelles. DOSY result shows that larger percentage of peptide binds to GM1 containing bicelles than that of the control PC bicelles. Bound peptide induces leakage of the bicelles entrapped carboxyfluorescein. Percentage of leakage is higher from control PC bicelles than that of the GM1 containing bicelles. In the presence of control PC bicelles melittin acquired fully ?-helical structure. But in the presence of GM1 containing bicelles the peptide is not fully ?-helical i.e., some random coil structure is present in this folded form. The present study shows that GM1 has an effect on membrane active antimicrobial peptide melittin. PMID:23850803

Khatun, Ummul Liha; Mukhopadhyay, Chaitali

2013-01-01

192

GM2 gangliosidosis in British Jacob sheep.  

PubMed

GM2 gangliosidosis (Tay-Sachs disease) was diagnosed in 6- to 8-month-old pedigree Jacob lambs from two unrelated flocks presenting clinically with progressive neurological dysfunction of 10 day's to 8 week's duration. Clinical signs included hindlimb ataxia and weakness, recumbency and proprioceptive defects. Histopathological examination of the nervous system identified extensive neuronal cytoplasmic accumulation of material that stained with periodic acid--Schiff and Luxol fast blue. Electron microscopy identified membranous cytoplasmic bodies within the nervous system. Serum biochemistry detected a marked decrease in hexosaminidase A activity in the one lamb tested, when compared with the concentration in age matched controls and genetic analysis identified a mutation in the sheep hexa allele G444R consistent with Tay-Sachs disease in Jacob sheep in North America. The identification of Tay-Sachs disease in British Jacob sheep supports previous evidence that the mutation in North American Jacob sheep originated from imported UK stock. PMID:24309906

Wessels, M E; Holmes, J P; Jeffrey, M; Jackson, M; Mackintosh, A; Kolodny, E H; Zeng, B J; Wang, C B; Scholes, S F E

2014-01-01

193

Ordering Transitions in Micrometer-Thick Films of Nematic Liquid Crystals Driven by Self-Assembly of Ganglioside GM1  

PubMed Central

We report an investigation of the self-assembly of the monosialoganglioside (GM1) at interfaces formed between aqueous solutions of 10 µM GM1 (at 25°C) and micrometer-thick films of the nematic liquid crystal (LC) 4’-pentyl-4-cyanobiphenyl (5CB). We observe the process of spontaneous transfer of GM1 onto the interfaces to be accompanied by continuous ordering transitions within the micrometer-thick films of the LC. At saturation coverage, the GM1 orders the LC in an orientation that is perpendicular to the interface, an orientation that is similar to that caused by phospholipids such as dilaurylphosphatidylcholine (DLPC). This result suggests an interaction between the LC and GM1 that is dominated by the hydrophobic tails of the GM1. Relative to DLPC, however, we observe the dynamics of the LC ordering transition driven by GM1 to be slow (2 hours for DLPC versus 100 hours for GM1). To provide insight into the origins of the slow dynamics of the GM1-induced ordering transition in the LC, we performed two additional measurements. First, we quantified the time-dependent adsorption of GM1 at the LC interface by using fluorescently-labeled GM1. Second, we used the Langmuir-Schaefer method to transfer preorganized monolayers of GM1 from an air-water interface to the aqueous-LC interface. Results obtained from these two experiments are consistent with a physical picture in which the final stages of spontaneous adsorption/ordering of GM1 at the aqueous-LC interface dictate the dynamics of the LC ordering transition. This rate limiting process underlying the ordering transition was substantially accelerated by heating the system above the phase transition temperature of GM1 (26 °C), suggesting that the phase state of the GM1 micellar aggregates in bulk solution strongly influences the kinetics of the final stages of ordering/adsorption of GM1 at the LC interface. Overall, these results and others presented in this manuscript reveal that it is possible to decorated interfaces of a nematic LC with GM1, and that the assembly of GM1 at these interfaces impacts the dynamic and equilibrium ordering of the LC.

Lin, I-Hsin; Meli, Maria-Victoria; Abbott, Nicholas L.

2009-01-01

194

Substrate reduction therapy with miglustat in chronic GM2 gangliosidosis type Sandhoff: results of a 3-year follow-up.  

PubMed

GM2 gangliosidosis type Sandhoff is caused by a defect of beta-hexosaminidase, an enzyme involved in the catabolism of gangliosides. It has been proposed that substrate reduction therapy using N-butyl-deoxynojirimycin (miglustat) may delay neurological progression, at least in late-onset forms of GM2 gangliosidosis. We report the results of a 3-year treatment with miglustat (100 mg t.i.d) in a patient with chronic Sandhoff disease manifesting with an atypical, spinal muscular atrophy phenotype. The follow-up included serial neurological examinations, blood tests, abdominal ultrasound, and neurophysiologic, cognitive, brain, and muscle MRI studies. We document some minor effects on neurological progression in chronic Sandhoff disease by miglustat treatment, confirming the necessity of phase II therapeutic trials including early-stage patients in order to assess its putative efficacy in chronic Sandhoff disease. PMID:20821051

Masciullo, Marcella; Santoro, Massimo; Modoni, Anna; Ricci, Enzo; Guitton, Jerome; Tonali, Pietro; Silvestri, Gabriella

2010-12-01

195

Clinical, enzymatic, and molecular characterisation of a Portuguese family with a chronic form of GM2-gangliosidosis B1 variant  

Microsoft Academic Search

Mutations in the hexosaminidase A gene (HEXA) causing the B1 variant of GM2-gangliosidosis result in the presence of a mutant enzyme protein with a catalytically defective alpha subunit. A rare and panethnically distributed mutation, transition G533A (Arg178His), is known to be a common allele among Portuguese patients with the subacute phenotype. We now report the presence of an Arg178His allele

M G Ribeiro; T Sonin; R A Pinto; A Fontes; H Ribeiro; E Pinto; M M Palmeira; M C Sá Miranda

1996-01-01

196

Synthesis of novel NBD-GM1 and NBD-GM2 for the transfer activity of GM2-activator protein by a FRET-based assay system.  

PubMed

The ganglioside-activator protein is an essential cofactor for the lysosomal degradation of ganglioside GM2 (GM2) by beta-hexosaminidase A. It mediates the interaction between the water-soluble exohydrolase and its membrane-embedded glycolipid substrate at the lipid-water interphase. Mutations in the gene encoding this glycoprotein result in a fatal neurological storage disorder, the AB variant of GM2-gangliosidosis. In order to efficiently and sensitively probe the glycolipid binding and membrane activity of this cofactor, we synthesized two new fluorescent glycosphingolipid (GSL) probes, 2-NBD-GM1 and 2-NBD-GM2. Both compounds were synthesized in a convergent and multistep synthesis starting from the respective gangliosides isolated from natural sources. The added functionality of 2-aminogangliosides allowed us to introduce the chromophore into the region between the polar head group and the hydrophobic anchor of the lipid. Both fluorescent glycolipids exhibited an extremely low off-rate in model membranes and displayed very efficient resonance energy transfer to rhodamine-dioleoyl phosphoglycerol ethanolamine (rhodamine-PE) as acceptor. The binding to GM2-activator protein (GM2AP) and the degrading enzyme was shown to be unaltered compared to their natural analogues. A novel fluorescence-resonance energy transfer (FRET) assay was developed to monitor in real time the protein-mediated intervesicular transfer of these lipids from donor to acceptor liposomes. The data obtained indicate that this rapid and robust system presented here should serve as a valuable tool to probe quantitatively and comprehensively the membrane activity of GM2AP and other sphingolipid activator proteins and facilitate further structure-function studies aimed at delineating independently the lipid- and the enzyme-binding mode of these essential cofactors. PMID:16079415

Schwarzmann, Günter; Wendeler, Michaela; Sandhoff, Konrad

2005-12-01

197

Effect of GM1 ganglioside after focal cerebral ischemia in halothane-anesthetized cats.  

PubMed

The effect of the ganglioside GM1 was studied in a focal cerebral ischemia model in 30 cats consisting of 2 hours of middle cerebral artery occlusion followed by 4 hours of recirculation. The cerebrocortical electrical activity, extracellular potassium activity, and microcirculation indicated by NAD/NADH fluorescence were measured during occlusion as well as during recirculation in the core of the middle cerebral artery territory, while the cerebral metabolic rate for glucose (ICMRgl) was measured at the end of recirculation. The cats were classified into either mildly or moderately severe stroke groups based on the depression of the cerebrocortical electrical activity on the occluded side. Of 12 cats with only a mild stroke, six were administered GM1 intravenously 30 minutes after occlusion, while six cats were not treated. Of 12 cats with a moderate stroke, six were treated and six were left untreated. In six additional cats, only a sham insult was undertaken. In the cats with mild stroke, GM1 treatment significantly increased lCMRgl in the peripheral middle cerebral artery territory compared with the untreated cats; for the six treated cats, lCMRgl was normalized toward the control level, whereas it was depressed in the six untreated cats. There were no other significant effects of GM1 treatment on the other measured parameters. A potential protective effect of anesthesia is discussed. PMID:2728048

Urbanics, R; Greenberg, J H; Toffano, G; Reivich, M

1989-06-01

198

GLTP Mediated Non-Vesicular GM1 Transport between Native Membranes  

PubMed Central

Lipid transfer proteins (LTPs) are emerging as key players in lipid homeostasis by mediating non-vesicular transport steps between two membrane surfaces. Little is known about the driving force that governs the direction of transport in cells. Using the soluble LTP glycolipid transfer protein (GLTP), we examined GM1 (monosialotetrahexosyl-ganglioside) transfer to native membrane surfaces. With artificial GM1 donor liposomes, GLTP can be used to increase glycolipid levels over natural levels in either side of the membrane leaflet, i.e., external or cytosolic. In a system with native donor- and acceptor-membranes, we find that GLTP balances highly variable GM1 concentrations in a population of membranes from one cell type, and in addition, transfers lipids between membranes from different cell types. Glycolipid transport is highly efficient, independent of cofactors, solely driven by the chemical potential of GM1 and not discriminating between the extra- and intracellular membrane leaflet. We conclude that GLTP mediated non-vesicular lipid trafficking between native membranes is driven by simple thermodynamic principles and that for intracellular transport less than 1 µM GLTP would be required in the cytosol. Furthermore, the data demonstrates the suitability of GLTP as a tool for artificially increasing glycolipid levels in cellular membranes.

Mjumjunov-Crncevic, Esmina; Walrafen, David; Spitta, Luis; Thiele, Christoph; Lang, Thorsten

2013-01-01

199

Coexpression of Ganglioside Antigen Fuc-GM1, Neural-Cell Adhesion Molecule, Carcinoembryonic Antigen, and Carbohydrate Tumor-Associated Antigen CA 50 in Lung Cancer  

Microsoft Academic Search

With the aid of specific monoclonal antibodies, tumor tissues from 68 patients with lung cancer were examined for their expression of two small cell lung carcinoma (SCLC) antigens, Fuc-GMl (fucosyl GM1; IV2FucII3NeuAc GgOse4) and neural-cell adhesion molecule (NCAM), and two broader tumor antigens, carcinoembryonic antigen (CEA) and carbohydrate cancer-associated antigen CA 50. Expression of Fuc-GMl was seen in 75% and

Fred-Thomas Brezicka; Sante Olling; Bengt Bergman; Håkan Berggren; Carl-Peter Engström; Sten Hammarström; Jan Holmgren; Sture Larsson; Leif Lindholm

1992-01-01

200

Host Factors Determine Anti-GM1 Response Following Oral Challenge of Chickens with Guillain-Barr? Syndrome Derived Campylobacter jejuni Strain GB11  

PubMed Central

Background Anti-ganglioside antibodies with a pathogenic potential are present in C. jejuni-associated Guillain-Barré syndrome (GBS) patients and are probably induced by molecular mimicry. Immunization studies in rabbits and mice have demonstrated that these anti-ganglioside antibodies can be induced using purified lipo-oligosaccharides (LOS) from C. jejuni in a strong adjuvant. Methodology/Principal Findings To investigate whether natural colonization of chickens with a ganglioside-mimicking C. jejuni strain induces an anti-ganglioside response, and to investigate the diversity in anti-ganglioside response between and within genetically different chicken lines, we orally challenged chickens with different C. jejuni strains. Oral challenge of chickens with a C. jejuni strain from a GBS patient, containing a LOS that mimics ganglioside GM1, induced specific IgM and IgG anti-LOS and anti-GM1 antibodies. Inoculation of chickens with the Penner HS:3 serostrain, without a GM1-like structure, induced anti-LOS but no anti-ganglioside antibodies. We observed different patterns of anti-LOS/ganglioside response between and within the five strains of chickens. Conclusions Natural infection of chickens with C. jejuni induces anti-ganglioside antibodies. The production of antibodies is governed by both microbial and host factors.

Ang, C. Wim; Dijkstra, Jeroen R.; de Klerk, Marcel A.; Endtz, Hubert Ph.; van Doorn, Pieter A.; Jacobs, Bart C.; Wagenaar, Jaap A.

2010-01-01

201

Pyrimethamine as a potential pharmacological chaperone for late-onset forms of GM2 gangliosidosis.  

PubMed

Late-onset GM2 gangliosidosis is composed of two related, autosomal recessive, neurodegenerative diseases, both resulting from deficiency of lysosomal, heterodimeric beta-hexosaminidase A (Hex A, alphabeta). Pharmacological chaperones (PC) are small molecules that can stabilize the conformation of a mutant protein, allowing it to pass the quality control system of the endoplasmic reticulum. To date all successful PCs have also been competitive inhibitors. Screening for Hex A inhibitors in a library of 1040 Food Drug Administration-approved compounds identified pyrimethamine (PYR (2,4-diamino 5-(4-chlorophenyl)-6-ethylpyrimidine)) as the most potent inhibitor. Cell lines from 10 late-onset Tay-Sachs (11 alpha-mutations, 2 novel) and 7 Sandhoff (9 beta-mutations, 4 novel) disease patients, were cultured with PYR at concentrations corresponding to therapeutic doses. Cells carrying the most common late-onset mutation, alphaG269S, showed significant increases in residual Hex A activity, as did all 7 of the beta-mutants tested. Cells responding to PC treatment included those carrying mutants resulting in reduced Hex heat stability and partial splice junction mutations of the inherently less stable alpha-subunit. PYR, which binds to the active site in domain II, was able to function as PC even to domain I beta-mutants. We concluded that PYR functions as a mutation-specific PC, variably enhancing residual lysosomal Hex A levels in late-onset GM2 gangliosidosis patient cells. PMID:17237499

Maegawa, Gustavo H B; Tropak, Michael; Buttner, Justin; Stockley, Tracy; Kok, Fernando; Clarke, Joe T R; Mahuran, Don J

2007-03-23

202

The Mechanism of Polyplexes Internalization into Cells: Testing the GM1/Caveolin-1-Mediated Lipid Raft Mediated Endocytosis Pathway  

PubMed Central

The GM1/caveolin-1 lipid raft mediated endocytosis mechanism was explored for generation 5 and 7 poly(amidoamine) dendrimer polyplexes employing the Cos-7, 293A, C6, HeLa, KB, and HepG2 cell lines. Expression levels of GM1 and caveolin-1 were measured using Dot Blot and Western Blot, respectively. The level of GM1 in the cell plasma membrane was adjusted by incubation with exogenous GM1 or ganglioside inhibitor PPMP and the level of CAV-1 was adjusted by up-regulation with the adenovirus vector expressed Caveolin-1(AdCav-1). Cholera toxin B subunit was employed as a positive control for uptake in all cases. No evidence was found for a GM1/caveolin-1 lipid raft mediated endocytosis mechanism for the generation 5 and 7 poly(amidoamine) dendrimer polyplexes.

Mullen, Douglas G.; Baker, James R.

2010-01-01

203

A case of GM2 gangliosidosis of late onset  

Microsoft Academic Search

A case of GM2-gangliosidosis commencing by the age of 5 years is described, in which hyperacusis, dementia, and fits were prominent clinical features. In addition to the typical ganglioside pattern on thin layer chromatography and the presence of membranous bodies in electron microscopic studies and characteristic histology and histochemistry, there was biochemical evidence of a gross reduction in heat-labile hexosaminidase

P. Buxton; J. N. Cumings; R. B. Ellis; B. D. Lake; W. G. P. Mair; J. R. Roberts; E. P. Young

1972-01-01

204

Molecular and Clinical Heterogeneity of Adult GM2 Gangliosidosis  

Microsoft Academic Search

Adult GM2 gangliosidosis is a rare autosomal recessive disease with widely varying neurological and psychiatric manifestations. It is caused by marked deficiency, but not total absence, of ?-hexosaminidase (Hex) A, due to a single base change in the ?-subunit gene of Hex, resulting in a substitution of Ser for Gly at position 269 in the ?-subunit of the enzyme. The

Ruth Navon

1991-01-01

205

A first total synthesis of a novel sulfated ganglioside, 3'-O-sulfo-GM1b.  

PubMed

A first total synthesis of a novel sulfated ganglioside, 3'-O-sulfo-GM1b, is described. The suitably protected gangliotriose (GgOSe3) derivative, 2-(trimethylsilyl)ethyl (2-acetamido-4,6-O-benzylidene-2-deoxy-beta-D-galactopyranosyl)-(1-->4)-(2,6-di-O-benzyl-3-O-p-methoxybenzyl-beta-D-galactopyranosyl)-(1-->4)-2,3,6-tri-O-benzyl-beta-D-glucopyranoside was glycosylated with the alpha-NeuAc-(2-->3)-galactose donor to give the protected GM1b oligosaccharide (95%). After proper manipulation of the protecting groups, the oligosaccharide was converted into the target ganglioside by the successive introduction of the ceramide and sulfo groups, followed by complete deprotection. PMID:12423971

Komori, Tatsuki; Kondo, Saori; Ando, Hironume; Ishida, Hideharu; Kiso, Makoto

2002-10-01

206

GM1 structure determines SV40-induced membrane invagination and infection  

Microsoft Academic Search

Incoming simian virus 40 (SV40) particles enter tight-fitting plasma membrane invaginations after binding to the carbohydrate moiety of GM1 gangliosides in the host cell plasma membrane through pentameric VP1 capsid proteins. This is followed by activation of cellular signalling pathways, endocytic internalization and transport of the virus via the endoplasmic reticulum to the nucleus. Here we show that the association

Helge Ewers; Winfried Römer; Alicia E. Smith; Kirsten Bacia; Serge Dmitrieff; Wengang Chai; Roberta Mancini; Jürgen Kartenbeck; Valérie Chambon; Ludwig Berland; Ariella Oppenheim; Günter Schwarzmann; Ten Feizi; Petra Schwille; Pierre Sens; Ludger Johannes; Ari Helenius

2009-01-01

207

The immunohistochemical localization of the glycosphingolipid asialo-GM1 in the intestine of weaned piglets.  

PubMed

The duodenum, jejunum, ileum, cecum and colon of three male hybrid piglets, 4 weeks old just after weaning, were investigated for the immunohistochemical localization of the asialoganglioside, GM1 (asialo-GM1). The study revealed various degrees of labelling for this acid glycosphingolipid in neural, epithelial and blood elements in all the gut segments. The immunolabelled neural structures, represented by ganglionic perikarya and nerve fibers, were distributed throughout the intestinal wall and showed quantitative variations in the various regions. In contrast the numerical evaluation of labelled epithelial cells was encountered only in the terminal jejunum and along the entire ileum, cecum and large intestine. In addition, a heterogeneous population of immunolabelled leukocytes was spread randomly in the lamina propria and submucosa of the entire intestine and did not show any apparent quantitative fluctuations between the different parts. The observations regarding the typical distribution patterns of the asialoganglioside GM1 in ganglionic perikarya and epithelial cells of weaned piglets are discussed in relation to their possible functional significance in the intestine and other mammalian organs. PMID:19740529

Trandaburu, Ioana; Oswald, Isabelle P; Trandaburu, Tiberiu

2011-02-01

208

Ganglioside G M1 metabolism in living human fibroblasts with ?-galactosidase deficiency  

Microsoft Academic Search

The uptake and catabolism of [3H-ceramide]-GM1 was followed in living fibroblasts from patient with different forms of ß-galactosidase deficiency. Gangliosides are identified according to the nomenclature of Svennerholm (1963). A total inability to metabolize the ingested substrate was found in infantile GM1-gangliosidosis whereas cells from an adult GM1-gangliosidosis variant showed a slower rate of degradation, compared with controls. Morquio B

G. M. S. Mancini; A. T. Hoogeveen; H. Galjaard; J. E. Mansson; L. Svennerholm

1986-01-01

209

An inversion of 25 base pairs causes feline G M2 gangliosidosis variant 0  

Microsoft Academic Search

In GM2 gangliosidosis variant 0, a defect in the ?-subunit of lysosomal ?-N-acetylhexosaminidase (EC 3.2.1.52) causes abnormal accumulation of GM2 ganglioside and severe neurodegeneration. Distinct feline models of GM2 gangliosidosis variant 0 have been described in both domestic shorthair and Korat cats. In this study, we determined that the causative mutation of GM2 gangliosidosis in the domestic shorthair cat is

Douglas R. Martin; Barbara K. Krum; G. S. Varadarajan; Terri L. Hathcock; Bruce F. Smith; Henry J. Baker

2004-01-01

210

Mutations in the GM1 binding site of simian virus 40 VP1 alter receptor usage and cell tropism.  

PubMed

Polyomaviruses are nonenveloped viruses with capsids composed primarily of 72 pentamers of the viral VP1 protein, which forms the outer shell of the capsid and binds to cell surface oligosaccharide receptors. Highly conserved VP1 proteins from closely related polyomaviruses recognize different oligosaccharides. To determine whether amino acid changes restricted to the oligosaccharide binding site are sufficient to determine receptor specificity and how changes in receptor usage affect tropism, we studied the primate polyomavirus simian virus 40 (SV40), which uses the ganglioside GM1 as a receptor that mediates cell binding and entry. Here, we used two sequential genetic screens to isolate and characterize viable SV40 mutants with mutations in the VP1 GM1 binding site. Two of these mutants were completely resistant to GM1 neutralization, were no longer stimulated by incorporation of GM1 into cell membranes, and were unable to bind to GM1 on the cell surface. In addition, these mutant viruses displayed an infection defect in monkey cells with high levels of cell surface GM1. Interestingly, one mutant infected cells with low cell surface GM1 more efficiently than wild-type virus, apparently by utilizing a different ganglioside receptor. Our results indicate that a small number of mutations in the GM1 binding site are sufficient to alter ganglioside usage and change tropism, and they suggest that VP1 divergence is driven primarily by a requirement to accommodate specific receptors. In addition, our results suggest that GM1 binding is required for vacuole formation in permissive monkey CV-1 cells. Further study of these mutants will provide new insight into polyomavirus entry, pathogenesis, and evolution. PMID:22514351

Magaldi, Thomas G; Buch, Michael H C; Murata, Haruhiko; Erickson, Kimberly D; Neu, Ursula; Garcea, Robert L; Peden, Keith; Stehle, Thilo; DiMaio, Daniel

2012-07-01

211

Distribution of ganglioside GM1 in L-alpha-dipalmitoylphosphatidylcholine/cholesterol monolayers: a model for lipid rafts.  

PubMed

The distribution of low concentrations of ganglioside GM1 in L-alpha-dipalmitoylphosphatidylcholine (DPPC) and DPPC/cholesterol monolayers supported on mica has been studied using atomic force microscopy (AFM). The monolayers studied correspond to a pure gel phase and a mixture of liquid-expanded (LE) and liquid-condensed (LC) phases for DPPC and to a single homogeneous liquid-ordered phase for 2:1 DPPC/cholesterol. The addition of 2.5-5% GM1 to phase-separated DPPC monolayers resulted in small round ganglioside-rich microdomains in the center and at the edges of the LC domains. Higher amounts of GM1 (10%) give numerous filaments in the center of the LC domains and larger patches at the edges. A gel phase DPPC monolayer containing GM1 showed large domains containing a network of GM1-rich filaments. The addition of GM1 to a liquid-ordered 2:1 DPPC/cholesterol monolayer gives small, round domains that vary in size from 50 to 150 nm for a range of surface pressures. Larger amounts of GM1 lead to coalescence of the small, round domains to give longer filaments that cover 30-40% of the monolayer surface for 10 mol % GM1. The results indicate that biologically relevant GM1 concentrations lead to submicron-sized domains in a cholesterol-rich liquid-ordered phase that is analogous to that found in detergent-insoluble membrane fractions, and are thought to be important in membrane microdomains or rafts. This demonstrates that AFM studies of model monolayers and bilayers provide a powerful method for the direct detection of microdomains that are too small for study with most other techniques. PMID:11053150

Yuan, C; Johnston, L J

2000-11-01

212

Synthesis of reference standards to enable single cell metabolomic studies of tetramethylrhodamine-labeled ganglioside GM1  

Microsoft Academic Search

Ganglioside GM1 and its seven potential catabolic products: asialo-GM1, GM2, asialo-GM2, GM3, Lac-Cer, Glc-Cer and Cer, were labeled with tetramethylrhodamine (TMR) to permit ultra-sensitive analysis using laser-induced fluorescence (LIF) detection. The preparation involved acylation of the homogenous C18lyso-forms of GM1, Lac-Cer, Glc-Cer and Cer with the N-hydroxysuccinimide ester of a ?-alanine-tethered 6-TMR derivative, followed by conversion of these labeled products

E. Andreas Larsson; Ulf Olsson; Colin D. Whitmore; Rita Martins; Guido Tettamanti; Ronald L. Schnaar; Norman J. Dovichi; Monica M. Palcic; Ole Hindsgaul

2007-01-01

213

Progressive dystonia symptomatic of juvenile GM2 gangliosidosis.  

PubMed

A 9-year-old boy showed a progressive generalized dystonia, with onset at the age of 4 years, combined with mental deterioration and behavioral disturbances. The values of beta-hexosaminidase activities studied in plasma, leukocytes, and fibroblasts obtained using two different substrates (MUG-NAc and MUG-NAc-6-S) were significantly reduced but higher than in Tay-Sachs disease and similar to those found in the juvenile chronic form of GM2 gangliosidosis. With anticholinergic therapy, for 1.5 years, the dystonic symptoms did not progress and the boy can still care for himself and attend school. The description of another case of the disease, clinically expressed as dystonia, corroborates the existence of a dystonic phenotype of GM2 gangliosidosis. PMID:1532632

Nardocci, N; Bertagnolio, B; Rumi, V; Angelini, L

1992-01-01

214

Association to HeLa cells and surface behavior of exogenous gangliosides studied with a fluorescent derivative of GM1  

SciTech Connect

Cultured HeLa cells were incubated with pyrene-GM1/{sup 3}H-radiolabeled GM1 ganglioside (1:4 M/M) mixtures for various times. The process of association of pyrene-GM1 with cells was qualitatively and quantitatively the same as that of {sup 3}H-GM1. The pyrene-GM1 and {sup 3}H-GM1 proportions in the various forms of association with cells were similar to that of the starting ganglioside mixture. After 2-h incubation, the association of ganglioside with cells was well established whereas almost no metabolic processing had occurred. During a 24-h incubation, pyrene- and {sup 3}H-GM1 underwent similar metabolic processing and gave rise to catabolic (GM2 and GM3) and anabolic (GDla) derivatives. Fluorescence spectroscopy experiments carried out with the excimer formation technique on subcellular fractions containing plasma membranes showed that exogenous ganglioside was, in part, associated with the cells in a micellar form removable by trypsin treatment, and in part inserted in a seemingly molecular dispersion. Addition of Ca{sup 2+} salts caused aggregation of the ganglioside, as indicated by the increase of the excimer:monomer fluorescence ratio. The phenomenon was Ca{sup 2+} concentration dependent (maximum at 10 mM), and subsequent addition of EDTA has no effect. The saccharide portion of exogenously incorporated pyrene-GM1 was available to interact with external ligands, as shown by its ability to bind cholera toxin whose addition reduced the collision rate among the ganglioside lipid moieties.

Masserini, M.; Giuliani, A.; Palestini, P.; Acquotti, D.; Pitto, M.; Chigorno, V.; Tettamanti, G. (Univ. of Milan (Italy))

1990-01-23

215

Interactions between the ganglioside GM1 and hexadecylphosphocholine (miltefosine) in monolayers at the air\\/water interface  

Microsoft Academic Search

The ganglioside, GM1, was studied as Langmuir monolayers at the air\\/water interface with surface pressure-area measurements in addition to Brewster angle microscopy. A characteristic plateau transition, observed on aqueous subphases of pH 2 and 6, 20°C, at the surface pressure of ca. 20mN\\/m, was attributed to the reorientation of GM1 polar group upon film compression. This transition was found to

Isabel Rey Gómez-Serranillos; José Miñones; Patrycja Dynarowicz-??tka; Eduardo Iribarnegaray; Matilde Casas

2005-01-01

216

Structural basis of the GM2 gangliosidosis B variant  

Microsoft Academic Search

To study the structural basis of the GM2 gangliosidosis B variant, we constructed the three-dimensional structures of the human ß-hexosaminidase a-subunit and the heterodimer of the a- and ß-subunits, Hex A, by homology modeling. The a-subunit is composed of two domains, domains I and II. Nine mutant models due to specific missense mutations were constructed as well and compared with

Fumiko Matsuzawa; Sei-ichi Aikawa; Hitoshi Sakuraba; HoangThiNgoc Lan; Akemi Tanaka; Kousaku Ohno; Yuko Sugimoto; Haruaki Ninomiya; Hirofumi Doi

2003-01-01

217

Identification of GM2-gangliosidosis B1 variant carriers  

Microsoft Academic Search

GM2-gangliosidosis B1 variant, considered a rare disorder with a wide geographical and ethnic distribution, appears to be exceptionally frequent in Portugal. In order to establish a carrier detection method for this disease we have determined the ratio of enzymatic activities against 4MUGS and 4MUG in urine from B1 variant obligate carriers and controls, using the total extract and the Hex

M. G. Ribeiro; R. Pinto; P. Oliveira; M. C. Sá Miranda

1993-01-01

218

The Csk-binding protein PAG regulates PDGF-induced Src mitogenic signaling via GM1  

PubMed Central

Spatial regulation is an important feature of signal specificity elicited by cytoplasmic tyrosine kinases of the Src family (SRC family protein tyrosine kinases [SFK]). Cholesterol-enriched membrane domains, such as caveolae, regulate association of SFK with the platelet-derived growth factor receptor (PDGFR), which is needed for kinase activation and mitogenic signaling. PAG, a ubiquitously expressed member of the transmembrane adaptor protein family, is known to negatively regulate SFK signaling though binding to Csk. We report that PAG modulates PDGFR levels in caveolae and SFK mitogenic signaling through a Csk-independent mechanism. Regulation of SFK mitogenic activity by PAG requires the first N-terminal 97 aa (PAG-N), which include the extracellular and transmembrane domains, palmitoylation sites, and a short cytoplasmic sequence. We also show that PAG-N increases ganglioside GM1 levels at the cell surface and, thus, displaces PDGFR from caveolae, a process that requires the ganglioside-specific sialidase Neu-3. In conclusion, PAG regulates PDGFR membrane partitioning and SFK mitogenic signaling by modulating GM1 levels within caveolae independently from Csk.

Veracini, Laurence; Simon, Valerie; Richard, Veronique; Schraven, Burkhart; Horejsi, Vaclav; Roche, Serge; Benistant, Christine

2008-01-01

219

The Csk-binding protein PAG regulates PDGF-induced Src mitogenic signaling via GM1.  

PubMed

Spatial regulation is an important feature of signal specificity elicited by cytoplasmic tyrosine kinases of the Src family (SRC family protein tyrosine kinases [SFK]). Cholesterol-enriched membrane domains, such as caveolae, regulate association of SFK with the platelet-derived growth factor receptor (PDGFR), which is needed for kinase activation and mitogenic signaling. PAG, a ubiquitously expressed member of the transmembrane adaptor protein family, is known to negatively regulate SFK signaling though binding to Csk. We report that PAG modulates PDGFR levels in caveolae and SFK mitogenic signaling through a Csk-independent mechanism. Regulation of SFK mitogenic activity by PAG requires the first N-terminal 97 aa (PAG-N), which include the extracellular and transmembrane domains, palmitoylation sites, and a short cytoplasmic sequence. We also show that PAG-N increases ganglioside GM1 levels at the cell surface and, thus, displaces PDGFR from caveolae, a process that requires the ganglioside-specific sialidase Neu-3. In conclusion, PAG regulates PDGFR membrane partitioning and SFK mitogenic signaling by modulating GM1 levels within caveolae independently from Csk. PMID:18695048

Veracini, Laurence; Simon, Valérie; Richard, Véronique; Schraven, Burkhart; Horejsi, Vaclav; Roche, Serge; Benistant, Christine

2008-08-11

220

Diagnosis of infantile and juvenile forms of G M2 gangliosidosis variant 0. residual activities toward natural and different synthetic substrates  

Microsoft Academic Search

p-Nitrophenyl-6-sulfo-2-acetamido-2-deoxy-ß-d-glucopyranoside, which is known to be a specific substrate for human hexosaminidase A, has recently been used successfully for diagnosis of variants B and B1 of GM2-gangliosidosis (Fuchs et al. 1983; Kytzia et al. 1983; Li et al. 1983). However, it is hydrolyzed by hexosaminidase S as well and is therefore not suitable for detection of patients with variant 0,

H.-J. Kytzia; U. Hinrichs; K. Sandhoff

1984-01-01

221

Post-partum psychosis in adult GM2 gangliosidosis. A case report.  

PubMed

Adult hexosaminidase A deficiency is a form of GM2 gangliosidosis with autosomal recessive inheritance. Only 35 cases (mostly among Ashkenazic Jews) have been reported worldwide. Symptoms include, in a third of the cases, psychosis. A 27-year-old sufferer with no prior psychiatric history, developed a post-partum psychosis, with affective and hebephrenic components, 3 days following her first delivery. She responded to lithium within 10 days of initiating treatment; the full episode lasted 1 month. We conclude that lithium is the preferred treatment for psychosis in such adult patients, especially in light of possible long-term neurological deterioration caused by phenothiazines. Ashkenazic Jews with atypical neurological syndromes presenting with psychosis should be tested for hexosaminidase A deficiency. PMID:2977954

Lichtenberg, P; Navon, R; Wertman, E; Dasberg, H; Lerer, B

1988-09-01

222

Binding, conformational transition and dimerization of amyloid-? peptide on GM1-containing ternary membrane: insights from molecular dynamics simulation.  

PubMed

Interactions of amyloid-? (A?) with neuronal membrane are associated with the progression of Alzheimer's disease (AD). Ganglioside GM1 has been shown to promote the structural conversion of A? and increase the rate of peptide aggregation; but the exact nature of interaction driving theses processes remains to be explored. In this work, we have carried out atomistic-scale computer simulations (totaling 2.65 µs) to investigate the behavior of A? monomer and dimers in GM1-containing raft-like membrane. The oligosaccharide head-group of GM1 was observed to act as scaffold for A?-binding through sugar-specific interactions. Starting from the initial helical peptide conformation, a ?-hairpin motif was formed at the C-terminus of the GM1-bound A?-monomer; that didn't appear in absence of GM1 (both in fluid POPC and liquid-ordered cholesterol/POPC bilayers and also in aqueous medium) within the simulation time span. For A?-dimers, the ?-structure was further enhanced by peptide-peptide interactions, which might influence the propensity of A? to aggregate into higher-ordered structures. The salt-bridges and inter-peptide hydrogen bonds were found to account for dimer stability. We observed spontaneous formation of intra-peptide D(23)-K(28) salt-bridge and a turn at V(24)GSN(27) region - long been accepted as characteristic structural-motifs for amyloid self-assembly. Altogether, our results provide atomistic details of A?-GM1 and A?-A? interactions and demonstrate their importance in the early-stages of GM1-mediated A?-oligomerisation on membrane surface. PMID:23951128

Manna, Moutusi; Mukhopadhyay, Chaitali

2013-01-01

223

Neuropathology of chronic GM2 gangliosidosis due to hexosaminidase A deficiency.  

PubMed

Autopsy studies of late-onset GM2 gangliosidosis are sparse and only one adult case is on record. The case of partial Hex A deficiency presented here started in childhood as spinal muscular atrophy which progressed slowly over 4 decades. Cognitive function remained intact throughout the entire course, but during the last few years of life allodynia supervened. The patient died at 44 years of age. In good correlation with clinical observations the autopsy findings showed the most severe accumulation of lipid and consequent regressive change in the anterior horns of the spinal cord. Extensive but less severe storage was found in other spinal cord neurons, brain stem and selected basal ganglia. Cerebral cortex was virtually spared by storage but was the site of excessive formation of lipofuscin which was also present in many other neurons in the CNS. Marked storage and ganglionic loss was also found in the dorsal root ganglia, and the fasciculus gracilis was severely depleted of myelinated fibers. Electron microscopy showed accumulated gangliosides almost exclusively in the form of single and coalescing zebra bodies. In conclusion, the pathology in this case of chronic GM2 gangliosidosis, though in part conforming with previous observations, differed in several aspects. First, the cerebral cortex was--with only a few exceptions--free of ganglioside storage. Also spared was the cerebellum. In addition, homogeneous accumulation of zebra bodies contrasted with heterogeneity of neuronal inclusions found in other chronic cases. Finally, the involvement of sensory neurons was prominent and potentially related to allodynia. Molecular study of HEXA gene in this patient showed an TATC1278/? genotype. PMID:18808061

Kornfeld, M

2008-01-01

224

The morphology of GM1 x/SM 0.6-x/Chol 0.4 planar bilayers supported on SiO 2 surfaces  

NASA Astrophysics Data System (ADS)

Ganglioside GM1 (GM1), sphingomyelin (SM) and cholesterol (Chol) are dominant lipid components of rafts in plasma membranes. The morphology of GM1 x/SM 0.6-x/Chol 0.4 SPBs on SiO 2 surfaces has been studied by atomic force microscopy and fluorescence microscopy at various ratios of GM1/SM ( x = 0-0.25). The unique changes in morphology depending on the GM1 concentrations are qualitatively explained by hydrogen bonding and the hydrophobic interactions between SM and Chol, and by hydrogen bonding and the steric effects between bulky GM1 headgroups under Ca 2+ existing conditions and the electrostatic repulsion between the negative charges of GM1 headgroups under Ca 2+ nonexisting conditions.

Mao, Yanli; Tero, Ryugo; Imai, Yosuke; Hoshino, Tyuji; Urisu, Tsuneo

2008-07-01

225

Synthesis of reference standards to enable single cell metabolomic studies of tetramethylrhodamine-labelled ganglioside GM1  

PubMed Central

Ganglioside GM1 and its seven potential catabolic products: asialo-GM1, GM2, asialo-GM2, GM3, Lac-Cer, Glc-Cer and Cer, were labelled with tetramethylrhodamine (TMR) to permit ultra-sensitive analysis using laser-induced fluorescence (LIF) detection. The preparation involved acylation of the homogenous C18 lyso-forms of GM1, Lac-Cer, Glc-Cer and Cer with the N-hydroxysuccinimide ester of a ?-alanine-tethered 6-TMR derivative, followed by conversion of these labelled products using galactosidase, sialidase and sialyltransferase enzymes. The TMR-glycolipd analogs produced are detectable on TLC down to the 1 ng level by naked eye. All 8 compounds could be separated in under 4 minutes in capillary electrophoresis where they could be detected at the zeptomole (ca 1000 molecule) level using LIF.

Larsson, E. Andreas; Olsson, Ulf; Whitmore, Colin; Martins, Rita; Tettamanti, Guido; Schnaar, Ronald L.; Dovichi, Norman J.; Palcic, Monica M.; Hindsgaul, Ole

2007-01-01

226

Synthesis of reference standards to enable single cell metabolomic studies of tetramethylrhodamine-labeled ganglioside GM1.  

PubMed

Ganglioside GM1 and its seven potential catabolic products: asialo-GM1, GM2, asialo-GM2, GM3, Lac-Cer, Glc-Cer and Cer, were labeled with tetramethylrhodamine (TMR) to permit ultra-sensitive analysis using laser-induced fluorescence (LIF) detection. The preparation involved acylation of the homogenous C(18)lyso-forms of GM1, Lac-Cer, Glc-Cer and Cer with the N-hydroxysuccinimide ester of a beta-alanine-tethered 6-TMR derivative, followed by conversion of these labeled products using galactosidase, sialidase, and sialyltransferase enzymes. The TMR-glycolipid analogs produced are detectable on TLC down to the 1 ng level by the naked eye. All eight compounds could be separated within 4 min in capillary electrophoresis where they could be detected at the zeptomole (ca. 1000 molecule) level using LIF. PMID:17069778

Larsson, E Andreas; Olsson, Ulf; Whitmore, Colin D; Martins, Rita; Tettamanti, Guido; Schnaar, Ronald L; Dovichi, Norman J; Palcic, Monica M; Hindsgaul, Ole

2007-02-26

227

Measuring Positive Cooperativity Using the Direct ESI-MS Assay. Cholera Toxin B Subunit Homopentamer Binding to GM1 Pentasaccharide  

NASA Astrophysics Data System (ADS)

Direct electrospray ionization mass spectrometry (ESI-MS) assay was used to investigate the stepwise binding of the GM1 pentasaccharide ?- D-Gal p-(1?3)-?-D-Gal pNAc-(1?4)[?-D-Neu5Ac-(2?3)]-?- D-Gal p-(1?4)-?-D-Glc p (GM1os) to the cholera toxin B subunit homopentamer (CTB5) and to establish conclusively whether GM1os binding is cooperative. Apparent association constants were measured for the stepwise addition of one to five GM1os to CTB5 at pH 6.9 and 22 °C. The intrinsic association constant, which was established from the apparent association constant for the addition of a single GM1os to CTB5, was found to be (3.2 ± 0.2) × 106 M-1. This is in reasonable agreement with the reported value of (6.4 ± 0.3) × 106 M-1, which was measured at pH 7.4 and 25 °C using isothermal titration calorimetry (ITC). Analysis of the apparent association constants provides direct and unambiguous evidence that GM1os binding exhibits small positive cooperativity. Binding was found to be sensitive to the number of ligand-bound nearest neighbor subunits, with the affinities enhanced by a factor of 1.7 and 2.9 when binding occurs next to one or two ligand-bound subunits, respectively. These findings, which provide quantitative support for the binding model proposed by Homans and coworkers [14], highlight the unique strengths of the direct ESI-MS assay for measuring cooperative ligand binding.

Lin, Hong; Kitova, Elena N.; Klassen, John S.

2014-01-01

228

Pathology of GM2 gangliosidosis in Jacob sheep.  

PubMed

The G(M2) gangliosidoses are a group of lysosomal storage diseases caused by defects in the genes coding for the enzyme hexosaminidase or the G(M2) activator protein. Four Jacob sheep from the same farm were examined over a 3-year period for a progressive neurologic disease. Two lambs were 6-month-old intact males and 2 were 8-month-old females. Clinical findings included ataxia in all 4 limbs, proprioceptive deficits, and cortical blindness. At necropsy, the nervous system appeared grossly normal. Histologically, most neurons within the brain, spinal cord, and peripheral ganglia were enlarged, and the cytoplasm was distended by foamy to granular material that stained positively with Luxol fast blue and Sudan black B stains. Other neuropathologic findings included widespread astrocytosis, microgliosis, and scattered spheroids. Electron microscopy revealed membranous cytoplasmic bodies within the cytoplasm of neurons. Biochemical and molecular genetic studies confirmed the diagnosis of G(M2) gangliosidosis. This form of G(M2) gangliosidosis in Jacob sheep is very similar to human Tay-Sachs disease and is potentially a useful animal model. PMID:21123862

Porter, B F; Lewis, B C; Edwards, J F; Alroy, J; Zeng, B J; Torres, P A; Bretzlaff, K N; Kolodny, E H

2011-07-01

229

[Recent advances in molecular genetics of GM2 gangliosidosis].  

PubMed

Recent advances in molecular genetics of GM2 gangliosidosis are reviewed. GM2 gangliosidosis is an autosomal recessive, neurodegenerative disease caused by a deficiency of beta-hexosaminidase (Hex, EC 3.2.1.52) A activity, resulting in accumulation of GM2 ganglioside in the lysosomes of neuronal cells. There are two catalytically active forms of this enzyme: Hex A, composed of one alpha and one beta subunits. Three forms of this disease, Tay-Sachs disease, Sandhoff disease, and GM2 activator deficiency, have been recognized according to whether the defect involves the alpha subunit, beta subunit, or GM2 activator protein, respectively. A number of gene abnormalities responsible for the disease have been identified and mutations specific for phenotypes and racial backgrounds are summarized. Recently, the murine models of human Tay-Sachs disease and Sandhoff disease have been produced. With the finding of dramatically clinical phenotypes in these mice, these models could be useful for research on the pathogenesis or therapy of these diseases. PMID:8577047

Wakamatsu, N

1995-12-01

230

Role of Lipid Rafts and GM1 in the Segregation and Processing of Prion Protein  

PubMed Central

The prion protein (PrPC) is highly expressed within the nervous system. Similar to other GPI-anchored proteins, PrPC is found in lipid rafts, membrane domains enriched in cholesterol and sphingolipids. PrPC raft association, together with raft lipid composition, appears essential for the conversion of PrPC into the scrapie isoform PrPSc, and the development of prion disease. Controversial findings were reported on the nature of PrPC-containing rafts, as well as on the distribution of PrPC between rafts and non-raft membranes. We investigated PrPC/ganglioside relationships and their influence on PrPC localization in a neuronal cellular model, cerebellar granule cells. Our findings argue that in these cells at least two PrPC conformations coexist: in lipid rafts PrPC is present in the native folding (?-helical), stabilized by chemico-physical condition, while it is mainly present in other membrane compartments in a PrPSc-like conformation. We verified, by means of antibody reactivity and circular dichroism spectroscopy, that changes in lipid raft-ganglioside content alters PrPC conformation and interaction with lipid bilayers, without modifying PrPC distribution or cleavage. Our data provide new insights into the cellular mechanism of prion conversion and suggest that GM1-prion protein interaction at the cell surface could play a significant role in the mechanism predisposing to pathology.

Botto, Laura; Cunati, Diana; Coco, Silvia; Sesana, Silvia; Bulbarelli, Alessandra; Biasini, Emiliano; Colombo, Laura; Negro, Alessandro; Chiesa, Roberto; Masserini, Massimo; Palestini, Paola

2014-01-01

231

Asialo-GM1 and asialo-GM2 are putative adhesion molecules for Moraxella catarrhalis.  

PubMed

Moraxella catarrhalis is an important pathogen of respiratory and middle ear infections. We previously reported that the attachment of M. catarrhalis to pharyngeal epithelial cells is mediated by ganglioside M2 (GM2). Several sets of adhesins or receptors are involved in such attachment process. In this study, we used the same strains and similar bacterial culture conditions as those in our previous study, and demonstrated by thin layer chromatography that M. catarrhalis can also bind to asialo-GM1 (Gg4Cer) and asialo-GM2 (Gg3Cer). GalNAcbeta1-->4Galbeta1 is a common sequence in both Gg4Cer and Gg3Cer, and in many respiratory bacteria, this sequence acts as a receptor for attachment to host cells. Treatment of human pharyngeal epithelial cells with anti-GM2 and anti-Gg4Cer antibodies significantly decreased attachment of M. catarrhalis to these cells; however, treatment with anti-Gg3Cer antibody did not decrease M. catarrhalis attachment. Immunofluorescence microscopy revealed that human pharyngeal epithelial cells are positive for GM2 and Gg4Cer, but not for Gg3Cer. Our results indicate that Gg4Cer on human pharyngeal epithelial cells, and Gg3Cer,possibly on other cells, could serve as molecules for attachment of M. catarrhalis. PMID:12137200

Ahmed, Kamruddin; Suzuki, Yasuo; Miyamoto, Daisei; Nagatake, Tsuyoshi

2002-05-01

232

Tracking diffusion of GM1 gangliosides and zona pellucida binding molecules in sperm plasma membranes following cholesterol efflux.  

PubMed

The molecules on mammalian spermatozoa that mediate recognition and binding to the zona pellucida of the egg are still not understood. Current concepts favour their assembly into multimolecular complexes in the plasma membrane in response to cholesterol efflux, an important step during sperm capacitation. Here, we track in real time diffusion of cross-linked clusters containing zona-binding molecules and GM1 gangliosides in the plasma membrane of live boar spermatozoa before and after cholesterol reduction. Both GM1 gangliosides and zona-binding molecules partition into a low density Triton X100 resistant phase suggesting their association with lipid rafts. Initially, GM1 and zona-binding molecules localize to the apical ridge on the acrosome but following cholesterol efflux with methyl-beta-cyclodextrin, clusters containing zona-binding molecules diffuse randomly over the acrosomal domain. Diffusing clusters of either type do not access the postacrosome. Spermatozoa agglutinated head-to-head show contact-induced coalescence of GM1 gangliosides (but not zona-binding molecules) suggestive of a specific mechanosensitive response. Thus, cholesterol efflux initiates diffusion (and possibly formation) of novel lipid raft-like structures containing zona-binding molecules over the sperm acrosome. We hypothesise that in combination with contact coalescence, these mechanisms concentrate important molecules to the appropriate site on the sperm surface to mediate zona binding. PMID:20060391

Jones, Roy; Howes, Elizabeth; Dunne, Paul D; James, Peter; Bruckbauer, Andreas; Klenerman, David

2010-03-15

233

GPR37 protein trafficking to the plasma membrane regulated by prosaposin and GM1 gangliosides promotes cell viability.  

PubMed

The subcellular distribution of the G protein-coupled receptor GPR37 affects cell viability and is implicated in the pathogenesis of parkinsonism. Intracellular accumulation and aggregation of GPR37 cause cell death, whereas GPR37 located in the plasma membrane provides cell protection. We define here a pathway through which the recently identified natural ligand, prosaposin, promotes plasma membrane association of GPR37. Immunoabsorption of extracellular prosaposin reduced GPR37(tGFP) surface density and decreased cell viability in catecholaminergic N2a cells. We found that GPR37(tGFP) partitioned in GM1 ganglioside-containing lipid rafts in the plasma membrane of live cells. This partitioning required extracellular prosaposin and was disrupted by lipid raft perturbation using methyl-?-cyclodextrin or cholesterol oxidase. Moreover, complex formation between GPR37(tGFP) and the GM1 marker cholera toxin was observed in the plasma membrane. These data show functional association between GPR37, prosaposin, and GM1 in the plasma membrane. These results thus tie together the three previously defined components of the cellular response to insult. Our findings identify a mechanism through which the receptor's natural ligand and GM1 may protect against toxic intracellular GPR37 aggregates observed in parkinsonism. PMID:24371137

Lundius, Ebba Gregorsson; Vukojevic, Vladana; Hertz, Ellen; Stroth, Nikolas; Cederlund, Andreas; Hiraiwa, Masao; Terenius, Lars; Svenningsson, Per

2014-02-21

234

Sodium-calcium exchanger complexed with GM1 ganglioside in nuclear membrane transfers calcium from nucleoplasm to endoplasmic reticulum  

PubMed Central

The inner membrane of the nuclear envelope (NE) was previously shown to contain a Na/Ca exchanger (NCX) tightly linked to GM1 ganglioside that mediates transfer of nucleoplasmic Ca2+ to the NE lumen and constitutes a cytoprotective mechanism. This transfer was initially observed with isolated nuclei and is now demonstrated in living cells in relation to subcellular Ca2+ dynamics. Four cell lines with varying expression of NCX and GM1 in the NE were transfected with cameleon-fluorescent Ca2+ indicators genetically targeted to NE/endoplasmic reticulum (ER) and nucleoplasm to monitor [Ca2+]ne/er and [Ca2+]n respectively. Cytosolic Ca2+ ([Ca2+]cyt) was indicated with fura-2. Thapsigargin caused progressive loss of [Ca2+]ne/er, which was rapidly replaced on addition of extrinsic Ca2+ to those cells containing fully functional NCX/GM1: differentiated NG108–15 and C6 cells. Reduced elevation of [Ca2+]ne/er following thapsigargin depletion occurred in cells containing little or no GM1 in the NE: undifferentiated NG108–15 and NG-CR72 cells. No change in [Ca2+]ne/er due to applied Ca2+ was seen in Jurkat cells, which entirely lack NCX. Ca2+ entry to NE/ER was also blocked by KB-R7943, inhibitor of NCX. [Ca2+]n and [Ca2+]cyt were elevated independent of [Ca2+]ne/er and remained in approximate equilibrium with each other. Ca2+ rise in the ER originated in the NE region and extended to the entire ER network. These results indicate the nuclear NCX/GM1 complex acts to gate Ca2+ transfer from cytosol to ER, an alternate route to the sarcoplasmic/endoplasmic reticulum calcium ATPase pump. They also suggest a possible contributory mechanism for independent regulation of nuclear Ca2+.

Wu, Gusheng; Xie, Xin; Lu, Zi-Hua; Ledeen, Robert W.

2009-01-01

235

Clinical and Molecular Heterogeneity in Hereditary ?-Galactosidase Deficiency  

Microsoft Academic Search

Results of a molecular analysis of GM1-gangliosidosis and galactosialidosis in our laboratory are briefly reviewed. A common single base substitution was found in adult\\/chronic form of GM1-gangliosidosis among heterogeneous ?-galactosidase gene mutations, and restriction site analysis was successfully performed for diagnosis of homozygotes and heterozygotes. All adult galactosialidosis patients had a common mutation at a splice junction which caused skipping

Yoshiyuki Suzuki; Hitoshi Sakuraba; Akihiro Oshima; Kunihiro Yoshida; Michie Shimmoto; Takako Takano; Yukiko Fukuhara

1991-01-01

236

Bile and Unsaturated Fatty Acids Inhibit the Binding of Cholera Toxin and Escherichia coli Heat-Labile Enterotoxin to GM1 Receptor  

Microsoft Academic Search

Cholera toxin (CT) is an archetypal bacterial toxin that binds with a high affinity to the receptor ganglioside GM1 on the intestinal epithelial surface and that causes the severe watery diarrhea characteristic of the disease cholera. Blockage of the interaction of CT with the GM1 receptor is an attractive approach for therapeutic intervention. We report here that crude bile prevents

Arpita Chatterjee; Rukhsana Chowdhury

2008-01-01

237

Cholesterol accelerates the binding of Alzheimer's ?-amyloid peptide to ganglioside GM1 through a universal hydrogen-bond-dependent sterol tuning of glycolipid conformation.  

PubMed

Age-related alterations of membrane lipids in brain cell membranes together with high blood cholesterol are considered as major risk factors for Alzheimer's disease. Yet the molecular mechanisms by which these factors increase Alzheimer's risk are mostly unknown. In lipid raft domains of the plasma membrane, neurotoxic Alzheimer's beta-amyloid (Abeta) peptides interact with both cholesterol and ganglioside GM1. Recent data also suggested that cholesterol could stimulate the binding of Abeta to GM1 through conformational modulation of the ganglioside headgroup. Here we used a combination of physicochemical and molecular modeling approaches to decipher the mechanisms of cholesterol-assisted binding of Abeta to GM1. With the aim of decoupling the effect of cholesterol on GM1 from direct Abeta-cholesterol interactions, we designed a minimal peptide (Abeta5-16) containing the GM1-binding domain but lacking the amino acid residues involved in cholesterol recognition. Using the Langmuir technique, we showed that cholesterol (but not phosphatidylcholine or sphingomyelin) significantly accelerates the interaction of Abeta5-16 with GM1. Molecular dynamics simulations suggested that Abeta5-16 interacts with a cholesterol-stabilized dimer of GM1. The main structural effect of cholesterol is to establish a hydrogen-bond between its own OH group and the glycosidic-bond linking ceramide to the glycone part of GM1, thereby inducing a tilt in the glycolipid headgroup. This fine conformational tuning stabilizes the active conformation of the GM1 dimer whose headgroups, oriented in two opposite directions, form a chalice-shaped receptacle for Abeta. These data give new mechanistic insights into the stimulatory effect of cholesterol on Abeta/GM1 interactions. They also support the emerging concept that cholesterol is a universal modulator of protein-glycolipid interactions in the broader context of membrane recognition processes. PMID:23772214

Fantini, Jacques; Yahi, Nouara; Garmy, Nicolas

2013-01-01

238

Tracking diffusion of GM1 gangliosides and zona pellucida binding molecules in sperm plasma membranes following cholesterol efflux  

Microsoft Academic Search

The molecules on mammalian spermatozoa that mediate recognition and binding to the zona pellucida of the egg are still not understood. Current concepts favour their assembly into multimolecular complexes in the plasma membrane in response to cholesterol efflux, an important step during sperm capacitation. Here, we track in real time diffusion of cross-linked clusters containing zona-binding molecules and GM1 gangliosides

Roy Jones; Elizabeth Howes; Paul D. Dunne; Peter James; Andreas Bruckbauer; David Klenerman

2010-01-01

239

GM1 ganglioside prevents seizures, Na +,K +ATPase activity inhibition and oxidative stress induced by glutaric acid and pentylenetetrazole  

Microsoft Academic Search

Monosialoganglioside (GM1) is a glycosphingolipid that protects against some neurological conditions, such as seizures and ischemia. Glutaric acidemia type I (GA-I) is an inherited disease characterized by striatal degeneration, seizures, and accumulation of glutaric acid (GA). In this study, we show that GA inhibits Na+,K+-ATPase activity and increases oxidative damage markers (total protein carbonylation and thiobarbituric acid-reactive substances—TBARS) production in

Michele Rechia Fighera; Luiz Fernando Freire Royes; Ana Flávia Furian; Mauro Schneider Oliveira; Natália Gindri Fiorenza; Roberto Frussa-Filho; João Carlos Petry; Rafael Correa Coelho; Carlos Fernando Mello

2006-01-01

240

Busy period analysis for M\\/G\\/1 and G\\/M\\/1 type queues with restricted accessibility  

Microsoft Academic Search

We consider two models of M\\/G\\/1 and G\\/M\\/1 type queueing systems with restricted accessibility. Let (V(t))t?0 be the virtual waiting time process, let Sn be the time required for a full service of the nth customer and let ?n be his arrival time. In both models there is a capacity bound v??(0,?). In Model I the amount of service given

David Perry; Wolfgang Stadje; S. Zacks

2000-01-01

241

Anti-Asialo GM1 NK Cell Depleting Antibody Does Not Alter the Development of Bleomycin Induced Pulmonary Fibrosis  

PubMed Central

Despite circumstantial evidence postulating a protective role for NK cells in many fibrotic conditions, their contribution to the development of pulmonary fibrosis has yet to be tested. Lung-migrating NK cells are thought to attenuate the development of bleomycin induced pulmonary fibrosis (BIPF) by providing anti-fibrotic mediators and cytokines, such as IFN-?. If true, we reasoned that depletion of NK cells during experimentally-induced fibrotic disease would lead to exacerbated fibrosis. To test this, we treated mice with NK cell-depleting antisera (anti-asialo GM1) and evaluated lung inflammation and fibrosis in the BIPF model. While NK cell infiltration into the airways was maximal at day 10 after bleomycin injection, NK cells represented a minor portion (1–3%) of the total leukocytes in BAL fluid. Anti-asialo GM1 significantly abrogated NK cell numbers over the course of the disease. Depletion of NK cells with anti-asialo GM1 before and throughout the BIPF model, or during just the fibrotic phase did not alter fibrosis development or affect the levels of any of the pro-inflammatory/pro-fibrotic cytokines measured (IL-1?, IL-17, IFN-?, TGF-? and TNF-?). In addition, adoptively transferred NK cells, which were detectable systemically and in the airways throughout BIPF, failed to impact lung fibrosis. These findings indicate that NK cells likely do not play an essential protective role in controlling pulmonary fibrosis development.

Monnier, Justin; Zabel, Brian A.

2014-01-01

242

Asymmetric Structural Features in Single Supported Lipid Bilayers Containing Cholesterol and GM1 Resolved with Synchrotron X-Ray Reflectivity  

PubMed Central

The cell membrane comprises numerous protein and lipid molecules capable of asymmetric organization between leaflets and liquid-liquid phase separation. We use single supported lipid bilayers (SLBs) to model cell membranes, and study how cholesterol and asymmetrically oriented ganglioside receptor GM1 affect membrane structure using synchrotron x-ray reflectivity. Using mixtures of cholesterol, sphingomyelin, and 1,2-dioleoyl-sn-glycero-3-phosphocholine, we characterize the structure of liquid-ordered and liquid-disordered SLBs in terms of acyl-chain density, headgroup size, and leaflet thickness. SLBs modeling the liquid-ordered phase are 10 Å thicker and have a higher acyl-chain electron density (??chain? = 0.33 e?/Å3) compared to SLBs modeling the liquid-disordered phase, or pure phosphatidylcholine SLBs (??chain? = 0.28 e?/Å3). Incorporating GM1 into the distal bilayer leaflet results in membrane asymmetry and thickening of the leaflet of 4–9 Å. The structural effect of GM1 is more complex in SLBs of cholesterol/sphingomyelin/1,2-dioleoyl-sn-glycero-3-phosphocholine, where the distal chains show a high electron density (??chain? = 0.33 e?/Å3) and the lipid diffusion constant is reduced by ?50%, as measured by fluorescence microscopy. These results give quantitative information about the leaflet asymmetry and electron density changes induced by receptor molecules that penetrate a single lipid bilayer.

Reich, Christian; Horton, Margaret R.; Krause, Barbel; Gast, Alice P.; Radler, Joachim O.; Nickel, Bert

2008-01-01

243

Interactions between the ganglioside GM1 and hexadecylphosphocholine (miltefosine) in monolayers at the air/water interface.  

PubMed

The ganglioside, GM1, was studied as Langmuir monolayers at the air/water interface with surface pressure-area measurements in addition to Brewster angle microscopy. A characteristic plateau transition, observed on aqueous subphases of pH 2 and 6, 20 degrees C, at the surface pressure of ca. 20 mN/m, was attributed to the reorientation of GM1 polar group upon film compression. This transition was found to disappear at alkaline subphases (pH 10) due to the hydration of fully ionized polar group, hindering its reorientation. The interactions between GM1 and hexadecylphosphocholine (miltefosine) were investigated in mixed monolayers and analyzed with the mean molecular areas, excess areas of mixing and the excess free energy of mixing versus film composition plots. The monolayers stability, quantified by the collapse pressure values, as well as the strength of interaction was found to diminish in the following order: pH 6>pH 2>pH 10. The strongest interaction occurs for mixed films of miltefosine molar fraction, XM=0.7-0.8, especially at low pressure region, and are explained as being due to the surface complex formation of 3:1 or 4:1 (miltefosine:ganglioside) stoichiometry (XM=0.75 or 0.8, respectively). PMID:15698758

Gómez-Serranillos, Isabel Rey; Miñones, José; Dynarowicz-?atka, Patrycja; Iribarnegaray, Eduardo; Casas, Matilde

2005-03-10

244

Alpha-locus hexosaminidase genetic compound with juvenile gangliosidosis phenotype: clinical, genetic, and biochemical studies.  

PubMed Central

A 3-year-old boy developed progressive neurological deterioration in his third year, characterized by dementia, ataxia, myoclonic jerks, and bilateral macular cherry-red spots. Hexosaminidase A (HEX A) was partially decreased in the patient's serum, leukocytes, and cultured skin fibroblasts. Hexosaminidase was studied in serum and leukocytes from family members. Four members of the paternal branch appeared to be carriers of classical infantile Tay-Sachs allele, HEX alpha 2, probably receiving the gene from one great-grandparent of Ashkenazi origin. In the maternal branch, no one was a carrier of classical infantile Tay-Sachs disease, but five individuals were carriers of a milder alpha-locus defect. The patient, therefore, was a genetic compound of two different alpha-locus hexosaminidase mutations. At least 21 families with late-infantile or juvenile GM2 gangliosidosis have been reported, 18 of them with alpha-locus mutations, and three with beta-locus mutations. Genetic compounds of hexosaminidase have been reported in at least seven families, five with alpha-locus mutations and two with beta-locus mutations. The compound had the phenotype of infantile Tay-Sachs disease in one family, infantile Sandhoff disease in another, and the normal phenotype in the rest.

Johnson, W G; Cohen, C S; Miranda, A F; Waran, S P; Chutorian, A M

1980-01-01

245

Protein catabolism in fibroblasts cultured from patients with mucolipidosis II and other lysosomal disorders.  

PubMed Central

Protein catabolism in fibroblasts cultured from the skin of normal individuals and of patients with mucolipidosis II (I-cell disease) and several other lysosomal storage diseases was examined by metabolic labelling with [3H]leucine and following the fate of radioactive proteins in pulse-chase experiments. In mucolipidosis II cells, overall protein degradative rates were found to be distinctly lower than in normal control cells. To distinguish lysosomal from non-lysosomal degradation, labelling experiments were carried out in the presence and absence of 10 mM NH4Cl, an inhibitor of lysosomal function. It was found that mucolipidosis II fibroblasts exhibited a markedly reduced rate of lysosomal protein degradation, whereas the rate of nonlysosomal degradation appeared normal. Serum and amino acid starvation led to a marked increase in lysosomal protein degradation in normal cells, but had only a minimal effect on that in mucolipidosis II fibroblasts. The specific activities of cathepsins B, H and L were profoundly diminished in all mucolipidosis II cell lines tested. Lysosomal protein degradation in a mucolipidosis III cell line was impaired to a similar degree as in mucolipidosis II cells, whereas it was decreased to a lesser extent in fibroblasts from patients with mucopolysaccharidoses I and VI, galactosialidosis and GM1-gangliosidosis. We conclude that fibroblasts from patients with mucolipidosis II and III have a severely compromised capacity for endogenous lysosomal protein degradation that appears to result from multiple cathepsin deficiency. This lysosomal defect is likely to have pathophysiological consequences.

Kopitz, J; Arnold, A; Meissner, T; Cantz, M

1993-01-01

246

Cerebral sponginess and GM3 gangliosidosis; ultrastructure and probable pathogenesis.  

PubMed

Extensive multifocal vacuolation of the cerebral hemispheres, brain stem, cerebellum, optic nerves and spinal cord were demonstrated in a 3 1/2 month-old infant. This co-existed with marked increases in cerebral and hepatic ganglioside GM3 (hematoside), absence of its higher homologues (GM1 and GM2) and absence of tissue N-acetylgalactosaminyl transferase. Ultrastructurally, there are major abnormalities in myelin and astroglia. The absence of identifiable "storage" material is believed to correlate with an enzymatic defect involved in ganglioside anabolism. A familial occurrence of this disorder is strongly suggested by the clinical history. PMID:167132

Tanaka, J; Garcia, J H; Max, S R; Viloria, J E; Kamijyo, Y; McLaren, N K; Cornblath, M; Brady, R O

1975-05-01

247

Evidence for a role of ganglioside GM1 in antigen presentation: binding enhances presentation of Escherichia coli enterotoxin B subunit (EtxB) to CD4(+) T cells.  

PubMed

Successful antigen presentation by antigen-presenting cells is governed by a number of factors including the efficiency of antigen capture by cell-surface receptors, targeting to compartments of antigen processing, surface expression of MHC II-peptide complexes and presence of co-stimulatory signals. Ganglioside GM1 is an important component of membrane glycosphingolipids, and has been implicated in cell differentiation, apoptosis and signal transduction pathways. Using the B subunit of Escherichia coli enterotoxin (EtxB), a potent immunogen that binds GM1 with high affinity, and a non-binding mutant of EtxB, EtxB(G33D), we demonstrate that GM1 is intimately involved in several aspects of antigen presentation. Thus, GM1-mediated presentation of EtxB by B cells and CD11c(+) dendritic cells (DC) significantly enhanced the proliferation and cytokine expression of EtxB-specific CD4(+) T cells. Investigation regarding potential mechanisms revealed that EtxB binding directly augments the expression of MHC class II on B cells, and fractionation of B cells demonstrated that EtxB binding to GM1 results in rapid internalization and targeting to class II-rich compartments. GM1-mediated uptake of antigens and access to class II compartments in B cells can be exploited to significantly enhance the presentation of ovalbumin-conjugated to EtxB. These results demonstrate that GM1 can play an important role in antigen presentation via the MHC II pathway. PMID:11282993

Nashar, T O; Betteridge, Z E; Mitchell, R N

2001-04-01

248

Potential efficacy and toxicity of GM1 ganglioside against trimethyltin-induced brain lesions in rats: comparison with protracted food restriction.  

PubMed

GM1 ganglioside (one week each at 10, 5, and 2.5 mg GM1/kg per day, ip) or gradual food restriction leading to a reduction in body weight to 75% of control were tested for their ability to block or reverse histopathologic and behavioral effects of trimethyltin (TMT) poisoning in rats. TMT (a single oral gavage of 6.0 mg TMT HCI/kg body weight) reduced hippocampal weight, decreased hippocampal cell counts, decreased autoshaped learning measures, and suppressed progressive fixed ratio (PFR) lever pressing without affecting stable lever pressing. Neither GM1 nor greater food restriction affected hippocampal weight. Greater food restriction prevented TMT's effects on autoshaping but not on PFR behavior, was without behavioral effects in animals not treated with TMT, and did not affect hippocampal histology. GM1 prevented certain TMT-induced decrements in autoshaping and PFR behavior but also suppressed autoshaping and stimulated stable fixed ratio behavior in animals not treated with TMT. GM1 also reduced hippocampal serotonin concentration, another "lesion-like" change. GM1 blocked TMT-induced hippocampal CA3b cell loss, but did not protect CA3c cells, the main locus of TMT hippocampal damage. The results support the idea that exogenous GM1 is a potent neuroactive agent with complex actions in intact organisms, potentially beneficial and potentially toxic. Like GM1, food restriction induces complex and potentially beneficial effects, but it lacked GM1's biochemical and behavioral "side effects" (i.e. toxicity) in these experiments. PMID:7566684

Bollweg, G; Balaban, C; Cox, H J; Berra, B; Sparber, S B

1995-01-01

249

Histopathologic correlates of radial stripes on MR images in lysosomal storage disorders  

Microsoft Academic Search

BACKGROUND AND PURPOSE: Radially oriented hypointense stripes in hyperintense cerebral white matter are recognized on T2-weighted images of certain lysosomal storage disorders. We compared in vivo and postmortem MR imaging with histopathologic findings in three patients with metachromatic leukodystrophy (MLD), globoid cell leukodystrophy (GLD), and infantile GM1 gangliosidosis (GM1) to understand this characteristic MR imaging pattern. METHODS: The in vivo

J. Patrick van der Voorn; Petra J. W. Pouwels; Wout Kamphorst; James M. Powers; Martin Lammens; Frederik Barkhof; Marjo S. van der Knaap

2005-01-01

250

Ganglioside GM1-mediated transcytosis of cholera toxin bypasses the retrograde pathway and depends on the structure of the ceramide domain.  

PubMed

Cholera toxin causes diarrheal disease by binding ganglioside GM1 on the apical membrane of polarized intestinal epithelial cells and trafficking retrograde through sorting endosomes, the trans-Golgi network (TGN), and into the endoplasmic reticulum. A fraction of toxin also moves from endosomes across the cell to the basolateral plasma membrane by transcytosis, thus breeching the intestinal barrier. Here we find that sorting of cholera toxin into this transcytotic pathway bypasses retrograde transport to the TGN. We also find that GM1 sphingolipids can traffic from apical to basolateral membranes by transcytosis in the absence of toxin binding but only if the GM1 species contain cis-unsaturated or short acyl chains in the ceramide domain. We found previously that the same GM1 species are needed to efficiently traffic retrograde into the TGN and endoplasmic reticulum and into the recycling endosome, implicating a shared mechanism of action for sorting by lipid shape among these pathways. PMID:23884419

Saslowsky, David E; te Welscher, Yvonne M; Chinnapen, Daniel J-F; Wagner, Jessica S; Wan, Joy; Kern, Eli; Lencer, Wayne I

2013-09-01

251

GM2 gangliosidosis in an adult pet rabbit.  

PubMed

A 1.5-year-old neutered male rabbit was presented with chronic nasal discharge and ataxia. Rapid progression of neurological signs was noted subsequent to general anaesthesia and the rabbit was humanely destroyed due to the poor prognosis. At necropsy examination there were no gross changes affecting the brain or spinal cord. Microscopical examination revealed that the perikarya of numerous neurons in the brain and spinal cord were distended by the intracytoplasmic accumulation of pale, finely granular to vacuolar material. Transmission electron microscopy showed this to be composed of concentric membranous cytoplasmic bodies. Thin layer chromatography revealed elevation of GM2 ganglioside in the brain of this rabbit compared with that of an unaffected control rabbit. Enzymatically, there was markedly reduced activity of tissue ?-hexosaminidase A in brain and liver tissue from the rabbit. This was a result of an almost complete absence of the enzymatic activity of the ?-subunit of that enzyme. These findings are consistent with sphingolipidosis comparable with human GM2 gangliosidosis variant B1. PMID:22878054

Rickmeyer, T; Schöniger, S; Petermann, A; Harzer, K; Kustermann-Kuhn, B; Fuhrmann, H; Schoon, H-A

2013-02-01

252

Structural basis of the GM2 gangliosidosis B variant.  

PubMed

To study the structural basis of the GM2 gangliosidosis B variant, we constructed the three-dimensional structures of the human beta-hexosaminidase alpha-subunit and the heterodimer of the alpha- and beta-subunits, Hex A, by homology modeling. The alpha-subunit is composed of two domains, domains I and II. Nine mutant models due to specific missense mutations were constructed as well and compared with the wild type to determine structural defects. These nine mutations were divided into five groups according to structural defects. R178H is deduced to affect the active site directly, because R178 is important for binding to the substrate. C458Y and W420C are predicted to cause drastic structural changes in the barrel structure carrying the active site pocket. R504C/H is deduced to introduce a disruption of an essential binding with D494 in the beta-subunit for dimerization. R499C/H, located in an extra-helix, is deduced to disrupt hydrogen bonds with domain I and the barrel. R170W and L484P are deduced to affect the interface between domains I and II, causing destabilization. The structural defects reflect the biochemical abnormalities of the disease. PMID:14577003

Matsuzawa, Fumiko; Aikawa, Sei-ichi; Sakuraba, Hitoshi; Lan, Hoang Thi Ngoc; Tanaka, Akemi; Ohno, Kousaku; Sugimoto, Yuko; Ninomiya, Haruaki; Doi, Hirofumi

2003-01-01

253

A Single Native Ganglioside GM1-Binding Site Is Sufficient for Cholera Toxin To Bind to Cells and Complete the Intoxication Pathway  

PubMed Central

ABSTRACT Cholera toxin (CT) from Vibrio cholerae is responsible for the majority of the symptoms of the diarrheal disease cholera. CT is a heterohexameric protein complex with a 240-residue A subunit and a pentameric B subunit of identical 103-residue B polypeptides. The A subunit is proteolytically cleaved within a disulfide-linked loop to generate the A1 and A2 fragments. The B subunit of wild-type (wt) CT binds 5 cell surface ganglioside GM1 (GM1) molecules, and the toxin-GM1 complex traffics from the plasma membrane (PM) retrograde through endosomes and the Golgi apparatus to the endoplasmic reticulum (ER). From the ER, the enzymatic A1 fragment retrotranslocates to the cytosol to cause disease. Clustering of GM1 by multivalent toxin binding can structurally remodel cell membranes in ways that may assist toxin uptake and retrograde trafficking. We have recently found, however, that CT may traffic from the PM to the ER by exploiting an endogenous glycosphingolipid pathway (A. A. Wolf et al., Infect. Immun. 76:1476–1484, 2008, and D. J. F. Chinnapen et al., Dev. Cell 23:573–586, 2012), suggesting that multivalent binding to GM1 is dispensable. Here we formally tested this idea by creating homogenous chimeric holotoxins with defined numbers of native GM1 binding sites from zero (nonbinding) to five (wild type). We found that a single GM1 binding site is sufficient for activity of the holotoxin. Therefore, remodeling of cell membranes by mechanisms that involve multivalent binding of toxin to GM1 receptors is not essential for toxicity of CT.

Jobling, Michael G.; Yang, ZhiJie; Kam, Wendy R.; Lencer, Wayne I.; Holmes, Randall K.

2012-01-01

254

Role of GM1 binding in the mucosal immunogenicity and adjuvant activity of the Escherichia coli heat-labile enterotoxin and its B subunit.  

PubMed Central

Escherichia coli (E. coli) heat-labile toxin (LT) is a potent mucosal immunogen and immunoadjuvant towards co-administered antigens. LT is composed of one copy of the A subunit, which has ADP-ribosylation activity, and a homopentamer of B subunits, which has affinity for the toxin receptor, the ganglioside GM1. Both the ADP-ribosylation activity of LTA and GM1 binding of LTB have been proposed to be involved in immune stimulation. We investigated the roles of these activities in the immunogenicity of recombinant LT or LTB upon intranasal immunization of mice using LT/LTB mutants, lacking either ADP-ribosylation activity, GM1-binding affinity, or both. Likewise, the adjuvant properties of these LT/LTB variants towards influenza virus subunit antigen were investigated. With respect to the immunogenicity of LT and LTB, we found that GM1-binding activity is essential for effective induction of anti-LTB antibodies. On the other hand, an LT mutant lacking ADP-ribosylation activity retained the immunogenic properties of the native toxin, indicating that ADP ribosylation is not critically involved. Whereas adjuvanticity of LTB was found to be directly related to GM1-binding activity, adjuvanticity of LT was found to be independent of GM1-binding affinity. Moreover, a mutant lacking both GM1-binding and ADP-ribosylation activity, also retained adjuvanticity. These results demonstrate that neither ADP-ribosylation activity nor GM1 binding are essential for adjuvanticity of LT, and suggest an ADP-ribosylation-independent adjuvant effect of the A subunit. Images Figure 1

de Haan, L; Verweij, W R; Feil, I K; Holtrop, M; Hol, W G; Agsteribbe, E; Wilschut, J

1998-01-01

255

Retrovirally mediated overexpression of versican v3 reverses impaired elastogenesis and heightened proliferation exhibited by fibroblasts from Costello syndrome and Hurler disease patients.  

PubMed

The phenotypic resemblance of patients with Costello syndrome and Hurler disease has been linked to impaired formation of elastic fibers that coincides with elevated cellular proliferation. Impaired elastogenesis in these diseases associates with respective abnormal accumulation of chondroitin sulfate and dermatan sulfate proteoglycans that induce cell surface shedding of elastin-binding protein (EBP) normally required for intracellular chaperoning of tropoelastin and its assembly into elastic fibers. A variant of the chondroitin sulfate proteoglycan versican, V3, which lacks chondroitin sulfate, has recently been shown to stimulate elastic fiber assembly and decrease proliferation when expressed by retroviral transduction in arterial smooth muscle cells. However, the mechanism(s) by which V3 influences this phenotype is not known. We now demonstrate that transduction of skin fibroblasts from Costello syndrome and Hurler disease patients with cDNA to versican V3 completely reverses impaired elastogenesis and restores normal proliferation of these cells. This phenotypic reversal is accompanied by loss of chondroitin sulfate from the cell surface and increased levels of EBP. Versican V3 transduction of skin fibroblasts from GM(1)-gangliosidosis patients, which lack EBP, failed to restore impaired elastogenesis. These results suggest that induction of elastic fiber production by gene transfer of versican V3 in skin fibroblasts is mediated by rescue of the tropoelastin chaperone, EBP. PMID:14695326

Hinek, Aleksander; Braun, Kathy R; Liu, Kela; Wang, Yanting; Wight, Thomas N

2004-01-01

256

The Natural History of Juvenile or Subacute GM2 Gangliosidosis: 21 New Cases and Literature Review of 134 Previously Reported  

PubMed Central

OBJECTIVE Juvenile GM2 gangliosidosis is a group of inherited neurodegenerative diseases caused by deficiency of lysosomal ?-hexosaminidase resulting in GM2 ganglioside accumulation in brain. The purpose of this study was to delineate the natural history of the condition and identify genotype-phenotype correlations that might be helpful in predicting the course of the disease in individual patients. METHODS A cohort of 21 patients with juvenile GM2 gangliosidosis, 15 with the Tay-Sachs variant and 6 with the Sandhoff variant, was studied prospectively in 2 centers. Our experience was compared with previously published reports on 134 patients. Information about clinical features, ?-hexosaminidase enzyme activity, and mutation analysis was collected. RESULTS In our cohort of patients, the mean (±SD) age of onset of symptoms was 5.3 ± 4.1 years, with a mean follow-up time of 8.4 years. The most common symptoms at onset were gait disturbances (66.7%), incoordination (52.4%), speech problems (28.6%), and developmental delay (28.6%). The age of onset of gait disturbances was 7.1 ± 5.6 years. The mean time for progression to becoming wheelchair-bound was 6.2 ± 5.5 years. The mean age of onset of speech problems was 7.0 ± 5.6 years, with a mean time of progression to anarthria of 5.6 ± 5.3 years. Muscle wasting (10.6 ± 7.4 years), proximal weakness (11.1 ± 7.7 years), and incontinence of sphincters (14.6 ± 9.7 years) appeared later in the course of the disease. Psychiatric disturbances and neuropathy were more prevalent in patients with the Sandhoff variant than in those with the Tay-Sachs variant. However, dysphagia, sphincter incontinence, and sleep problems occurred earlier in those with the Tay-Sachs variant. Cerebellar atrophy was the most common finding on brain MRI (52.9%). The median survival time among the studied and reviewed patients was 14.5 years. The genotype-phenotype correlation revealed that in patients with the Tay-Sachs variant, the presence of R178H and R499H mutations was predictive of an early onset and rapidly progressive course. The presence of either G269S or W474C mutations was associated with a later onset of symptoms along with a more slowly progressive disease course. CONCLUSIONS Juvenile GM2 gangliosidosis is clinically heterogeneous, not only in terms of age of onset and clinical features but also with regard to the course of the disease. In general, the earlier the onset of symptoms, the more rapidly the disease progresses. The Tay-Sachs and Sandhoff variants differed somewhat in the frequency of specific clinical characteristics. Speech deterioration progressed more rapidly than gait abnormalities in both the Tay-Sachs variant and Sandhoff variant groups. Among patients with the Tay-Sachs variant, the HEXA genotype showed a significant correlation with the clinical course.

Maegawa, Gustavo H. B.; Stockley, Tracy; Tropak, Michael; Banwell, Brenda; Blaser, Susan; Kok, Fernando; Giugliani, Roberto; Mahuran, Don; Clarke, Joe T. R.

2010-01-01

257

The restriction mechanism of Chinese university results efficiency based on the hybrid of VPRS and optimized GM(1,1)  

NASA Astrophysics Data System (ADS)

Grey system theory and rough set theory are two different mathematical tools which are used to deal with uncertain or incomplete information, and yet they are relevant and complementary to a certain degree. They both improve the generality of data presentation by reducing its accuracy. In the paper, based on the statistics of Chinese universities science and technology from 2002 year to 2011 year, the key factors which affect the transfer performance are figured out by applying variable precision rough set models, output performance and transfer performance are predicted by optimal GM(1,1) model. According to the above, the restriction mechanism of university R&D performance is analyzed from a whole view of operating model and key influencing factors, and the prospect model is suggested.

Jian, Lirong; Liu, Sifeng

2013-10-01

258

Metabolic studies in older mentally retarded patients: significance of metabolic testing and correlation with the clinical phenotype.  

PubMed

In 471 adult mentally retarded adult patients (mean age 46 years; 92.6% males) living in an institution for the mentally retarded, a clinical examination, cytogenetic and molecular studies were done. 306 patients were screened for metabolic disorders. In 7 additional patients a metabolic disorder (phenylketonuria (n = 5), mucopolysaccharidosis type III (Sanfilippo syndrome, type A) (n = 1) and mucopolysaccharidosis type VII (Sly syndrome) (n = 1)) was diagnosed in the past. The abnormal metabolic findings in this group of 313 patients were classified in three categories and the clinical findings are reported: 1. metabolic disorders as the cause of mental retardation (MR), 2. metabolic disorders not explaining the MR, and 3. metabolic abnormalities of unknown significance. The first two groups included 16 patients, i.e. 26.2% of the group of monogenic disorders and 3.4% of the total population: phenylketonuria (PKU) (n = 5), S-sulfocysteinuria (n = 3), mucopolysaccharidosis type III (Sanfilippo syndrome, type A) (n = 1) and Gm1-gangliosidosis type 3 (n = 1) (first group), and mucopolysaccharidosis type VII (Sly syndrome) (n = 1), Niemann-Pick syndrome, type B (n = 1), cystinuria (n = 1) and hyperprolinemia type 1 (n = 3) (second group). The third group included patients with citrullinemia (n = 2), methionine sulphoxide reductase deficiency (n = 1), ornithinemia (n = 1), glycinuria (n = 20), neuraminaciduria (n = 8), uraciluria (n = 6) and diabetes mellitus (n = 2). Screening for Congenital Disorders of Glycosylation (CDG) in 144 patients and for Smith-Lemli-Opitz syndrome (SLO) in a selected group of 6 patients was normal. Of the total group of 306 patients screened for inborn errors of metabolism, only 5 (1.6%) were found with a true metabolic disorder. These 5 patients presented clinical symptoms, neurodegenerative or behavioural problems, indicating further metabolic screening. The present study illustrates that a selected group of patients with mental retardation of unknown origin are candidates for metabolic screening, especially if aberrant behaviour, neurodegenerative problems or dysmorphic features are present. PMID:11332972

Van Buggenhout, G J; Trijbels, J M; Wevers, R; Trommelen, J C; Hamel, B C; Brunner, H G; Fryns, J P

2001-01-01

259

C6 cells express a sodium-calcium exchanger/GM1 complex in the nuclear envelope but have no exchanger in the plasma membrane: comparison to astrocytes.  

PubMed

Previous work demonstrated the presence of an isoform of Na(+)/Ca(2+) exchanger in the nuclear envelope of neurons and NG108-15 cells that is tightly associated with GM1 ganglioside and potentiated by the latter. This contrasted with the Na(+)/Ca(2+) exchanger(s) in the plasma membrane, which were suggested to associate more loosely with GM1. To study these aspects of Na(+)/Ca(2+) exchanger expression in nonneuronal neural cells, we have examined nuclear and plasma membrane exchanger patterns in astrocytes and C6 cells, a glia-derived line. We find both cell types contain the tightly associated exchanger/GM1 complex in the nuclear envelope but, surprisingly, only astrocytes possess Na(+)/Ca(2+) exchanger activity in the plasma membrane. This is the first reported example of a cell (C6) with Na(+)/Ca(2+) exchangers in the nuclear envelope but not in the plasma membrane. RT-PCR established the presence of the NCX1 subtype in C6 cells and both NCX1 and NCX2 in astrocytes. Comparison was made with NG108-15 cells, which have Na(+)/Ca(2+) exchangers in both nuclear and plasma membranes, and Jurkat cells, which have no Na(+)/Ca(2+) exchanger in either membrane. Culturing of C6 cells in the presence dibutyryl-cAMP caused upregulation of a high molecular weight isoform of the exchanger together with GM1 in the nuclear envelope, resulting in significant elevation of Na(+)/Ca(2+) exchanger activity in the latter. Application of exogenous GM1 to nuclei from non-treated cells also potentiated exchanger activity, although to a lesser degree. The Na(+)/Ca(2+) exchanger/GM1 complex occurs in the inner membrane of the nuclear envelope, suggesting a functional role in transferring Ca(2+) between nucleoplasm and the envelope lumen. PMID:15079865

Xie, Xin; Wu, Gusheng; Ledeen, Robert W

2004-05-01

260

Effect of the ganglioside GM1 on neurologic function, electroencephalogram amplitude, and histology in chronic middle cerebral artery occlusion in cats.  

PubMed

The effect of the ganglioside GM1 on amplitude of the electroencephalogram, neurologic function, and histology has been studied in chronic middle cerebral artery occlusion in cats. Ischemia was produced by a 2-hour occlusion of the left middle cerebral artery and was followed by a 7-day observation period. GM1 was intravenously administered 30 minutes after occlusion and daily during the observation period. Using the reduction in the electroencephalogram amplitude to measure stroke severity, three cats with mild, three cats with moderate, and three cats with severe stroke were treated with 5 mg/kg GM1. Nine cats, three in each group, were treated with 30 mg/kg GM1, while nine cats, three in each group, received middle cerebral artery occlusion but no treatment. In all cats there was a precipitous fall in mean electroencephalogram amplitude during occlusion, followed by a secondary fall during the observation period. Treated cats showed better recovery of electroencephalogram amplitude during the first 4 hours of reperfusion and a smaller secondary fall than untreated cats. Treated cats, especially those treated with 5 mg/kg GM1, showed significant recovery of neurologic deficits compared with untreated cats. Histologic damage was less in treated cats than in untreated cats. Some cats treated with 30 mg/kg GM1 exhibited convulsions, whereas no untreated cat showed any seizure activity. Our findings suggest that gangliosides may improve the recovery of both neurologic deficits and morphologic damage in the central nervous system. These positive effects might be tentatively explained by stimulation of enzymatic activities such as Na+, K+-ATPase and adenyl cyclase. PMID:3400101

Komatsumoto, S; Greenberg, J H; Hickey, W F; Reivich, M

1988-08-01

261

1H-NMR assignments of GM1-oligosaccharide in deuterated water at 500 MHz by two-dimensional spin-echo J-correlated spectroscopy  

SciTech Connect

The 1H-NMR spectra of the oligosaccharide derived from monosialoganglioside GM1 (GM1 = beta-D-galactosyl-(1-3)-beta-D-N-acetylgalactosaminyl-(1-4)- (alpha-N-acetylneuraminyl-(2-3)-)-beta-D-galactosyl-(1-4)-b eta-D-glucosylceramide) (GM1OS) and its reduced form (GM1OS-R) have been obtained at 500 MHz in D2O. Through the combined use of one-dimensional and homonuclear two-dimensional spin-echo J-correlated (2D SECSY) spectra of GM1OS-R, the assignments for the ring protons of GM1OS are made. Data on chemical shifts and coupling constants of GM1OS including the alpha-linked neuraminic acid protons, in aqueous solution, are tabulated. Due to the very small coupling constants (less than 2 Hz) and the closeness in chemical shifts (less than 0.04 ppm) for the pair of correlated peaks in the two-dimensional spectrum, the information on the connectivities of the H5 ring protons of the neutral sugar residues is missing. Second-order coupling also blurs this information. Data are compared with those obtained for ganglioside GM1 in dimethyl sulfoxide (DMSO; the actual composition therein was 97% DMSO-d6 and 3% D2O) by T. A. W. Koerner, J. H. Prestegard, P. C. Demou, and R. K. Yu. While the heterogeneity of chemical shifts for the H5, H6a, and H6b protons diminishes in D2O, that for A-9a and A-9b remains. The latter suggests an intraneuraminic acid conformation involving the glycerol side chain unaffected by the solvent. Moreover, the chemical shifts of the III-1, III-2, and A-4 protons (and perhaps the II-4, IV-2, and A-8 protons) in D2O exhibit unusual upfield shifts compared with those in DMSO. This indicates that the intramolecular interactions between GalNAc residue III and neuraminic acid present in DMSO are weakened in D2O. The effect of temperature on the conformation is also examined and appears to be minimal (less than 0.02 ppm) in the range 22-50 degrees C.

Ong, R.L.; Yu, R.K.

1986-02-15

262

A common mutation site in the beta-galactosidase gene originates in Puerto Rico.  

PubMed

Several mutation sites have been found in the beta-galactosidase gene of patients with GM1 gangliosidosis. In a previous report we found a common point mutation site in American patients with GM1 gangliosidosis resulting in a 208Arg --> Cys amino acid substitution. From the patients' family history, we suggested that this mutation may have come to South and North America via Puerto Rico. Four new patients with infantile GM1 gangliosidosis have been analyzed with allele-specific hybridization. Two siblings from Puerto Rico of Spanish ancestry are homozygous for this mutation. Another patient also from Puerto Rico is heterozygous for this allele, and another black patient does not have this mutation. These results support our initial hypothesis that this mutation has probably arisen in Puerto Rico. PMID:8652017

Chiu, N C; Qian, W H; Shanske, A L; Brooks, S S; Boustany, R M

1996-01-01

263

The GM1 Gangliosidoses  

Microsoft Academic Search

The gangliosidoses are a group of lysosomal storage diseases characterized by the accumulation of these complex glycolipids\\u000a in multiple organs of the body. They manifest a predominantly neurological phenotype, a fact that is probably related to their\\u000a high prevalence in nervous tissues. The typical presentation is that of a progressive neurodegenerative disease with onset\\u000a in early life followed by loss

Gustavo Charria-Ortiz

264

Molecular and structural studies of the GM2 gangliosidosis 0 variant  

Microsoft Academic Search

To determine the molecular basis of the GM2 gangliosidosis 0 variant, we constructed a three-dimensional structure of the\\u000a human ?-hexosaminidase ?-subunit by homology modeling. It is composed of two domains, domains I and II, and has three disulfide\\u000a bonds. C534 is located on an extra helix in domain II and forms a disulfide bond with C551. The extra helix is

Hitoshi Sakuraba; Fumiko Matsuzawa; Sei-ichi Aikawa; Hirofumi Doi; Masaharu Kotani; Hou Lin; Kousaku Ohno; Akemi Tanaka; Hideo Yamada; Ei-ichiro Uyama

2002-01-01

265

GM2 gangliosidosis (Sandhoff's disease): two year follow-up by MRI  

Microsoft Academic Search

Two children with GM-2 gangliosidosis type 0 (Sandhoff's disease) followed up by MRI at 1.5 Tesla for 1.8 years are reported. One was presymptomatic at the first MRI examination. As her neurological status deteriorated, MRI showed low signal in bilaterally, on T2-weighted images the white matter with involvement of the optic radiations. In the second, MRI correlated well with the

W. Koelfen; M. Freund; W. Jaschke; S. Koenig; C. Schultze

1994-01-01

266

Genetic complementation in somatic cell hybrids of four variants of infantile G M2 gangliosidosis  

Microsoft Academic Search

Summary  Cell hybridizations between fibroblasts of four variants (B, O, AB, and B1) of infantile GM2 gangliosidosis were performed. Cocultivated as well as hybrid cells were analyzed for their capability to degrade exogenously\\u000a added [3H]-GM2. Hybridization of variant AB fibroblasts with fibroblasts of variant O, variant B, or variant B1 resulted in an enhanced\\u000a rate of GM2 hydrolysis, showing intergenic complementation.

S. Sonderfeld; S. Brendler; K. Sandhoff; H. Galjaard; A. T. Hoogeveen

1985-01-01

267

Generalized gangliosidosis: Acid ?-galactosidase deficiency with early onset, rapid mental deterioration and minimal bone dysplasia  

Microsoft Academic Search

This report concerns a 3-month-old girl with rapidly progressive psychomotor retardation, hepatomegaly, vacuolated lymphocytes, minimal bone dysplasia and normal excretion of acid mucopolysaccharides. A deficiency of acid ß-galactosidase was demonstrated in isolated leucocytes and in a liver biopsy. The diagnosis of generalized gangliosidosis due to deficiency of ß-galactosidase was also based on the absence of the enzyme activity from cultured

H. Fricker; J. S. O'Brien; F. Vassella; E. Gugler; J. P. Mühlethaler; M. Spycher; U. N. Wiesmann; N. Herschkowitz

1976-01-01

268

Responses of cortical noradrenergic and somatostinergic fibres and terminals to adjacent strokes and subsequent treatment with NGF and/or the ganglioside GM1.  

PubMed

The occurrence of sprouting by fibre systems in the neocortex following lesion is still a controversial issue. In previous studies, we showed a nerve growth factor (NGF)-induced sprouting and hypertrophy of presynaptic terminals in the cholinergic fibres of the rat neocortex following stroke-type lesions, effects that were potentiated by the monosialoganglioside GM1. The present study investigated whether exogenous NGF and/or GM1 treatment could also affect the noradrenergic and somatostinergic systems in the neocortex. Immediately following unilateral vascular decortication, adult rats received, via minipump, a 7-day infusion of vehicle, NGF (12 microg/day) and/or GM1 (1.5 mg/day) into the cerebroventricular space. Thirty days postlesion, the animals were perfused with histological fixatives, the brains were removed, and relevant sections were processed for dopamine beta-hydroxylase and somatostatin immunocytochemistry at the light and electron microscopic levels. A Quantimet 920 image analysis system was used for the quantification of fibre length and size of presynaptic boutons. The lesion caused a reduction in the dopamine beta-hydroxylase-immunoreactive fibre length, which was not attenuated by either NGF or GM1 treatment or both. The somatostatin-immunoreactive network, in contrast, was unaffected by the lesion, and there was no sprouting of somatostatin fibres following trophic factor therapy. We also found no significant differences in the size and number of synapses of both the dopamine beta-hydroxylase-immunoreactive and somatostatin-immunoreactive boutons following lesion and drug treatments. These results indicate that NGF and/or GM1 therapies do not cause regrowth in the noradrenergic and somatostatinergic cortical fibre networks or their presynaptic elements following a cortical devascularizing lesion. PMID:9404724

Tajrine, D; Garofalo, L; Cuello, A C; Ribeiro-da-Silva, A

1997-11-15

269

Molecular heterogeneity in the infantile and juvenile forms of Sandhoff disease (O-variant GM2 gangliosidosis).  

PubMed

There are two major beta-hexosaminidase, EC 3.2.1.52, isozymes in normal human tissues. They exist as active dimers of alpha- and/or beta-subunits. A defect of their beta-subunit results in Sandhoff disease (O-variant GM2 gangliosidosis), an inherited, clinically heterogeneous, lysosomal storage disease. The status of the HEXB gene, pre beta-polypeptide chain mRNA, and residual beta-hexosaminidase activities were examined in a clinically and ethnically diverse collection of 16 fibroblast cell lines from patients with Sandhoff disease. Differentiation of the two major clinical types, infantile and juvenile onset, could be made by the determination of the activity of the residual beta-hexosaminidase eluting in the same pH range as hexosaminidase A. All the juvenile lines were found to have normal or reduced levels of pre beta-chain mRNA and no gross abnormalities in the HEXB gene. Of the 11 infantile type cell lines examined, four were found to contain no detectable pre beta-chain mRNA. Two cell lines in this group contained partial gene deletions localized to the 5' end of the HEXB gene. One of these cell lines has previously been assigned to the single complementation group in Sandhoff disease, conclusively demonstrating that the primary gene defect in the majority of Sandhoff cases is in the HEXB gene itself. These data suggest that each clinical group is made up of a collection of different HEXB mutations. PMID:3017984

O'Dowd, B F; Klavins, M H; Willard, H F; Gravel, R; Lowden, J A; Mahuran, D J

1986-09-25

270

Selection of GM2, fucosyl GM1, globo H and polysialic acid as targets on small cell lung cancers for antibody mediated immunotherapy  

Microsoft Academic Search

Glycolipids GM2, GD2, GD3, fucosyl GM1, sialyl Lewis a (sLea) and globo H, and polysialic acid on embryonal NCAM, are cell-surface antigens expressed on small cell lung cancer (SCLC) biopsy specimens. They are all candidates for inclusion in a polyvalent, antibody-inducing vaccine or for adoptive therapy with monoclonal antibodies (mAbs) against SCLC. To identify the minimum optimal combination of target

P. O. Livingston; C. Hood; L. M. Krug; N. Warren; M. G. Kris; T. Brezicka; G. Ragupathi

2005-01-01

271

Sites and temporal changes of gangliosides GM1\\/GM2 storage in the Niemann–Pick disease type C mouse brain  

Microsoft Academic Search

Niemann–Pick disease type C (NPC) is a progressive neurodegenerative disorder with characteristic storage of glycolipids in the brain. This study investigated cellular origin and temporal changes of monosialoganglioside storage in the Balb\\/c npcnih mouse brain by immunohistochemistry. Anti-GM1 gave positive staining of the hippocampus, thalamus, cerebellar molecular and Purkinje cell layers in the 3-week old NPC mouse brain and in

Miyako Taniguchi; Yoko Shinoda; Haruaki Ninomiya; Marie T. Vanier; Kousaku Ohno

2001-01-01

272

Phase variation of a beta-1,3 galactosyltransferase involved in generation of the ganglioside GM1-like lipo-oligosaccharide of Campylobacter jejuni.  

PubMed

Ganglioside mimicry by Campylobacter jejuni lipo-oligosaccharide (LOS) is thought to be a critical factor in the triggering of the Guillain-Barré and Miller-Fisher syndrome neuropathies after C. jejuni infection. The combination of a completed genome sequence and a ganglioside GM1-like LOS structure makes C. jejuni NCTC 11168 a useful model strain for the identification and characterization of the genes involved in the biosynthesis of ganglioside-mimicking LOS. Genome analysis identified a putative LOS biosynthetic cluster and, from this, we describe a putative gene (ORF Cj1139c), which we have termed wlaN, with a significant level of similarity to a number of bacterial glycosyltransferases. Mutation of this gene in C. jejuni NCTC 11168 resulted in a LOS molecule of increased electrophoretic mobility, which also failed to bind cholera toxin. Comparison of LOS structural data from wild type and the mutant strain indicated lack of a terminal beta-1,3-linked galactose residue in the latter. The wlaN gene product was demonstrated unambiguously as a beta-1,3 galactosyltransferase responsible for converting GM2-like LOS structures to GM1-like by in vitro expression. We also show that the presence of an intragenic homopolymeric tract renders the expression of a functional wlaN gene product phase variable, resulting in distinct C. jejuni NCTC 11168 cell populations with alternate GM1 or GM2 ganglioside-mimicking LOS structures. The distribution of wlaN among a number of C. jejuni strains with known LOS structure was determined and, for C. jejuni NCTC 12500, similar wlaN gene phase variation was shown to occur, so that this strain has the potential to synthesize a GM1-like LOS structure as well as the ganglioside GM2-like LOS structure proposed in the literature. PMID:10931344

Linton, D; Gilbert, M; Hitchen, P G; Dell, A; Morris, H R; Wakarchuk, W W; Gregson, N A; Wren, B W

2000-08-01

273

Impairment of ganglioside metabolism in cultured fibroblasts from Salla patients  

Microsoft Academic Search

The metabolic processing of sialoglycolipids (gangliosides) was investigated in cultures of skin fibroblasts obtained from two patients affected with Salla disease. Cultured fibroblasts were fed with GM1 ganglioside [3H]-radiolabelled at the sialic acid ([NeuAc-3H]GM1) or sphingosine ([Sph-3H]GM1) moiety. Formation of metabolites was followed in pulse-chase experiments. It was observed that: (a) Salla fibroblasts, fed with [NeuAc-3H]GM1 accumulate radioactive free sialic

Marina Pitto; Vanna Chigorno; Martin Renlund; Guido Tettamanti

1996-01-01

274

Krabbe's globoid cell leucodystrophy. Studies on galactosylceramide beta-galactosidase and non-specific beta-galactosidase of leucocytes, cultured skin fibroblasts, and amniotic fluid cells.  

PubMed Central

Galactosylceramide beta-galactosidase (cerebrosidase) and nonspecific beta-galactosidase activities were measured in both cultured skin fibroblasts and leucocytes from a family with Krabbe's globoid cell leucodystrophy (GLD). The activities of these enzymes were also determined in cultured skin fibroblasts of a patient with GM1 gangliosidosis and in cultured amniotic fluid cells. While cerebrosidase activity was deficient in GLD fibroblasts and leucocytes, its activity in GM1 gangliosidosis fibroblasts was increased. Two forms of each enzyme were found on isoelectric focusing, but in the GM1 gangliosidosis fibroblasts, cerebrosidase activity occurred as a single but intermediate peak. The use of cultured cells in assessing isoenzyme abnormalities associated with certain neurolipidoses is discussed.

Besley, G T; Bain, A D

1976-01-01

275

Lysosomal multienzymatic complex-related diseases: a genetic study among Portuguese patients.  

PubMed

The functional activity of lysosomal enzymes sialidase, ?-galactosidase and N-acetylaminogalacto-6-sulfate-sulfatase in the cell depends on their association in a multienzyme complex with cathepsin A. Mutations in any of the components of this complex result in functional deficiency thereby causing severe lysosomal storage disorders. Here, we report the molecular defects underlying sialidosis (mutations in sialidase; gene NEU1), galactosialidosis (mutations in cathepsin A; gene PPGB) and GM1 gangliosidosis (mutations in ?-galactosidase; gene GLB1) in Portuguese patients. We performed molecular studies of the PPGB, NEU1 and GLB1 genes in biochemically diagnosed Portuguese patients. Gene expression was determined and the effect of each mutation predicted at protein levels. In the NEU1 gene, we found three novel missense mutations (p.P200L, p.D234N and p.Q282H) and one nonsense mutation (p.R341X). In the PPGB gene, we identified two missense mutations, one novel (p.G86V) and one already described (p.V104M), as well as two new deletions (c.230delC and c.991-992delT) that give rise to non-functional proteins. We also present the first molecular evidence of a causal missense mutation localized to the cathepsin A active site. Finally, in the GLB1 gene, we found six different mutations, all of them previously described (p.R59H, p.R201H, p.H281Y, p.W527X, c.1572-1577InsG and c.845-846delC). Seven novel mutations are reported here, contributing to our knowledge of the mutational spectrum of these diseases and to a better understanding of the genetics of the lysosomal multienzymatic complex. The results of this study will allow carrier detection in affected families and prenatal molecular diagnosis, leading to the improvement of genetic counseling. PMID:21214877

Coutinho, M F; Lacerda, L; Macedo-Ribeiro, S; Baptista, E; Ribeiro, H; Prata, M J; Alves, S

2012-04-01

276

Clinical and molecular analysis of GM2 gangliosidosis in two apparent littermate kittens of the Japanese domestic cat  

Microsoft Academic Search

This case report documents clinical and molecular findings in two littermate kittens of the Japanese domestic cat with GM2 gangliosidosis variant 0. Analysis included detailed physical, magnetic resonance imaging, biochemical, pathological and genetic examinations. At first, these littermate kittens showed typical cerebellar signs at approximately 2 months of age. About 2 months later, they progressively showed other neurological signs and

Daisuke Hasegawa; Osamu Yamato; Masanori Kobayashi; Michio Fujita; Shinichiro Nakamura; Kimimasa Takahashi; Hiroyuki Satoh; Toru Shoda; Daisuke Hayashi; Masahiro Yamasaki; Yoshimitsu Maede; Toshiro Arai; Hiromitsu Orima

2007-01-01

277

Reduced GM1 ganglioside in CFTR-deficient human airway cells results in decreased ?1-integrin signaling and delayed wound repair.  

PubMed

Loss of cystic fibrosis transmembrane conductance regulator (CFTR) function reduces chloride secretion and increases sodium uptake, but it is not clear why CFTR mutation also results in progressive lung inflammation and infection. We previously demonstrated that CFTR-silenced airway cells migrate more slowly during wound repair than CFTR-expressing controls. In addition, CFTR-deficient cells and mouse models have been reported to have altered sphingolipid levels. Here, we investigated the hypothesis that reduced migration in CFTR-deficient airway epithelial cells results from altered sphingolipid composition. We used cell lines derived from a human airway epithelial cell line (Calu-3) stably transfected with CFTR short hairpin RNA (CFTR-silenced) or nontargeting short hairpin RNA (controls). Cell migration was measured by electric cell substrate impedance sensing (ECIS). Lipid analyses, addition of exogenous glycosphingolipids, and immunoblotting were performed. We found that levels of the glycosphingolipid, GM1 ganglioside, were ~60% lower in CFTR-silenced cells than in controls. CFTR-silenced cells exhibited reduced levels of activated ?1-integrin, phosphorylated tyrosine 576 of focal adhesion kinase (pFAK), and phosphorylation of Crk-associated substrate (pCAS). Addition of GM1 (but not GM3) ganglioside to CFTR-silenced cells restored activated ?1-integrin, pFAK, and pCAS to near control levels and partially restored (~40%) cell migration. Our results suggest that decreased GM1 in CFTR-silenced cells depresses ?1-integrin signaling, which contributes to the delayed wound repair observed in these cells. These findings have implications for the pathology of cystic fibrosis, where altered sphingolipid levels in airway epithelial cells could result in a diminished capacity for wound repair after injury. PMID:24500283

Itokazu, Yutaka; Pagano, Richard E; Schroeder, Andreas S; O'Grady, Scott M; Limper, Andrew H; Marks, David L

2014-05-01

278

Galectin-3 protein regulates mobility of N-cadherin and GM1 ganglioside at cell-cell junctions of mammary carcinoma cells.  

PubMed

Galectin-3 binding to cell surface glycoproteins, including branched N-glycans generated by N-acetylglucosaminyltransferase V (Mgat5) activity, forms a multivalent, heterogeneous, and dynamic lattice. This lattice has been shown to regulate integrin and receptor tyrosine kinase signaling promoting tumor cell migration. N-cadherin is a homotypic cell-cell adhesion receptor commonly overexpressed in tumor cells that contributes to cell motility. Here we show that galectin-3 and N-cadherin interact and colocalize with the lipid raft marker GM1 ganglioside in cell-cell junctions of mammary epithelial cancer cells. Disruption of the lattice by deletion of Mgat5, siRNA depletion of galectin-3, or competitive inhibition with lactose stabilizes cell-cell junctions. It also reduces, in a p120-catenin-dependent manner, the dynamic pool of junctional N-cadherin. Proteomic analysis of detergent-resistant membranes (DRMs) revealed that the galectin lattice opposes entry of many proteins into DRM rafts. N-cadherin and catenins are present in DRMs; however, their DRM distribution is not significantly affected by lattice disruption. Galectin lattice integrity increases the mobile fraction of the raft marker, GM1 ganglioside binding cholera toxin B subunit Ctb, at cell-cell contacts in a p120-catenin-independent manner, but does not affect the mobility of either Ctb-labeled GM1 or GFP-coupled N-cadherin in nonjunctional regions. Our results suggest that the galectin lattice independently enhances lateral molecular diffusion by direct interaction with specific glycoconjugates within the adherens junction. By promoting exchange between raft and non-raft microdomains as well as molecular dynamics within junction-specific raft microdomains, the lattice may enhance turnover of N-cadherin and other glycoconjugates that determine junctional stability and rates of cell migration. PMID:22846995

Boscher, Cécile; Zheng, Yu Zi; Lakshminarayan, Ramya; Johannes, Ludger; Dennis, James W; Foster, Leonard J; Nabi, Ivan R

2012-09-21

279

Galectin-3 Protein Regulates Mobility of N-cadherin and GM1 Ganglioside at Cell-Cell Junctions of Mammary Carcinoma Cells*  

PubMed Central

Galectin-3 binding to cell surface glycoproteins, including branched N-glycans generated by N-acetylglucosaminyltransferase V (Mgat5) activity, forms a multivalent, heterogeneous, and dynamic lattice. This lattice has been shown to regulate integrin and receptor tyrosine kinase signaling promoting tumor cell migration. N-cadherin is a homotypic cell-cell adhesion receptor commonly overexpressed in tumor cells that contributes to cell motility. Here we show that galectin-3 and N-cadherin interact and colocalize with the lipid raft marker GM1 ganglioside in cell-cell junctions of mammary epithelial cancer cells. Disruption of the lattice by deletion of Mgat5, siRNA depletion of galectin-3, or competitive inhibition with lactose stabilizes cell-cell junctions. It also reduces, in a p120-catenin-dependent manner, the dynamic pool of junctional N-cadherin. Proteomic analysis of detergent-resistant membranes (DRMs) revealed that the galectin lattice opposes entry of many proteins into DRM rafts. N-cadherin and catenins are present in DRMs; however, their DRM distribution is not significantly affected by lattice disruption. Galectin lattice integrity increases the mobile fraction of the raft marker, GM1 ganglioside binding cholera toxin B subunit Ctb, at cell-cell contacts in a p120-catenin-independent manner, but does not affect the mobility of either Ctb-labeled GM1 or GFP-coupled N-cadherin in nonjunctional regions. Our results suggest that the galectin lattice independently enhances lateral molecular diffusion by direct interaction with specific glycoconjugates within the adherens junction. By promoting exchange between raft and non-raft microdomains as well as molecular dynamics within junction-specific raft microdomains, the lattice may enhance turnover of N-cadherin and other glycoconjugates that determine junctional stability and rates of cell migration.

Boscher, Cecile; Zheng, Yu Zi; Lakshminarayan, Ramya; Johannes, Ludger; Dennis, James W.; Foster, Leonard J.; Nabi, Ivan R.

2012-01-01

280

Galectin-1 is a major receptor for ganglioside GM1, a product of the growth-controlling activity of a cell surface ganglioside sialidase, on human neuroblastoma cells in culture.  

PubMed

Cell density-dependent inhibition of growth and neural differentiation in the human neuroblastoma cell line SK-N-MC are associated with a ganglioside sialidase-mediated increase of GM1 and lactosylceramide at the cell surface. Because these glycolipids expose galactose residues, we have initiated the study of the potential role of galectins in such cellular events. Using specific antibodies, galectin-1 but not galectin-3 was found to be present at the cell surface. Assessment of carbohydrate-dependent binding revealed a saturable amount of ligand sites approaching 2.6 x 10(6) galectin-1 molecules bound/cell. Presence during cell culture of the sialidase inhibitor 2-deoxy-2,3-dehydro-N-acetylneuraminic acid or of the GM1-binding cholera toxin B subunit effected a decrease of the presentation of galectin-1 ligands by 30-50%. The assumption that GM1 is a major ligand for galectin-1 was reinforced by the correlation between the number of carbohydrate-dependent 125I-iodinated GM1-neoganglioprotein binding sites and the amount of immunoreactive surface galectin-1, the marked sensitivity of probe binding to the presence of anti-galectin-1 antibody, and the inhibition of cell adhesion to surface-immobilized GM1 by the antibody. The results open the possibility that the carbohydrate-dependent interaction between ganglioside GM1 and galectin-1 may relay sialidase-dependent alterations in this cell system. PMID:9556610

Kopitz, J; von Reitzenstein, C; Burchert, M; Cantz, M; Gabius, H J

1998-05-01

281

Vacuolating Megalencephalic Leukoencephalopathy in 12 Israeli Patients  

Microsoft Academic Search

Leukodystrophy with macrocephaly as the main features of infantile neurodegenerative disease are characteristics of Canavan's disease, L-2-hydroxyglutaric aciduria, type I glutaric aciduria, and Alexander's disease. Also occasionally described are occidental congenital muscular dystrophy, GM2-gangliosidosis, metachromatic leukodystrophy, Krabbe's disease, and mucopolysaccharidosis. Since 1995, over 60 patients with a new syndrome, vacuolating megalencephalic leukoencephalopathy, have been described. The syndrome is characterized by

Bruria Ben-Zeev; Varda Gross; Tamar Kushnir; Ruth Shalev; Chen Hoffman; Yael Shinar; Eilo Pras; Nathan Brand

2001-01-01

282

Late onset GM2 gangliosidosis mimicking spinal muscular atrophy.  

PubMed

A case of late onset GM2 gangliosidodis with spinal muscular atrophy phenotype followed by cerebellar and extrapyramidal symptoms is presented. Genetic analysis revealed compound heterozygous mutation in exon 10 of the HEXA gene. Patient has normal intelligence and emotional reactivity. Neuroimaging tests of the brain showed only cerebellar atrophy consistent with MR spectroscopy (MRS) abnormalities. (18)F-fluorodeoxyglucose positron emission tomography (18)F-FDG PET/CT of the brain revealed glucose hypometabolism in cerebellum and in temporal and occipital lobes bilaterally. PMID:23820084

Jamrozik, Z; Lugowska, A; Go??biowski, M; Królicki, L; M?czewska, J; Ku?ma-Kozakiewicz, M

2013-09-25

283

GM2 gangliosidosis in Saudi Arabia: multiple mutations and considerations for future carrier screening.  

PubMed

The GM2 gangliosidose, Tay-Sachs and Sandhoff diseases, are a class of lysosomal storage diseases in which relentless neurodegeneration results in devastating neurological disability and premature death. Primary prevention is the most effective intervention since no effective therapy is currently available. An extremely successful model for the prevention of GM2 gangliosidosis in the Ashkenazi Jewish community is largely attributable to the very limited number of founder mutations in that population. Consistent with our previous observation of allelic heterogeneity in consanguineous populations, we show here that these diseases are largely caused by private mutations which present a major obstacle in replicating the Ashkenazi success story. Alternative solutions are proposed which can also be implemented for other autosomal recessive diseases in our population. PMID:21567908

Kaya, Namik; Al-Owain, Mohammad; Abudheim, Nada; Al-Zahrani, Jawaher; Colak, Dilek; Al-Sayed, Moeen; Milanlioglu, Aysel; Ozand, Pinar T; Alkuraya, Fowzan S

2011-06-01

284

A Trp474Cys mutation in the alpha-subunit of beta-hexosaminidase causes a subacute encephalopathic form of G{sub M2} gangliosidosis, type 1  

SciTech Connect

Mutations in the HEXA gene that encodes the {alpha}-subunit of the heterodimeric lysosomal enzyme {beta}-hexosaminidase A, or Hex A ({alpha}{beta}), cause G{sub M2} gangliosidosis, type 1. The infantile form (Tay-Sachs disease) results when there is no residual Hex A activity, while less severe and more variable clinical phenotypes result when residual Hex A activity is present. A non-Jewish male who presented with an acute psychotic episode at age 16 was diagnosed with a subacute encephalopathic form of G{sub M2} gangliosidosis. At age 19, chronic psychosis with intermittent acute exacerbations remains the most disabling symptom in this patient and his affected brother although both exhibit some ataxia and moderately severe dysarthria. We have found a 4 bp insertion (+TATC 1278) associated with infantile Tay-Sachs disease on one allele; no previously identified mutation was found on the second allele. SSCP analysis detected a shift in exon 13 and sequencing revealed a G1422C mutation in the second allele that results in a Trp474Cys substitution. The presence of the mutation was confirmed by the loss of HaeIII and ScrFI sites in exon 13 PCR products from the subjects and their father. The mutation was introduced into the {alpha}-subunit cDNA and Hex S ({alpha}{alpha}) and Hex A ({alpha}{beta}) were transiently expressed in monkey COS-7 cells. The Trp474Cys mutant protein had approximately 5% and 12% of wild-type Hex S and Hex A activity, respectively. Western blot analysis revealed a small amount of residual mature {alpha}-subunit and a normal level of precursor protein. We conclude that the Trp474Cys mutation is the cause of the Hex A deficiency associated with a subacute (juvenile-onset) phenotype in this patient. Like other mutations in exon 13 of HEXA, it appears to affect intracellular processing. Studies of the defect in intracellular processing are in progress.

Petroulakis, E.; Cao, Z.; Salo, T. [Univ. of Manitoba, Winnipeg (Canada)] [and others

1994-09-01

285

[Molecular pathogenesis and therapeutic approach of GM2 gangliosidosis].  

PubMed

Tay-Sachs and Sandhoff diseases (GM2 gangliosidoses) are autosomal recessive lysosomal storage diseases caused by gene mutations in HEXA and HEXB, each encoding human lysosomal ?-hexosaminidase ?-subunits and ?-subunits, respectively. In Tay-Sachs disease, excessive accumulation of GM2 ganglioside (GM2), mainly in the central nervous system, is caused by a deficiency of the HexA isozyme (?? heterodimer), resulting in progressive neurologic disorders. In Sandhoff disease, combined deficiencies of HexA and HexB (?? homodimer) cause not only the accumulation of GM2 but also of oligosaccharides carrying terminal N-acetylhexosamine residues (GlcNAc-oligosaccharides), resulting in systemic manifestations including hepatosplenomegaly as well as neurologic symptoms. Hence there is little clinically effective treatment for these GM2 gangliosidoses. Recent studies on the molecular pathogenesis in Sandhoff disease patients and disease model mice have shown the involvement of microglial activation and chemokine induction in neuroinflammation and neurodegeneration in this disease. Experimental and therapeutic approaches, including recombinant enzyme replacement, have been performed using Sandhoff disease model mice, suggesting the future application of novel techniques to treat GM2 gangliosidoses (Hex deficiencies), including Sandhoff disease as well as Tay-Sachs disease. In this study, we isolated astrocytes and microglia from the neonatal brain of Sandhoff disease model mice and demonstrated abnormalities of glial cells. Moreover, we demonstrated the therapeutic effect of an intracerebroventricular administration of novel recombinant human HexA carrying a high content of M6P residue in Sandhoff disease model mice. PMID:23370522

Tsuji, Daisuke

2013-01-01

286

The Mutations in Ashkenazi Jews with Adult GM2 Gangliosidosis, the Adult Form of Tay-Sachs Disease  

Microsoft Academic Search

The adult form of Tay-Sachs disease, adult GM2 gangliosidosis, is an autosomal recessive disorder that results from mutations in the alpha chain of beta -hexosaminidase A. This disorder, like infantile Tay-Sachs disease, is more frequent in the Ashkenazi Jewish population. A point mutation in the alpha -chain gene was identified that results in the substitution of Gly269 with Ser in

Ruth Navon; Richard L. Proia

1989-01-01

287

GM2 gangliosidosis associated with a HEXA missense mutation in Japanese Chin dogs: a potential model for Tay Sachs disease.  

PubMed

GM2 gangliosidosis is a fatal lysosomal storage disease caused by a deficiency of ?-hexosaminidase (EC 3.2.1.52). There are two major isoforms of the enzyme: hexosaminidase A composed of an ? and a ? subunit (encoded by HEXA and HEXB genes, respectively); and, hexosaminidase B composed of two ? subunits. Hexosaminidase A requires an activator protein encoded by GM2A to catabolize GM2 ganglioside, but even in the absence of the activator protein, it can hydrolyze the synthetic substrates commonly used to assess enzyme activity. GM2 gangliosidosis has been reported in Japanese Chin dogs, and we identified the disease in two related Japanese Chin dogs based on clinical signs, histopathology and elevated brain GM2 gangliosides. As in previous reports, we found normal or elevated hexosaminidase activity when measured with the synthetic substrates. This suggested that the canine disease is analogous to human AB variant of G(M2) gangliosidosis, which results from mutations in GM2A. However, only common neutral single nucleotide polymorphisms were found upon sequence analysis of the canine ortholog of GM2A from the affected Japanese Chins. When the same DNA samples were used to sequence HEXA, we identified a homozygous HEXA:c967G>A transition which predicts a p.E323K substitution. The glutamyl moiety at 323 is known to make an essential contribution to the active site of hexosaminidase A, and none of the 128 normal Japanese Chins and 92 normal dogs of other breeds that we tested was homozygous for HEXA:c967A. Thus it appears that the HEXA:c967G>A transition is responsible for the GM2 gangliosidosis in Japanese Chins. PMID:23266199

Sanders, Douglas N; Zeng, Rong; Wenger, David A; Johnson, Gary S; Johnson, Gayle C; Decker, Jared E; Katz, Martin L; Platt, Simon R; O'Brien, Dennis P

2013-01-01

288

Unusual Presentation of GM2 Gangliosidosis Mimicking a Brain Stem Tumor in a 3YearOld Girl  

Microsoft Academic Search

Summary: We report a case of GM2 gangliosidosis revealed by MR imaging of an isolated brain stem abnormality in a 3-year-old girl referred for gait difficulties related to ataxia and pyramidal signs. Brain MR imaging displayed a brain stem lesion with high signal intensity on fluid-attenuated inversion recovery and T2-weighted images, suggesting ei- ther a tumor or an inflammatory process.

Marie-Cecile Nassogne; Marie-Christine Commare; Arielle Lellouch-Tubiana; Sophie Emond; Michel Zerah; Catherine Caillaud; Lucie Hertz-Pannier; Jean-Marie Saudubray

289

Biochemical and Molecular Aspects of Late-Onset GM2Gangliosidosis: B1 Variant as a Prototype  

Microsoft Academic Search

Clinical phenotypes of GM2-gangliosidosis are complex. In the past 5 years it has become possible to dissect out the phenotypic complexity on the basis of abnormalities on the DNA level. Available data on the 18 disease-causing mutations so far identified in the P-hexosaminidase ?-gene allow an oversimplified generalization; mutations that produce no or highly unstable mRNA cause the most severe

Kunihiko Suzuki; Marie T. Vanier

1991-01-01

290

Ultrastructural pathology of human lymphocytes in lysosomal disorders: a contribution to their morphological diagnosis  

Microsoft Academic Search

Ultrastructural examination of peripheral lymphocytes was performed in 28 cases of various lysosomal diseases, including infantile, late infantile and juvenile neuronal ceroid-lipofuscinoses (NCL), mucopolysaccharidoses (MPS), juvenile and adult metachromatic leukodystrophies (MLD), GM1-gangliosidosis, one patient with presumed mucolipidosis type IV, mucolipidosis type III, and glycogenosis type II. Based on our own observations on the ultrastructure of lymphocytes in lysosomal disorders, our

K. Ikeda; H. H. Goebel; U. Burck; A. Kohlschütter

1982-01-01

291

Clinical and molecular analysis of GM2 gangliosidosis in two apparent littermate kittens of the Japanese domestic cat.  

PubMed

This case report documents clinical and molecular findings in two littermate kittens of the Japanese domestic cat with GM2 gangliosidosis variant 0. Analysis included detailed physical, magnetic resonance imaging, biochemical, pathological and genetic examinations. At first, these littermate kittens showed typical cerebellar signs at approximately 2 months of age. About 2 months later, they progressively showed other neurological signs and subsequently died at about 7 months of age. Magnetic resonance imaging just before the death showed an enlarged ventricular system, T1 hyperintensity in the internal capsule, and T2 hyperintensity in the white matter of the whole brain. Histological findings suggested a type of lysosomal storage disease. Biochemical studies demonstrated that the kittens were affected with GM2 gangliosidosis variant 0, and a DNA assay finally demonstrated that these animals were homozygous for the mutation, which the authors had identified in a different family of the Japanese domestic cat. The findings in the present cases provide useful information about GM2 gangliosidosis variant 0 in Japanese domestic cats. PMID:17198760

Hasegawa, Daisuke; Yamato, Osamu; Kobayashi, Masanori; Fujita, Michio; Nakamura, Shinichiro; Takahashi, Kimimasa; Satoh, Hiroyuki; Shoda, Toru; Hayashi, Daisuke; Yamasaki, Masahiro; Maede, Yoshimitsu; Arai, Toshiro; Orima, Hiromitsu

2007-06-01

292

Ganglioside GM1/galectin-dependent growth regulation in human neuroblastoma cells: special properties of bivalent galectin-4 and significance of linker length for ligand selection.  

PubMed

Orchestrated upregulation of cell surface presentation of ganglioside GM1 and homodimeric galectin-1 is the molecular basis for growth regulation of human neuroblastoma (SK-N-MC) cells. Further study led to the discovery of competitive inhibition by galectin-3, prompting us to test tandem-repeat-type galectin-4 (two different lectin domains connected by a 42-amino-acid linker). This lectin bound to cells at comparably high affinity without involvement of the ganglioside, as disclosed by assays in the presence of cholera toxin B-subunit or galectin-1 and blocking glucosylceramide synthesis. Notably, when tested separately, binding of both lectin domains showed partial sensitivity to the bacterial agglutinin. Despite its ability for cross-linking surface association of galectin-4 did not affect proliferation, in contrast to homodimeric galectins. The truncation of linker length from 42 to 16 amino acids altered binding properties to let partial sensitivity to the bacterial lectin emerge. Cross-competition between parental and engineered proteins did not exceed 40%. No effect on cell growth was detected. This study reveals complete functional divergence between galectins differing in the spatial mode of lectin-site presentation and dependence of reactivity to distinct counter-receptor(s) on linker length. Due to the documented presence of galectin-4 in the nervous system and its affinity for sulfatide these in vitro results indicate the potential for a distinct functionality profile of this lectin in vivo, giving further research direction. PMID:22234579

Kopitz, Jürgen; Ballikaya, Seda; André, Sabine; Gabius, Hans-Joachim

2012-06-01

293

EXPERIENTIAL FACTORS IN THE EXPRESSION OF HYPERMOTILITY PRODUCED BY INTRADENTATE COLCHICINE: LACK OF EFFECT OF GM1 GANGLIOSIDE ON COLCHICINE-INDUCED LOSS OF GRANULE CELLS AND MOSSY FIBERS (JOURNAL VERSION)  

EPA Science Inventory

Adult, male Fischer-344 rats were given bilateral injections of 2.5 microgram colchicine or artificial cerebrospinal fluid into caudal and rostral sites of the dentate gyrus of the hippocampus. One group of rats received 21 consecutive daily injections of 20 mg/kg GM1 ganglioside...

294

Intracellular processing and maturation of mutant gene products in hereditary ?-galactosidase deficiency (?-galactosidosis)  

Microsoft Academic Search

Heterogeneous patterns of biosynthesis, post-translational processing, and degradation were demonstrated for mutant enzymes in three clinical forms of ß-galactosidase deficiency (ß-galactosidosis): juvenile GM1-gangliosidosis, adult GM1-gangliosidosis, and Morquio B disease. The precursor of the mutant enzyme in adult GM1-gangliosidosis was not phosphorylated, and only a small portion of the gene product reached the lysosomes. The enzyme in Morquio B disease was

Akihiro Oshima; Kunihiro Yoshida; Kohji Itoh; Ryoichi Kase; Hitoshi Sakuraba; Yoshiyuki Suzuki

1994-01-01

295

Anti-asialo GM1 antiserum treatment of lethally irradiated recipients before bone marrow transplantation: Evidence that recipient natural killer depletion enhances survival, engraftment, and hematopoietic recovery  

SciTech Connect

Natural killer (NK) cells are reported to have an important role in the resistance of lethally irradiated recipients to bone marrow transplantation (BMT). Therefore, we investigated the effects of recipient NK depletion on survival, chimerism, and hematopoietic reconstitution after lethal irradiation and the transplantation of limiting amounts of T-cell-deficient bone marrow (BM). When administered before BMT, anti-asialo GM1 (ASGM1) antiserum treatment, effective in depleting in vivo NK activity, was associated with a marked increase in survival in 3 of 3 allogeneic combinations (BALB/c into C3H/HeN, C57B1/6, or C3B6F1). This enhanced survival was independent of the susceptibility of each recipient strain to accept BALB/c BM. Moreover, recipient anti-ASGM1 treatment was also effective in increasing survival in recipients of syngeneic BM, suggesting that NK cells can adversely affect engraftment independent of genetically controlled polymorphic cell surface determinants. Analysis of chimerism in surviving animals 2 months post-BMT showed that recipient NK depletion significantly increased the level of donor engraftment when high doses of BM were transplanted. These studies also demonstrated that anti-ASGM1 pretreatment mainly resulted in an increase in extramedullary hematopoiesis in the second and third week after irradiation. Anti-ASGM1 treatment also dramatically accelerated the rate of appearance of donor-derived cells with a higher level of donor-cell engraftment apparent at a time when the differences in survival between NK-depleted and control BMT recipients became significant. Peripheral cell counts were also affected by NK depletion, with significantly enhanced platelet and red blood cell recovery and a moderate increase in granulocyte recovery.

Tiberghien, P.; Longo, D.L.; Wine, J.W.; Alvord, W.G.; Reynolds, C.W. (Program Resources, Inc., Frederick, MD (USA))

1990-10-01

296

Thymic involution and corticosterone level in Sandhoff disease model mice: new aspects the pathogenesis of GM2 gangliosidosis.  

PubMed

Sandhoff disease (SD) is a lysosomal disease caused by a mutation of the HEXB gene associated with excessive accumulation of GM2 ganglioside (GM2) in lysosomes and neurological manifestations. Production of autoantibodies against the accumulated gangliosides has been reported to be involved in the progressive pathogenesis of GM2 gangliosidosis, although the underlying mechanism has not been fully elucidated. The thymus is the key organ in the acquired immune system including the development of autoantibodies. We showed here that thymic involution and an increase in cell death in the organ occur in SD model mice at a late stage of the pathogenesis. Dramatic increases in the populations of Annexin-V(+) cells and terminal deoxynucletidyl transferase dUTP nick end labeling (TUNEL) (+) cells were observed throughout the thymuses of 15-week old SD mice. Enhanced caspase-3/7 activation, but not that of caspase-1/4, -6 ,-8, or -9, was also demonstrated. Furthermore, the serum level of corticosterone, a potent inducer of apoptosis of thymocytes, was elevated during the same period of apoptosis. Our studies suggested that an increase in endocrine corticosterone may be one of the causes that accelerate the apoptosis of thymocytes leading to thymic involution in GM2 gangliosidosis, and thus can be used as a disease marker for evaluation of the thymic condition and disease progression. PMID:21598013

Matsuoka, Kazuhiko; Tsuji, Daisuke; Taki, Takao; Itoh, Kohji

2011-10-01

297

[Hereditary lysosomal diseases in Mexico. III. Laboratory diagnosis of sphingolipidosis].  

PubMed

Enzymatic determinations of the levels of lysosomal enzymes in serum or leukocytes samples have been carried out for the diagnosis of 7 sphingolipidosis. This methodology has allowed us to study 49 homozygotes and 33 close relatives at risk for the carrier state of a particular sphingolipidosis. So far we have diagnosed: 21 Gaucher's disease patients, 17 metachromatic leukodistrophy, 4 Niemann-Pick, 4 GM2 gangliosidosis, 2 Fabry and one GM1 gangliosidosis. Limitations in the performance and interpretation of the levels of the defective enzyme in heterozygotes, homozygotes and those variants not detected with the assays described are discussed. PMID:1907757

Zetina, M E; González-Noriega, A

1991-01-01

298

AB Variant of Infantile GM2 Gangliosidosis: Deficiency of a Factor Necessary for Stimulation of Hexosaminidase A-Catalyzed Degradation of Ganglioside GM2 and Glycolipid GA2  

Microsoft Academic Search

Human kidney extracts heated to 60 degrees and devoid of hexosaminidase activity (2-acetamido-2-deoxy-beta -D-glucoside acetamidodeoxyglucohydrolase EC 3.2.1.30) stimulate more than 20-fold the hexosaminidase A-catalyzed degradation of ganglioside GM2 and of glycolipid GA2, the neuronal storage compounds of GM2 gangliosidosis. The stimulating factor of this extract, which is labile at temperatures above 60 degrees, is also present in kidney extracts from

E. Conzelmann; K. Sandhoff

1978-01-01

299

A Trp474Cys mutation in the alpha-subunit of beta-hexosaminidase causes a subacute encephalopathic form of G{sub M2} gangliosidosis, type 1  

Microsoft Academic Search

Mutations in the HEXA gene that encodes the α-subunit of the heterodimeric lysosomal enzyme β-hexosaminidase A, or Hex A (αβ), cause G{sub M2} gangliosidosis, type 1. The infantile form (Tay-Sachs disease) results when there is no residual Hex A activity, while less severe and more variable clinical phenotypes result when residual Hex A activity is present. A non-Jewish male who

E. Petroulakis; Z. Cao; T. Salo

1994-01-01

300

High Galactosidase and Ganglioside G M1 Levels in the Human Parotid Gland  

Microsoft Academic Search

Background: Ganglioside GM1 is a membrane glycolipid typical of nerve cell membranes, where it partakes in neu- rotransmitter release and is catabolized by the lysosomal -galactosidase (GM1ase) (EC 3.2.1.23). After demon- strating a novel degenerative disease of the parotid gland in mice deficient in GM1ase, mimicking the human stor- age disease GM1 gangliosidosis, we studied GM1ase and ganglioside GM1 content

Nakisa Nowroozi; Toshitsugu Kawata; Peixin Liu; Dale Rice; Joseph H. Zernik

2001-01-01

301

Determination of structural and functional overlap/divergence of five proto-type galectins by analysis of the growth-regulatory interaction with ganglioside GM1 in silico and in vitro on human neuroblastoma cells.  

PubMed

The growth-regulatory interplay between ganglioside GM1 on human SK-N-MC neuroblastoma cells and an endogenous lectin provides a telling example for glycan (polysaccharide) functionality. Galectin-1 is the essential link between the sugar signal and the intracellular response. The emerging intrafamily complexity of galectins raises the question on defining extent of their structural and functional overlap/divergence. We address this problem for proto-type galectins in this system: ganglioside GM1 as ligand, neuroblastoma cells as target. Using the way human galectin-1 interacts with this complex natural ligand as template, we first defined equivalent positioning for distinct substitutions in the other tested proto-type galectins, e.g., Lys63 vs. Leu60/Gln72 in galectins-2 and -5. As predicted from our in silico work, the tested proto-type galectins have affinity for the pentasaccharide of ganglioside GM1. In contrast to solid-phase assays, cell surface presentation of the ganglioside did not support binding of galectin-5, revealing the first level of regulation. Next, a monomeric proto-type galectin (CG-14) can impair galectin-1-dependent negative growth control by competitively blocking access to the shared ligand without acting as effector. Thus, the quaternary structure of proto-type galectins is an efficient means to give rise to functional divergence. The identification of this second level of regulation is relevant for diagnostic monitoring. It might be exploited therapeutically by producing galectin variants tailored to interfere with galectin activities associated with the malignant phenotype. Moreover, the given strategy for comparative computational analysis of extended binding sites has implications for the rational design of galectin-type-specific ligands. PMID:15523676

André, Sabine; Kaltner, Herbert; Lensch, Martin; Russwurm, Roland; Siebert, Hans-Christian; Fallsehr, Christine; Tajkhorshid, Emad; Heck, Albert J R; von Knebel Doeberitz, Magnus; Gabius, Hans-Joachim; Kopitz, Juergen

2005-03-10

302

Impairment of ganglioside metabolism in cultured fibroblasts from Salla patients.  

PubMed

The metabolic processing of sialoglycolipids (gangliosides) was investigated in cultures of skin fibroblasts obtained from two patients affected with Salla disease. Cultured fibroblasts were fed with GM1 ganglioside [3H]-radiolabelled at the sialic acid ([NeuAc-3H]GM1) or sphingosine ([Sph-3H]GM1) moiety. Formation of metabolites was followed in pulse-chase experiments. It was observed that: (a) Salla fibroblasts, fed with [NeuAc-3H]GM1 accumulate radioactive free sialic acid in the lysosomal compartment and show a much lower sialic acid re-cycling for biosynthetic purposes than control fibroblasts, as demonstrated by decreased incorporation of the label into glycolipids and glycoproteins; (b) Salla fibroblasts, fed with [NeuAc-3H]GM1 or [Sph-3H]GM1, tend to accumulate gangliosides GM2 and GM3, and to reduce the breakdown products following the desialosylation step, presumably as a consequence of the inhibition of sialidase by free sialic acid; (c) owing to (b) the basal production of the bioregulators of sphingoid nature, ceramide and sphingosine, is reduced, as well as re-cycling of these substances for biosynthetic purposes, with further reduction of the turnover rate of sphingolipids. The decreased turnover rate of sialoglycoconjugates and sphingolipids, together with the diminished formation of bioregulators of sphingoid nature, may play a relevant role in the pathogenesis of the disease. PMID:8920233

Pitto, M; Chigorno, V; Renlund, M; Tettamanti, G

1996-03-29

303

Novel mutations (Asn 484 Lys, Thr 500 Ala, Gly 438 Glu) in Morquio B disease  

Microsoft Academic Search

Primary deficiency of ?-galactosidase results in GM1 gangliosidosis and Morquio B disease. Of the more than 40 disease-causing mutations described in the Gal gene to date, about 75% are of the missense type and are scattered along the length of the gene. No single, major common mutation has been associated with GM1 gangliosidosis. However, a Trp 273 Leu mutation has

Richard D Bagshaw; Sunqu Zhang; Alina Hinek; Marie-Anne Skomorowski; Donald Whelan; Joe T. R Clarke; John W Callahan

2002-01-01

304

Characterization of an anti-beta-galactosidase antibody recognizing a precursor but not a mature enzyme in solution.  

PubMed

A monospecific antibody was raised against a recombinant human 84-kDa beta-galactosidase precursor protein, which had been produced with a baculovirus gene expression system and affinity-purified. It bound to the 64-kDa mature enzyme protein extracted from human fibroblasts and the antigenic recombinant precursor on immunoblotting, but neither the fibroblast-derived mature enzyme nor the 64-kDa mature protein-like tryptic product of the recombinant precursor protein was immunoprecipitated. We conclude that it specifically recognized the precursor but not the mature protein in solution. Immunoprecipitation with this anti-precursor antibody revealed that the precursor protein mainly accounted for the residual enzyme activity in fibroblasts from an adult GM1-gangliosidosis patient, and the mature protein accounted for the activity in fibroblasts from a juvenile GM1-gangliosidosis patient. PMID:8512554

Takiyama, N; Itoh, K; Oshima, A; Sakuraba, H; Suzuki, Y

1993-06-15

305

?-Galactosidase-deficient human fibroblasts: uptake and processing of the exogenous precursor enzyme expressed by stable transformant COS cells  

Microsoft Academic Search

COS-1 cells were transfected by electroporation with a cDNA for human acid ß-galactosidase cloned in our laboratory and stable transformants expressing the enzyme activity were selected. The precursor form of the enzyme was secreted in large quantities into the culture medium. The fibroblasts from patients with GM1-gangliosidosis or Morquio B disease showed a remarkable increase of enzyme activity, up to

Akihiro Oshima; Kohji Itoh; Yoshiro Nagao; Hitoshi Sakuraba; Yoshiyuki Suzuki

1990-01-01

306

Krabbe's globoid cell leucodystrophy. Studies on galactosylceramide beta-galactosidase and non-specific beta-galactosidase of leucocytes, cultured skin fibroblasts, and amniotic fluid cells  

Microsoft Academic Search

Galactosylceramide beta-galactosidase (cerebrosidase) and nonspecific beta-galactosidase activities were measured in both cultured skin fibroblasts and leucocytes from a family with Krabbe's globoid cell leucodystrophy (GLD). The activities of these enzymes were also determined in cultured skin fibroblasts of a patient with GM1 gangliosidosis and in cultured amniotic fluid cells. While cerebrosidase activity was deficient in GLD fibroblasts and leucocytes, its

G T Besley; A D Bain

1976-01-01

307

A frameshift mutation in the canine HEXB gene in toy poodles with GM2 gangliosidosis variant 0 (Sandhoff disease).  

PubMed

GM2 gangliosidosis variant 0 (Sandhoff disease, SD) is a fatal, progressive neurodegenerative lysosomal storage disease caused by mutations in the HEXB gene. Toy poodles recently were reported as the second breed of dog with SD. The present paper describes the molecular defect of this canine SD as the first identification of a pathogenic mutation in the canine HEXB gene. Genomic and complementary DNA sequences covering exonic regions of the canine HEXB gene, except exon 1, were analysed using DNA and RNA in an affected dog. A homozygous single base pair deletion of guanine in exon 3 was identified at nucleotide position 283 of the putative open reading frame (c.283delG). This mutation has the potential to cause a frameshift resulting in the alteration of valine at amino acid position 59 to a stop codon (p.V59fsX). Genotyping using the mutagenically separated PCR method demonstrated a correlation between phenotype and genotype in dogs with a pedigree related to the disease and that the mutation was rare in a randomly-selected population of toy poodles. These results strongly suggest that the deletion is pathogenic. PMID:22766310

Rahman, Mohammad M; Chang, Hye-Sook; Mizukami, Keijiro; Hossain, Mohammad A; Yabuki, Akira; Tamura, Shinji; Kitagawa, Masato; Mitani, Sawane; Higo, Takashi; Uddin, Mohammad M; Uchida, Kazuyuki; Yamato, Osamu

2012-12-01

308

Characterization of the molecular defect in a feline model for type II GM2-gangliosidosis (Sandhoff disease).  

PubMed Central

The Korat cat provides an animal model for type II GM2-gangliosidosis (Sandhoff disease) that may be suitable for tests of gene replacement therapy with the HEXB gene encoding the beta subunit of the beta-hexosaminidases. In the present report, we examined the brain and liver pathology of a typical Sandhoff-affected cat. We characterized the feline HEXB complementary DNA (cDNA) and determined the molecular defect in this feline model. cDNA libraries were produced from one normal and one affected animal, and cDNA clones homologous to human HEXB were sequenced. In the affected cDNA clone, the deletion of a cytosine residue at position +39 of the putative coding region results in a frame shift and a stop codon at base +191. This disease-related deletion was consistently detected by sequencing of cloned polymerase chain reaction amplified reverse transcribed messenger RNA from one more normal Korat and two additional affected animals. The defect was further demonstrated using single-strand conformational polymorphism analysis of the polymerase chain reaction products. In addition, alternative splicing of both normal and affected messenger RNAs was demonstrated. These results should facilitate the use of this animal model to assess gene therapy. Images Figure 1 Figure 3 Figure 4 Figure 5

Muldoon, L. L.; Neuwelt, E. A.; Pagel, M. A.; Weiss, D. L.

1994-01-01

309

GM2 Gangliosidosis B1 Variant: Biochemical and Molecular Characterization of Hexosaminidase A  

Microsoft Academic Search

The biochemical properties of hexosaminidase A (HexA) and the coding sequence of the ?-subunit were examined in a patient of Syrian ancestry with the B1 form of Tay-Sachs disease (TSD). The biochemical characteristics of the variant HexA suggest that both active sites are affected by the mutation(s). Kinetic studies with the ?-subunit specific substrate, 4 methylumbelliferyl-?-D-N-acetylglucosamine (MUG), revealed a significant

L. Peleg; F. Meltzer; M. Karpati; B. Goldman

1995-01-01

310

Therapeutic potential of intracerebroventricular replacement of modified human ?-hexosaminidase B for GM2 gangliosidosis.  

PubMed

To develop a novel enzyme replacement therapy for neurodegenerative Tay-Sachs disease (TSD) and Sandhoff disease (SD), which are caused by deficiency of ?-hexosaminidase (Hex) A, we designed a genetically engineered HEXB encoding the chimeric human ?-subunit containing partial amino acid sequence of the ?-subunit by structure-based homology modeling. We succeeded in producing the modified HexB by a Chinese hamster ovary (CHO) cell line stably expressing the chimeric HEXB, which can degrade artificial anionic substrates and GM2 ganglioside in vitro, and also retain the wild-type (WT) HexB-like thermostability in the presence of plasma. The modified HexB was efficiently incorporated via cation-independent mannose 6-phosphate receptor into fibroblasts derived from Tay-Sachs patients, and reduced the GM2 ganglioside accumulated in the cultured cells. Furthermore, intracerebroventricular administration of the modified HexB to Sandhoff mode mice restored the Hex activity in the brains, and reduced the GM2 ganglioside storage in the parenchyma. These results suggest that the intracerebroventricular enzyme replacement therapy involving the modified HexB should be more effective for Tay-Sachs and Sandhoff than that utilizing the HexA, especially as a low-antigenic enzyme replacement therapy for Tay-Sachs patients who have endogenous WT HexB. PMID:21487393

Matsuoka, Kazuhiko; Tamura, Tomomi; Tsuji, Daisuke; Dohzono, Yukie; Kitakaze, Keisuke; Ohno, Kazuki; Saito, Seiji; Sakuraba, Hitoshi; Itoh, Kohji

2011-06-01

311

Therapeutic Potential of Intracerebroventricular Replacement of Modified Human ?-Hexosaminidase B for GM2 Gangliosidosis  

PubMed Central

To develop a novel enzyme replacement therapy for neurodegenerative Tay-Sachs disease (TSD) and Sandhoff disease (SD), which are caused by deficiency of ?-hexosaminidase (Hex) A, we designed a genetically engineered HEXB encoding the chimeric human ?-subunit containing partial amino acid sequence of the ?-subunit by structure-based homology modeling. We succeeded in producing the modified HexB by a Chinese hamster ovary (CHO) cell line stably expressing the chimeric HEXB, which can degrade artificial anionic substrates and GM2 ganglioside in vitro, and also retain the wild-type (WT) HexB-like thermostability in the presence of plasma. The modified HexB was efficiently incorporated via cation-independent mannose 6-phosphate receptor into fibroblasts derived from Tay-Sachs patients, and reduced the GM2 ganglioside accumulated in the cultured cells. Furthermore, intracerebroventricular administration of the modified HexB to Sandhoff mode mice restored the Hex activity in the brains, and reduced the GM2 ganglioside storage in the parenchyma. These results suggest that the intracerebroventricular enzyme replacement therapy involving the modified HexB should be more effective for Tay-Sachs and Sandhoff than that utilizing the HexA, especially as a low-antigenic enzyme replacement therapy for Tay-Sachs patients who have endogenous WT HexB.

Matsuoka, Kazuhiko; Tamura, Tomomi; Tsuji, Daisuke; Dohzono, Yukie; Kitakaze, Keisuke; Ohno, Kazuki; Saito, Seiji; Sakuraba, Hitoshi; Itoh, Kohji

2011-01-01

312

Peripheral arteriovenous fistula as a cause of neonatal cardiac failure.  

PubMed

A newborn infant presented with cardiac failure secondary to a peripheral cavernous haemangioma. She was successfully treated surgically but was later diagnosed as having GM1 gangliosidosis. PMID:3943936

Miall-Allen, V M; Morgan, B; Cooper, P; Shinebourne, E A

1986-02-01

313

Profiling oligosaccharidurias by electrospray tandem mass spectrometry: quantifying reducing oligosaccharides.  

PubMed

A method to semiquantify urinary oligosaccharides from patients suffering from oligosaccharidurias is presented. 1-Phenyl-3-methyl-5-pyrazolone has been used to derivatize urinary oligosaccharides prior to analysis by electrospray ionization-tandem mass spectrometry (ESI-MS/MS). Disease-specific oligosaccharides were identified for several oligosaccharidurias, including GM1 gangliosidosis, GM2 gangliosidosis, sialic acid storage disease, sialidase/neuraminidase deficiency, galactosialidosis, I-cell disease, fucosidosis, Pompe and Gaucher diseases, and alpha-mannosidosis. The oligosaccharides were referenced against the internal standard, methyl lactose, to produce ratios for comparison with control samples. Elevations in specific urinary oligosaccharides were indicative of lysosomal disease and the defective catabolic enzyme. This method has been adapted to enable assay of large sample numbers and could readily be extended to other oligosaccharidurias and to monitor oligosaccharide levels in patients receiving treatment. It also has immediate potential for incorporation into a newborn screening program. PMID:16111643

Ramsay, Steven L; Meikle, Peter J; Hopwood, John J; Clements, Peter R

2005-10-01

314

Magnetic resonance imaging pattern recognition in hypomyelinating disorders.  

PubMed

Hypomyelination is observed in the context of a growing number of genetic disorders that share clinical characteristics. The aim of this study was to determine the possible role of magnetic resonance imaging pattern recognition in distinguishing different hypomyelinating disorders, which would facilitate the diagnostic process. Only patients with hypomyelination of known cause were included in this retrospective study. A total of 112 patients with Pelizaeus-Merzbacher disease, hypomyelination with congenital cataract, hypomyelination with hypogonadotropic hypogonadism and hypodontia, Pelizaeus-Merzbacher-like disease, infantile GM1 and GM2 gangliosidosis, Salla disease and fucosidosis were included. The brain scans were rated using a standard scoring list; the raters were blinded to the diagnoses. Grouping of the patients was based on cluster analysis. Ten clusters of patients with similar magnetic resonance imaging abnormalities were identified. The most important discriminating items were early cerebellar atrophy, homogeneity of the white matter signal on T(2)-weighted images, abnormal signal intensity of the basal ganglia, signal abnormalities in the pons and additional T(2) lesions in the deep white matter. Eight clusters each represented mainly a single disorder (i.e. Pelizaeus-Merzbacher disease, hypomyelination with congenital cataract, hypomyelination with hypogonadotropic hypogonadism and hypodontia, infantile GM1 and GM2 gangliosidosis, Pelizaeus-Merzbacher-like disease and fucosidosis); only two clusters contained multiple diseases. Pelizaeus-Merzbacher-like disease was divided between two clusters and Salla disease did not cluster at all. This study shows that it is possible to separate patients with hypomyelination disorders of known cause in clusters based on magnetic resonance imaging abnormalities alone. In most cases of Pelizaeus-Merzbacher disease, hypomyelination with congenital cataract, hypomyelination with hypogonadotropic hypogonadism and hypodontia, Pelizaeus-Merzbacher-like disease, infantile GM1 and GM2 gangliosidosis and fucosidosis, the imaging pattern gives clues for the diagnosis. PMID:20881161

Steenweg, Marjan E; Vanderver, Adeline; Blaser, Susan; Bizzi, Alberto; de Koning, Tom J; Mancini, Grazia M S; van Wieringen, Wessel N; Barkhof, Frederik; Wolf, Nicole I; van der Knaap, Marjo S

2010-10-01

315

Magnetic resonance imaging pattern recognition in hypomyelinating disorders  

PubMed Central

Hypomyelination is observed in the context of a growing number of genetic disorders that share clinical characteristics. The aim of this study was to determine the possible role of magnetic resonance imaging pattern recognition in distinguishing different hypomyelinating disorders, which would facilitate the diagnostic process. Only patients with hypomyelination of known cause were included in this retrospective study. A total of 112 patients with Pelizaeus–Merzbacher disease, hypomyelination with congenital cataract, hypomyelination with hypogonadotropic hypogonadism and hypodontia, Pelizaeus–Merzbacher-like disease, infantile GM1 and GM2 gangliosidosis, Salla disease and fucosidosis were included. The brain scans were rated using a standard scoring list; the raters were blinded to the diagnoses. Grouping of the patients was based on cluster analysis. Ten clusters of patients with similar magnetic resonance imaging abnormalities were identified. The most important discriminating items were early cerebellar atrophy, homogeneity of the white matter signal on T2-weighted images, abnormal signal intensity of the basal ganglia, signal abnormalities in the pons and additional T2 lesions in the deep white matter. Eight clusters each represented mainly a single disorder (i.e. Pelizaeus–Merzbacher disease, hypomyelination with congenital cataract, hypomyelination with hypogonadotropic hypogonadism and hypodontia, infantile GM1 and GM2 gangliosidosis, Pelizaeus–Merzbacher-like disease and fucosidosis); only two clusters contained multiple diseases. Pelizaeus–Merzbacher-like disease was divided between two clusters and Salla disease did not cluster at all. This study shows that it is possible to separate patients with hypomyelination disorders of known cause in clusters based on magnetic resonance imaging abnormalities alone. In most cases of Pelizaeus–Merzbacher disease, hypomyelination with congenital cataract, hypomyelination with hypogonadotropic hypogonadism and hypodontia, Pelizaeus–Merzbacher-like disease, infantile GM1 and GM2 gangliosidosis and fucosidosis, the imaging pattern gives clues for the diagnosis.

Steenweg, Marjan E.; Vanderver, Adeline; Blaser, Susan; Bizzi, Alberto; de Koning, Tom J.; Mancini, Grazia M. S.; van Wieringen, Wessel N.; Barkhof, Frederik; Wolf, Nicole I.

2010-01-01

316

Rapid and simple polymerase chain reaction-based diagnostic assays for GM2 gangliosidosis variant 0 (Sandhoff-like disease) in Japanese domestic cats.  

PubMed

Polymerase chain reaction (PCR)-based assays combined with microchip electrophoresis were developed and evaluated for diagnosis and genotyping of GM2 gangliosidosis variant 0 (Sandhoff-like disease) in Japanese domestic cats. A preliminary genotyping survey was carried out in the population of Japanese domestic cats (1,015 cats in total) in southern Japan. Three kinds of assays including PCR primer-induced restriction analysis (PIRA) and mutagenically separated (MS)-PCR were carried out using blood-stained Flinders Technology Associates filter papers (FTA cards) as templates. The PCR products were analyzed by both agarose gel and microchip electrophoreses. All assays were sufficient to determine the genotypes of this disease, but MS-PCR offered the most rapid and simplest test, as it does not need the restriction enzyme step required in PCR-PIRA. The use of microchip electrophoresis in combination with FTA cards for sampling could shorten the time required for genotyping and simplify the procedure as well. The genotyping survey in the current study did not find any cats that possessed the mutant allele, suggesting that the prevalence of this allele is low (<0.1%) in southern Japan. PMID:21398459

Rahman, Mohammad M; Shoubudani, Tomoaki; Mizukami, Keijiro; Chang, Hye-Sook; Hossain, Mohammad A; Yabuki, Akira; Mitani, Sawane; Higo, Takashi; Arai, Toshiro; Yamato, Osamu

2011-03-01

317

Retrovirus-mediated transfer and expression of beta-hexosaminidase alpha-chain cDNA in human fibroblasts from G(M2)-gangliosidosis B1 variant.  

PubMed

Mutations in the alpha-chain of lysosomal hexosaminidase (EC 3.2.1.52) underlie two distinct biochemical phenotypes known as variant B and variant B1 of G(M2) gangliosidosis. This paper shows that the transduction of human B1-type fibroblasts (producing catalytically inactive alpha-chains) with a retroviral vector encoding the human hexosaminidase alpha-chain leads to a complete correction of HexA (alpha beta dimer) activity with both synthetic and natural substrates. The alpha-subunit overexpression leads to a partial HexB (beta beta dimer) depletion corresponding to about 10% of control HexB activity. The newly synthesized enzyme is correctly processed and targeted to the lysosomes in transduced cells. The high levels of recombinant enzyme correctly produced the metabolic defect, enabling the cells efficiently to degrade the accumulated storage product present in lysosomes. The transduced fibroblasts are also able to secrete HexA efficiently into the culture medium. Moreover, transfer of the human transgene product to B1-type deficient fibroblasts lead to an increase of activity against 4MUGS, the alpha-chain specific synthetic substrate, up to 30% of the control mean activity level. This level of activity might be sufficient to restore the normal ganglioside G(M2) metabolism in recipient cells. The data obtained demonstrate that B1-type phenotype can be efficiently corrected by retrovirus-mediated gene transfer. PMID:11560770

Teixeira, C A; Sena-Esteves, M; Lopes, L; Sá Miranda, M C; Ribeiro, M G

2001-09-20

318

Real-time PCR genotyping assay for GM2 gangliosidosis variant 0 in toy poodles and the mutant allele frequency in Japan.  

PubMed

GM2 gangliosidosis variant 0 (Sandhoff disease, SD) is a fatal, progressive neurodegenerative lysosomal storage disease caused by mutations of the HEXB gene. In canine SD, a pathogenic mutation (c.283delG) of the canine HEXB gene has been identified in toy poodles. In the present study, a TaqMan probe-based real-time PCR genotyping assay was developed and evaluated for rapid and large-scale genotyping and screening for this mutation. Furthermore, a genotyping survey was carried out in a population of toy poodles in Japan to determine the current mutant allele frequency. The real-time PCR assay clearly showed all genotypes of canine SD. The assay was suitable for large-scale survey as well as diagnosis, because of its high throughput and rapidity. The genotyping survey demonstrated a carrier frequency of 0.2%, suggesting that the current mutant allele frequency is low in Japan. However, there may be population stratification in different places, because of the founder effect by some carriers. Therefore, this new assay will be useful for the prevention and control of SD in toy poodles. PMID:24161966

Rahman, Mohammad Mahbubur; Yabuki, Akira; Kohyama, Moeko; Mitani, Sawane; Mizukami, Keijiro; Uddin, Mohammad Mejbah; Chang, Hye-Sook; Kushida, Kazuya; Kishimoto, Miori; Yamabe, Remi; Yamato, Osamu

2014-03-01

319

Diagnosis and prevention of lysosomal storage diseases in Russia.  

PubMed

A special programme for the diagnosis and prevention of lysosomal storage diseases (LSD) was developed in the former USSR. All the patients from 814 families at risk were investigated using biochemical techniques. In total, 363 patients with mucopolysaccharidoses (MPS), mucolipidoses, glycoproteinoses, sphingolipidoses and other LSD were diagnosed; 55 families at risk sought prenatal diagnosis and 67 fetuses were investigated for MPS (types I, II, IIIA and IIIB, VI), Tay-Sachs disease, Sandhoff disease, GM1-gangliosidosis, metachromatic leukodystrophy, mannosidosis, Gaucher disease and multiple sulphatidosis; 17 affected fetuses were diagnosed and aborted. There was an ethnic distribution of different lysosomal storage diseases in the former USSR. PMID:8127076

Krasnopolskaya, K D; Mirenburg, T V; Aronovich, E L; Lebedeva, T V; Odinokova, O N; Demina, N A; Kozlova, V M; Kuznetsov, M I

1993-01-01

320

Analysis of urinary oligosaccharides in lysosomal storage disorders by capillary high-performance anion-exchange chromatography-mass spectrometry.  

PubMed

Many lysosomal storage diseases are characterized by an increased urinary excretion of glycoconjugates and oligosaccharides that are characteristic for the underlying enzymatic defect. Here, we have used capillary high-performance anion-exchange chromatography (HPAEC) hyphenated to mass spectrometry to analyze free oligosaccharides from urine samples of patients suffering from the lysosomal storage disorders fucosidosis, ?-mannosidosis, G(M1)-gangliosidosis, G(M2)-gangliosidosis, and sialidosis. Glycan fingerprints were registered, and the patterns of accumulated oligosaccharides were found to reflect the specific blockages of the catabolic pathway. Our analytical approach allowed structural analysis of the excreted oligosaccharides and revealed several previously unpublished oligosaccharides. In conclusion, using online coupling of HPAEC with mass spectrometric detection, our study provides characteristic urinary oligosaccharide fingerprints with diagnostic potential for lysosomal storage disorders. PMID:22526647

Bruggink, Cees; Poorthuis, Ben J H M; Deelder, André M; Wuhrer, Manfred

2012-06-01

321

Processing of lysosomal beta-galactosidase. The C-terminal precursor fragment is an essential domain of the mature enzyme.  

PubMed

Lysosomal beta-D-galactosidase (beta-gal), the enzyme deficient in the autosomal recessive disorders G(M1) gangliosidosis and Morquio B, is synthesized as an 85-kDa precursor that is C-terminally processed into a 64-66-kDa mature form. The released approximately 20-kDa proteolytic fragment was thought to be degraded. We now present evidence that it remains associated to the 64-kDa chain after partial proteolysis of the precursor. This polypeptide was found to copurify with beta-gal and protective protein/cathepsin A from mouse liver and Madin-Darby bovine kidney cells and was immunoprecipitated from human fibroblasts but not from fibroblasts of a G(M1) gangliosidosis and a galactosialidosis patient. Uptake of wild-type protective protein/cathepsin A by galactosialidosis fibroblasts resulted in a significant increase of mature and active beta-gal and its C-terminal fragment. Expression in COS-1 cells of mutant cDNAs encoding either the N-terminal or the C-terminal domain of beta-gal resulted in the synthesis of correctly sized polypeptides without catalytic activity. Only when co-expressed, the two subunits associate and become catalytically active. Our results suggest that the C terminus of beta-gal is an essential domain of the catalytically active enzyme and provide evidence that lysosomal beta-galactosidase is a two-subunit molecule. These data may give new significance to mutations in G(M1) gangliosidosis patients found in the C-terminal part of the molecule. PMID:10744681

van der Spoel, A; Bonten, E; d'Azzo, A

2000-04-01

322

A child with macrocephaly: case report of a patient with megalencephalic leukoencephalopathy with subcortical cysts and a compound heterozygosity for two mutations in the MLC1 gene.  

PubMed

Megalencephaly is as a rule accompanied by macrocephaly, an occipitofrontal circumference (OFC) greater than the 98th percentile. Megalencephaly is divided into an anatomic type (developmental) and a metabolic type. Metabolic megalencephaly refers to various storage and degenerative encephalopathies. The differential diagnosis includes Alexander's disease, Canavan's disease, glutaric aciduria type 1, GM1 and GM2 gangliosidosis, merosin-deficient variant of congenital muscular dystrophy and megalencephalic leukoencephalopathy with subcortical cysts (MLC). The distinctive features of this syndrome are enlarged cranial circumference, present at birth or starting in the first year of life, and magnetic resonance imaging (MRI) evidence of diffuse with matter abnormalities with subcortical cysts in the tips of the temporal lobes and in frontoparietal subcortical areas. Mutations in the MLC1 gene have been found as causative of MLC in 60-70 % of affected subjects, without genotype-phenotype correlation. The child we describe presented with progressive macrocephaly not associated with dysmorphic features and large abdominoscrotal hydrocele. At the age of 8 months, encephalic MRI showed anomalies suggestive for MLC and brainstem auditory evoked potentials (BAEP) documented alterations of signal conduction in right tracts. At the time, clinical neurologic examination was normal. Extensive metabolic assays were within normal range. Sequence analysis for MLC1 gene revealed a compound heterozygosity for two mutations in MLC1 gene, inherited from healthy non consanguineous parents. PMID:21487377

Delmonaco, A G; Gaidolfi, E; Scheper, G C; Girardo, E; Molinatto, C; Belligni, E; Ferrero, G B; Cirillo Silengo, M; Van Der Knaap, M

2011-04-01

323

Sphingolipidoses in Turkey.  

PubMed

During the last 5 years 2057 children under the age of 5 with various neurologic symptoms with the suspected diagnosis of lysosomal storage diseases were referred to our hospital from different universities and state hospitals. We were able to separate sphingolipidoses by lysosomal enzyme screening. A total of 300 patients (15%) with sphingolipidoses were diagnosed; there were deficiencies of arylsulfatase A [metachromatic leukodystrophy (MLD)] in 93 (31%), hexosaminidase [Sandhoff disease (SHD)] in 62 (20.7%), hexosaminidase A [Tay-Sachs disease (TSD)] in 15 (5%), beta-galactosidase (GM1 gangliosidosis) in 35 (11.7%), alpha-galactosidase (Fabry disease) in one (0.3%) cerebroside beta-galactosidase (Krabbe disease) in 65 (21.7%) and glucosylceramidase (Gaucher disease) in 29 (9.6%). SHD (20.7%), MLD (31%) and Krabbe disease (21.7%) were common. Prenatal enzymatic diagnosis was made in 70 at risk pregnancies, 64 for TSD and SHD, three for MLD and three for GM1 gangliosidosis by using chorionic villus biopsy in 54, cord blood samples in 12 and cultured amniotic fluid cells in four. Seventeen fetuses were found to be affected. We have calculated the relative frequency and minimum incidence of sphingolipidoses in Turkey. The combined incidence of sphingolipidoses is 4.615 per 100,000 live births. The calculated incidences are 1.43, 0.95, 1, 0.23, 0.54, 0.45, 0.015 per 100,000 live births for MLD, SHD, Krabbe, Gaucher, TSD, GM1 gangliosidosis and Fabry diseases, respectively. The real incidence, which covers all subtypes of this group of diseases, should be greater than this number. The results suggested that, as a group, sphingolipidoses are relatively common and represent an important health problem in Turkey and some rare autosomal recessive diseases of Turkey are due to 'founder effect' created by consanguineous marriages. PMID:15275696

Ozkara, Hatice Asuman; Topçu, Meral

2004-09-01

324

Distribution of enzyme-bearing cells in GM2 gangliosidosis mice: regionally specific pattern of cellular infiltration following bone marrow transplantation.  

PubMed

Tissue distribution of beta-hexosaminidase was investigated using 5-bromo-4-chloro-3-indolyl N-acetyl beta-D-glucosaminide (X-Hex) as substrate in wild-type mice, four GM2 gangliosidosis model mice (Hexa-/-, Hexb-/-, Gm2a-/- and Hexa-/-Hexb-/-) and Hexb-/- mice that received bone marrow transplantation (BMT). In wild-type mice histochemical localization of beta-hexosaminidase was detected in the perikarya of the majority of neurons, small process-bearing microglial cells, perivascular macrophages, and macrophages in the choroid plexus and leptomeninges. X-Hex positivity was also noted in the renal tubular epithelium and macrophages in the liver and spleen. The staining pattern in the Gm2a-/- and Hexa-/- mice was generally similar to those of wild type, but in these mice, X-Hex stain was also noted in some storage neurons with swollen perikarya. No X-Hex-positive cells were detected in Hexb-/- or Hexa-/-Hexb-/- (DKO) mice. In Hexb-/- mice that received wild-type BMT (Hexb-/- +WBMT), many X-Hex-positive cells were detected in the spleen, and to a far lesser extent, in liver and kidney. In the CNS of these mice, X-Hex-positive cells were largely detected in the leptomeninges and choroid plexus. Some positive cells were also detected, mostly in the perivascular regions of the cerebrum, in particular in the regions of the posterior thalamus, brain stem and spinal cord. Some of X-Hex-positive cells were immunoreactive with Mac-1 and F4/80 antibodies and, thus, were cells of microglia/macrophage lineage. X-Hex-positive staining was not detected in neurons in these mice despite clinical improvement following BMT. This is the first time, as far as we know, that the regional distribution of the donor cells in the CNS has been investigated in a model of neuronal storage disease. Our study indicated that donor-derived cells of microglia/macrophage lineage infiltrated the CNS in a regionally specific manner following the BMT. PMID:10672323

Oya, Y; Proia, R L; Norflus, F; Tifft, C J; Langaman, C; Suzuki, K

2000-02-01

325

Inheritance of Lysosomal Acid ? Galactosidase Activity and Gangliosides in Crosses of DBA\\/2J and Knockout Mice  

Microsoft Academic Search

GM1 gangliosidosis is a progressive neurodegenerative disease caused by deficiencies in lysosomal acid ß-galactosidase (ß-gal) and involves accumulation and storage of ganglioside GM1 and its asialo form (GA1) in brain and visceral tissues. Similar to the infantile\\/juvenile human disease forms, B6\\/129Sv ß-gal knockout (ko) mice express residual tissue ß-gal activity and significant elevations of brain GM1, GA1, and total gangliosides.

Eric C. Hauser; Julie L. Kasperzyk; Alessandra d'Azzo; Thomas N. Seyfried

2004-01-01

326

Liquid chromatography/electrospray ionisation-tandem mass spectrometry quantification of GM2 gangliosides in human peripheral cells and plasma.  

PubMed

GM2 gangliosidosis is a group of inherited neurodegenerative disorders resulting primarily from the excessive accumulation of GM2 gangliosides (GM2) in neuronal cells. As biomarkers for categorising patients and monitoring the effectiveness of developing therapies are lacking for this group of disorders, we sought to develop methodology to quantify GM2 levels in more readily attainable patient samples such as plasma, leukocytes, and cultured skin fibroblasts. Following organic extraction, gangliosides were partitioned into the aqueous phase and isolated using C18 solid-phase extraction columns. Relative quantification of three species of GM2 was achieved using LC/ESI-MS/MS with d35GM1 18:1/18:0 as an internal standard. The assay was linear over the biological range, and all GM2 gangliosidosis patients were demarcated from controls by elevated GM2 in cultured skin fibroblast extracts. However, in leukocytes only some molecular species could be used for differentiation and in plasma only one was informative. A reduction in GM2 was easily detected in patient skin fibroblasts after a short treatment with media from normal cells enriched in secreted ?-hexosaminidase. This method may show promise for measuring the effectiveness of experimental therapies for GM2 gangliosidosis by allowing quantification of a reduction in the primary storage burden. PMID:24769373

Fuller, Maria; Duplock, Stephen; Hein, Leanne K; Rigat, Brigitte A; Mahuran, Don J

2014-08-01

327

Gangliosidosis with total hexosaminidase deficiency: Clinical, biochemical and ultrastructural studies and comparison with conventional cases of Tay-Sachs disease  

Microsoft Academic Search

Biochemical studies were performed on brain biopsies, and ultrastructural studies on brain and liver biopsies from three children presenting clinically the infantile form of Tay-Sachs disease. Gangliosides were markedly increased both in grey and white matter, and consisted mainly of fraction GM2. In one case (patient 1), the amount of N-acetylaminotrihexosyl-ceramide, the asialo-residue of ganglioside GM2, was much larger than

G. Fontaine; A. Résibois; M. Tondeur; G. Jonniaux; J. P. Farriaux; W. Voet; E. Maillard; H. Loeb

1973-01-01

328

W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.  

PubMed

Mutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G-->C (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G-->C mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband. PMID:9603435

Petroulakis, E; Cao, Z; Clarke, J T; Mahuran, D J; Lee, G; Triggs-Raine, B

1998-01-01

329

Immunological evidence for deficiency in an activator protein for sulfatide sulfatase in a variant form of metachromatic leukodystrophy.  

PubMed Central

Cultured skin fibroblasts from the patient described by Shapiro and co-workers as having a variant form of metachromatic leukodystrophy (MLD) [Shapiro, L.J., Aleck, K. A., Kaback, M.M., Itabashi, H., Desnick, R.J., Brand, N., Stephens, R.L., Fluharty, A.L. & Kihara, H. (1979) Pediatr. Res. 13, 1179-1181] were confirmed to have a partial deficiency (25-40% of controls) of arylsulfatase A activity in vitro and a severe inability to metabolize [14C]stearic acid-labeled sulfatide presented in the medium. When 150 micrograms of purified activator protein for GM1 ganglioside beta-galactosidase and sulfatide sulfatase was added in 4 ml of medium with the 14C-labeled sulfatide, correction of the sulfatide metabolism to the normal range was found. Monospecific antibodies to this activator protein were prepared in rabbits, and they were used to examine cultured cells for the presence of crossreacting material by Ouchterlony double immunodiffusion and rocket immunoelectrophoresis. Cell extracts from controls and from patients with GM1 gangliosidosis and MLD were found to have a single line of identity. By comparison to known concentrations of purified activator protein, cell extracts from controls were found to have 0.76 +/- 0.32 micrograms of activator protein (mean +/- 1 SD, n = 10) per mg of solubilized protein, whereas those from patients with type 1 GM1 gangliosidosis and late infantile MLD had 1.53 and 1.41 micrograms/mg, respectively. Cell extracts from the patient with a variant form of MLD had no visible precipitin line by Ouchterlony double immunodiffusion and only a diffuse nonspecific region of staining by rocket immunoelectrophoresis. These immunologic studies provide evidence for a deficiency in the activator protein required for normal catabolism of sulfatide in the cells from this patient and possibly provide a method for diagnosis of similar patients. Images

Inui, K; Emmett, M; Wenger, D A

1983-01-01

330

Clinical phenotype of patients with neuropathy associated with monoclonal gammopathy: a comparative study and a review of the literature.  

PubMed

The objective of this study was to investigate if the clinical and electrophysiological phenotype of patients with polyneuropathy associated with IgM monoclonal gammopathy (IgM-PNP) is related to the presence of antibodies against gangliosides or myelin-associated glycoprotein (MAG). We compared clinical and nerve conduction study (NCS) characteristics of 11 IgM-PNP patients with antibodies against asialo-GM1 or gangliosides (GM1, GD1a, GD1b, GM2 or GQ1b) to 11 consecutive IgM-PNP patients with anti-MAG neuropathy and to 9 IgM-PNP patients without antibodies against either MAG or gangliosides. Patients with anti-ganglioside antibodies could not be differentiated from those with anti-MAG antibodies based on clinical characteristics. However, within the group of anti-ganglioside antibody positive patients, antibodies against GD1b and GQ1b were associated with a purely sensory neuropathy (p = 0.002), while asymmetric weakness with symmetric sensory loss was associated with anti-asialo-GM1 antibodies. In conclusion, polyneuropathy associated with IgM monoclonal gammopathy and anti-ganglioside antibodies clinically resembles anti-MAG neuropathy. Pure sensory neuropathy and marked asymmetry may suggest the presence of anti-ganglioside rather than anti-MAG antibodies. PMID:24781837

Stork, Abraham C J; van der Pol, W-Ludo; Franssen, Hessel; Jacobs, Bart C; Notermans, Nicolette C

2014-07-01

331

Diagnostic Approach to Childhood-onset Cerebellar Atrophy: A 10-Year Retrospective Study of 300 Patients  

PubMed Central

Hereditary ataxias associated with cerebellar atrophy are a heterogeneous group of disorders. Selection of appropriate clinical and genetic tests for patients with cerebellar atrophy poses a diagnostic challenge. Neuroimaging is a crucial initial investigation in the diagnostic evaluation of ataxia in childhood, and the presence of cerebellar atrophy helps guide further investigations. We performed a detailed review of 300 patients with confirmed cerebellar atrophy on magnetic resonance imaging over a 10-year period. A diagnosis was established in 47% of patients: Mitochondrial disorders were most common, followed by the neuronal ceroid lipofuscinoses, ataxia telangectasia, and late GM2-gangliosidosis. We review the common causes of cerebellar atrophy in childhood and propose a diagnostic approach based on correlating specific neuroimaging patterns with clinical and genetic diagnoses.

Al-Maawali, Almundher; Blaser, Susan; Yoon, Grace

2013-01-01

332

Diagnostic approach to childhood-onset cerebellar atrophy: a 10-year retrospective study of 300 patients.  

PubMed

Hereditary ataxias associated with cerebellar atrophy are a heterogeneous group of disorders. Selection of appropriate clinical and genetic tests for patients with cerebellar atrophy poses a diagnostic challenge. Neuroimaging is a crucial initial investigation in the diagnostic evaluation of ataxia in childhood, and the presence of cerebellar atrophy helps guide further investigations. We performed a detailed review of 300 patients with confirmed cerebellar atrophy on magnetic resonance imaging over a 10-year period. A diagnosis was established in 47% of patients: Mitochondrial disorders were most common, followed by neuronal ceroid lipofuscinosis, ataxia telangiectasia, and late-onset GM2 gangliosidosis. We review the common causes of cerebellar atrophy in childhood and propose a diagnostic approach based on correlating specific neuroimaging patterns with clinical and genetic diagnoses. PMID:22764178

Al-Maawali, Almundher; Blaser, Susan; Yoon, Grace

2012-09-01

333

Cav2.1 voltage-dependent Ca2+ channel current is inhibited by serum from select patients with Guillain-Barré syndrome.  

PubMed

To investigate the pathophysiological mechanisms of immune-mediated peripheral neuropathies, we studied the effects of sera from patients with Guillain-Barré syndrome (GBS) on the Cav2.1 voltage-dependent calcium channel (VDCC) current in Purkinje cells. Using the whole-cell recording technique, Cav2.1 VDCC current was measured in cerebellar Purkinje cells in the presence of serum from GBS patients with acute motor axonal neuropathy (AMAN) or acute inflammatory demyelinating polyneuropathy (AIDP). The AMAN patient sera significantly inhibited the Cav2.1 VDCC current compared with healthy volunteer sera, and this inhibition was fully reversible by washing out the AMAN serum. Similarly, IgG purified from AMAN sera also inhibited the Cav2.1 VDCC current. However, the activation and inactivation kinetics of the Cav2.1 VDCC currents were not affected by serum from an AMAN patient. Moreover, the VDCC current of Purkinje cells was also inhibited by IgG anti-GM1 monoclonal antibody (anti-GM1 mAb). In an immunocytochemical study using double fluorescence staining, Purkinje cells were stained by monoclonal IgG anti-GM1 mAb. In contrast, AIDP patient and healthy volunteer sera did not affect the Cav2.1 VDCC current. These results suggest that in some case of GBS, particularly of AMAN patients with IgG anti-GM1 mAb, muscle weakness may be induced by dysfunction of Cav2.1 VDCC functioning at the motor nerve terminals. PMID:18478327

Nakatani, Yoshihiko; Hotta, Sayako; Utsunomiya, Iku; Tanaka, Keiko; Hoshi, Keiko; Ariga, Toshi; Yu, Robert K; Miyatake, Tadashi; Taguchi, Kyoji

2009-01-01

334

Anti-glycolipid antibodies in patients with neuropathy: a diagnostic assessment.  

PubMed

Anti-glycolipid antibodies are associated with immune-mediated neuropathies and screening is often performed as part of the diagnostic assessment for patients presenting with peripheral neuropathy. We report our experience in testing for immunoglobulin (Ig) G and IgM anti-glycolipid (GM1, GM2, GM3, GM4, GD1a, GD1b, GD2, GD3, GT1a, GT1b, GQ1b, sulfatides) antibodies in 290 consecutive patients presenting with neuropathy. Anti-glycolipid antibodies were detected significantly more often (43%) in patients who were diagnosed with definite immune-mediated neuropathy than in patients without a final diagnosis of immune-mediated neuropathy (control group) (23%). With positive and negative predictive values of 22% and 90%, respectively, anti-glycolipid antibodies are not a very reliable diagnostic tool in early patient contact. Certain antibodies (IgM to GM2, GT1a and IgG to GM3, GD3 and GT1b) were equally or more prevalent in the control group; clinicians should be aware of this distribution when receiving positive screening results for these antibodies. Concomitant IgG and IgM reactivities were found for GM1, GM2, GD1b and sulfatides, and were detected more frequently in patients with definite immune-mediated neuropathies. PMID:24417799

Johannis, Wibke; Renno, Joerg H; Klatt, Andreas R; Wielckens, Klaus

2014-03-01

335

Reassessment of rectal approach to neuropathology in childhood  

Microsoft Academic Search

A series of 93 rectal biopsies performed for diagnosis of suspected progressive neurometabolic disease between 1967 and 1973 is reviewed, and the results of this and of two previously published series totalling 307 biopsies are analysed.In GM1 and GM2 gangliosidosis, Batten's disease, and certain other neuronal storage diseases rectal biopsy is a reliable diagnostic alternative to brain biopsy. However, the

E. M. Brett; B. D. Lake

1975-01-01

336

Novel mutations (Asn 484 Lys, Thr 500 Ala, Gly 438 Glu) in Morquio B disease.  

PubMed

Primary deficiency of beta-galactosidase results in GM1 gangliosidosis and Morquio B disease. Of the more than 40 disease-causing mutations described in the Gal gene to date, about 75% are of the missense type and are scattered along the length of the gene. No single, major common mutation has been associated with GM1 gangliosidosis. However, a Trp 273 Leu mutation has been commonly found in the majority of patients with Morquio B disease defined genotypically to date. We now report three new mutations in three Morquio B patients where the Trp 273 Leu mutation is absent. Two of the mutations, C1502G (Asn 484 Lys) and A1548G (Thr 500 Ala), were found in twins (one male, one female) who display a mild form of Morquio B disease and keratan sulfate in the urine. In their fibroblasts, residual activity was 1.9% and 2.1% of controls. On Western blots, the 84-kDa precursor and the 64-kDa mature protein were barely detectable. The occurrence of a 45-kDa degradation product indicates that the mutated protein reached the lysosome but was abnormally processed. In the third case, we identified only a G1363A (Gly 438 Glu) mutation (a major deletion on the second allele has not been ruled out). This female patient too displays a very mild form of the disease with a residual activity of 5.7% of control values. In fibroblasts from this case, the 84-kDa precursor and the 45-kDa degradation product were present, while the mature 64-kDa form was barely detectable. The occurrence of these three mutations in the same area of the protein may define a domain involved in keratan sulfate degradation. PMID:12393180

Bagshaw, Richard D; Zhang, Sunqu; Hinek, Alina; Skomorowski, Marie Anne; Whelan, Donald; Clarke, Joe T R; Callahan, John W

2002-12-12

337

Morquio's disease type B (beta-galactosidase deficiency) in three siblings.  

PubMed

The clinical and biochemical findings in 3 siblings with Morquio's disease type B (mucopolysaccharidosis (MPS) IV B) are presented. Their phenotype is characterised by short trunk dwarfism with kyphoscoliosis and thoracic deformity. Radiographic findings include general platyspondyly, dysplasia of the pelvis and epiphyseal abnormalities. The patients are of normal intelligence. In the urine of all 3 affected children abnormal oligosaccharide excretion was found by thin-layer chromatography and in 1 of them keratosulphaturia was detected. The clinical diagnosis was confirmed biochemically by demonstration of a profound deficiency of beta-galactosidase activity in cultured fibroblasts. The clinical picture is compared with that of other cases in the literature and the possible molecular basis of the different phenotypes of beta-galactosidase deficiency (variants of monosialo-ganglioside-1 (GM1)-gangliosidosis, Morquio's disease type B) is discussed. PMID:3120323

Beck, M; Petersen, E M; Spranger, J; Beighton, P

1987-11-21

338

Determination of sialylated and neutral oligosaccharides in urine by mass spectrometry.  

PubMed

This protocol describes a method to allow for the detection of specific oligosaccharide fragments in urine by tandem mass spectrometry. The detection of fragments with specific masses indicates the presence of one of a number of diseases where the deficiency of lysosomal enzymes involved in the degradation of the glyco- moieties of glycoproteins is present in the patient. This method describes the derivatization of oligosaccharides present in urine with phenyl-1-methylpyrazolone, which renders them hydrophobic, thus allowing desalting with Combi cleanup columns prior to injection. This method allows the detection of storage of oligosaccharides, which may indicate the presence of one of the infantile Pompe disease, ?-mannosidosis, Gm1-gangliosidosis, Sandhoff disease, sialidosis, galactosialidosis, I-cell disease, and aspartylglucosaminuria. PMID:22241656

Clements, Peter R

2012-01-01

339

Synthesis of 1,5-Dideoxy-1,5-iminoribitol C-Glycosides through a Nitrone-Olefin Cycloaddition Domino Strategy: Identification of Pharmacological Chaperones of Mutant Human Lysosomal ?-Galactosidase.  

PubMed

We report herein a newly developed domino reaction that facilitates the synthesis of new 1,5-dideoxy-1,5-iminoribitol iminosugar C-glycosides 7a-e and 8. The key intermediate in this approach is a six-membered cyclic sugar nitrone that is generated in situ and trapped by an alkene dipolarophile via a [2 + 3] cycloaddition reaction to give the corresponding isooxazolidines 10a-e in a "one-pot" protocol. The iminoribitol C-glycosides 7a-e and 8 were found to be modest ?-galactosidase (bGal) inhibitors. However, compounds 7c and 7e showed "pharmacological chaperone" activity for mutant lysosomal bGal activity and facilitated its recovery in GM1 gangliosidosis patient fibroblasts by 2-6-fold. PMID:24735108

Siriwardena, Aloysius; Sonawane, Dhiraj P; Bande, Omprakash P; Markad, Pramod R; Yonekawa, Sayuri; Tropak, Michael B; Ghosh, Sougata; Chopade, Balu A; Mahuran, Don J; Dhavale, Dilip D

2014-05-16

340

Prenatal and postnatal studies of a late infantile GM2 gangliosidosis in a family of Syrian origin: a possible B1 variant.  

PubMed

We describe late infantile Tay-Sachs disease with high residual hexosaminidase A activity in two siblings of a Syrian Druze family. The patients' leukocytes had 26% of normal hexosaminidase A activity when tested with the conventional fluorogenic substrate 4-methyl-umbelliferyl-2-acetamido-2-deoxy-beta-D-glucopyranoside (4-MUG) and only about 10% when assayed with the sulfated substrate, 4-methyl-umbelliferal- beta-N-acetyl-glucosamine-6-sulfate (4-MUGS). According to the standard procedure of the heterozygote screening program (employing 4-MUG and heat inactivation), the parents were not diagnosed as an at-risk couple since the father was classified as a noncarrier. However, both parents' levels were clearly within the carrier range on the basis of 4-MUGS. The unique catalytic characteristics of the patients' enzyme forward the assumption that the affected sibs are B1 variants. The parents' enzymatic levels, together with their known consanguinity, might indicate that these patients are homozygotes for the rare mutation and not genetic compounds as has been documented for most of the infantile B1 variants. To the best of our knowledge this is the first reported case of B1 variant in a child of that extraction. PMID:8244659

Shukry, A; Goldman, B; Shihab, S; Peleg, L

1993-10-01

341

Preceding infections and anti-ganglioside antibody profiles assessed by a dot immunoassay in 306 French Guillain-Barré syndrome patients.  

PubMed

We describe by an in-house dot immunoassay, specific anti-ganglioside and sulfatide antibodies, by comparing the results from a large group of 134 infected French GBS patients and those from 172 noninfected French GBS and 142 control groups. A recent infection was identified in 134/306 (43.8%) GBS patients: Campylobacter jejuni (24.6%) was the most common agent, followed by cytomegalovirus (12.4%), Mycoplasma pneumoniae (3.2%) and Epstein-Barr virus (1.3%). Anti-ganglioside antibodies were detected in 97/306 (31.7%) of total GBS patients, 82/134 (61.2%) of GBS patients with a recent identified infection and 15/172 (8.7%) of the patients without identified infection. According to the specificities and antibody classes, four specific IgG antibody profiles were individualised against the two major GM1 and GD1a gangliosides in motor axonal C. jejuni-associated GBS variants, against GQ1b and disialylated gangliosides in Miller Fisher syndrome and its variants. One specific IgM profile against GM2 was found in 16/38 (42%) of severe sensory demyelinating CMV-associated GBS and in 8/17 (47%) of subjects with recent CMV infection with no neurological disease. IgG or IgM antibodies to GM1 were found in 5/10 M. pneumoniae-infected patients. IgM antibodies to GM1 were observed in the control groups, 15% of the 74 patients with amyotrophic lateral sclerosis, 19% of the 51 patients with chronic inflammatory demyelinating polyneuropathy, and 9% of the 21 healthy control subjects. The fine specificity of the four IgG antibody profiles and the IgM anti-GM2 profile is closely related to the nature of the preceding infections and the pattern of clinical features. PMID:21516465

Caudie, Christiane; Quittard Pinon, Arnaud; Taravel, Didier; Sivadon-Tardy, Valérie; Orlikowski, David; Rozenberg, Flore; Sharshar, Tarek; Raphaël, Jean Claude; Gaillard, Jean Louis

2011-11-01

342

Lending a helping hand, screening chemical libraries for compounds that enhance beta-hexosaminidase A activity in GM2 gangliosidosis cells.  

PubMed

Enzyme enhancement therapy is an emerging therapeutic approach that has the potential to treat many genetic diseases. Candidate diseases are those associated with a mutant protein that has difficulty folding and/or assembling into active oligomers in the endoplasmic reticulum. Many lysosomal storage diseases are candidates for enzyme enhancement therapy and have the additional advantage of requiring only 5-10% of normal enzyme levels to reduce and/or prevent substrate accumulation. Our long experience in working with the beta-hexosaminidase (EC 3.2.1.52) isozymes system and its associated deficiencies (Tay-Sachs and Sandhoff disease) lead us to search for possible enzyme enhancement therapy-agents that could treat the chronic forms of these diseases which express 2-5% residual activity. Pharmacological chaperones are enzyme enhancement therapy-agents that are competitive inhibitors of the target enzyme. Each of the known beta-hexosaminidase inhibitors (low microm IC50) increased mutant enzyme levels to >or= 10% in chronic Tay-Sachs fibroblasts and also attenuated the thermo-denaturation of beta-hexosaminidase. To expand the repertoire of pharmacological chaperones to more 'drug-like' compounds, we screened the Maybridge library of 50,000 compounds using a real-time assay for noncarbohydrate-based beta-hexosaminidase inhibitors and identified several that functioned as pharmacological chaperones in patient cells. Two of these inhibitors had derivatives that had been tested in humans for other purposes. These observations lead us to screen the NINDS library of 1040 Food and Drug Administration approved compounds for pharmacological chaperones. Pyrimethamine, an antimalarial drug with well documented pharmacokinetics, was confirmed as a beta-hexosaminidase pharmacological chaperone and compared favorably with our best carbohydrate-based pharmacological chaperone in patient cells with various mutant genotypes. PMID:17894780

Tropak, Michael B; Mahuran, Don

2007-10-01

343

Molecular basis of adult-onset and chronic GM2 gangliosidoses in patients of Ashkenazi Jewish origin: substitution of serine for glycine at position 269 of the alpha-subunit of beta-hexosaminidase.  

PubMed Central

Chronic and adult-onset GM2 gangliosidoses are neurological disorders caused by marked deficiency of the A isoenzyme of beta-hexosaminidase; they occur in the Ashkenazi Jewish population, though less frequently than classic (infantile) Tay-Sachs disease. Earlier biosynthetic studies had identified a defective alpha-subunit that failed to associate with the beta-subunit. We have now found a guanosine to adenosine transition at the 3' end of exon 7, which causes substitution of serine for glycine at position 269 of the alpha-subunit [designated 269 (Gly----Ser) substitution]. An RNase protection assay was used to localize the mutation to a segment of mRNA from fibroblasts of a patient with the adult-onset disorder. That segment of mRNA (after reverse transcription) and a corresponding segment of genomic DNA were amplified by the polymerase chain reaction and sequenced by the dideoxy method. The sequence analysis, together with an assay based on the loss of a ScrFI restriction site, showed that the patient was a compound heterozygote who had inherited the 269 (Gly----Ser) mutation from his father and an allelic null mutation from his mother. The 269 (Gly----Ser) mutation, in compound heterozygosity with a presumed null allele, was also found in fetal fibroblasts with an association-defective phenotype and in cells from five patients with chronic GM2 gangliosidosis. It was not found in beta-hexosaminidase A-deficient cells obtained from patients with infantile Tay-Sachs disease nor in cells from individuals who do not have beta-hexosaminidase A deficiency. However, there must be additional mutations with similar consequences, since the 269 (Gly----Ser) substitution was not present in fibroblasts from two patients with juvenile GM2 gangliosidosis even though these had an association-defective alpha-subunit. Images

Paw, B H; Kaback, M M; Neufeld, E F

1989-01-01

344

Alpha-stat acid-base regulation during cardiopulmonary bypass improves neuropsychologic outcome in patients undergoing coronary artery bypass grafting.  

PubMed

Neuropsychologic impairment in patients undergoing cardiopulmonary bypass may be associated with cerebral blood flow changes arising from different management protocols for carbon dioxide tension during bypass. Seventy patients having coronary artery bypass grafting were randomized to either pH-stat or alpha-stat acid-base management during cardiopulmonary bypass with a membrane oxygenator. In each patient, cerebral blood flow (xenon 133 clearance), middle cerebral artery blood flow velocity (transcranial Doppler sonography), and cerebral oxygen metabolism (cerebral metabolic rate and cerebral extraction ratio) were measured during four phases of the operation: before bypass, during bypass (at hypothermia and at normothermia), and after bypass. A battery, of neuropsychologic tests were also conducted before and 6 weeks after the operation. During hypothermic (28 degrees C) bypass, cerebral blood flow was significantly (p < 0.001) greater in the pH-stat group (41 mlx100 gm(-1)xmin(-1); 95% confidence interval 39 to 43 mlx100 gm(-1)xmin(-1)) than in the alpha-stat group (24 mlx100 gm(-1)xmin(-1); confidence interval 22 to 26 mlx100 gm(-1)xmin(-1)) at constant pressure and How. Arterial carbon dioxide tensions were 41 mm Hg (40 to 41 mm Hg) and 26 mm Hg (25 to 27 mm Hg), respectively; pH was 7.36 (7.34 to 7.38) and 7.53 (7.51 to 7.55), respectively. Middle cerebral artery flow velocity was significantly (p < 0.05) reduced in the alpha-stat group to 87% (77% to 96%) of the prebypass value, whereas it was significantly (p < 0.05) increased (152%; 141% to 162%) in the pH-stat group. Cerebral extraction ratio for oxygen demonstrated relative cerebral hyperemia during hypothermic (28 degrees C) bypass in both the pH-stat and alpha-stat groups (0.12 [0.11 to 0.14] and 0.25 [0.22 to 0.28], respectively); however, hyperemia was significantly more pronounced in the pH-stat group, indicating greater disruption in cerebral autoregulation. Neuropsychologic impairment criteria of deterioration in results of three or more tests revealed that a significantly (Fisher's exact test, p = 0.02) higher proportion of patients in the pH-stat group fared poorly than in the alpha-stat group at 6 weeks (17/35, 48.6% [32% to 65.1%], and 7/35, 20% [6.7% to 33.2.2%], respectively). In conclusion, patients receiving alpha-stat management had less disruption of cerebral autoregulation during cardiopulmonary bypass, accompanied by a reduced incidence of postoperative cerebral dysfunction. PMID:8642829

Patel, R L; Turtle, M R; Chambers, D J; James, D N; Newman, S; Venn, G E

1996-06-01

345

A comparative study of cytoplasmic granules imaged by the real-time microscope, Nile Red and Filipin in fibroblasts from patients with lipid storage diseases.  

PubMed

Cytoplasmic granules in fibroblasts, visualized without stains, or labelled with Nile red, Filipin, or anti-LAMP-1 (lysosome-associated membrane protein 1), were imaged using the real-time microscope (RTM). New advances in light microscope technology were applied to detect cytoplasmic granules (RTM-visible granules) and characterize them by imaging contrast, size, shape, cellular distribution, composition, motion dynamics and quantity. Appearing as solid spheroids or ring structures, the majority of the RTM-visible granules contained Nile-red labelled neutral lipids. A smaller subpopulation, appearing dimmer, with less imaging contrast, contained Filipin-labelled free cholesterol. Most lipid storage granules have a diameter ranging from 0.3 mum to 0.6 mum, with a small population measuring up to 1 mum. They typically clustered in the perinuclear region and displayed relatively small oscillatory motion. Immunofluorescence based on LAMP-1 labelling highlighted granular structures that were distinct and separate from RTM-visible granules and other structures in the light modality of the microscope. RTM-visible granules were associated with disease phenotypes that have increased cellular neutral lipid stores corresponding to the Nile red-labelled droplets (e.g. triacylglycerides, cholesterol esters). As predicted, the fibroblast strains with a defect resulting in Wolman disease, when compared to control samples, consistently had RTM-visible granules, higher in imaging contrast and with larger diameters, that were labelled with Nile red, and also an increased frequency of Filipin-cholesterol complexes. By comparison, in fibroblasts where the lipid storage is less evident (Gaucher and Farber diseases) or from GM(1) gangliosidosis, where the primary storage substances are oligosaccharides, fewer and smaller RTM-visible granules were observed. In some cases, changes in contrast and morphology in the unstained cytoplasmic compartments were more evident than in the labelled structures. In summary, applying the RTM imaging system to fibroblasts enables differences between the various disease types to be seen and, in specific examples, a unique phenotype can be readily discerned. PMID:16435192

Pham, N-A; Gal, M R; Bagshaw, R D; Mohr, A J; Chue, B; Richardson, T; Callahan, J W

2005-01-01

346

A common mutation site in the ?-galactosidase gene originates in Puerto Rico  

Microsoft Academic Search

Several mutation sites have been found in the ?-galactosidase gene of patients with GMI gangliosidosis. In a previous report we found a common point mutation site in American patients with GMl gangliosidosis resulting in a 208Arg ? Cys amino acid substitution. From the patients' family history, we suggested that this mutation may have come to South and North America via

Nan-Chan Chin; Wei-Hua Qian; Alan L. Shanske; Susan Sklower Brooks; Rose-Mary Boustany

1996-01-01

347

Comparison of the canine and human acid {beta}-galactosidase gene  

SciTech Connect

Several canine cDNA libraries were screened with human {beta}-galactosidase cDNA as probe. Seven positive clones were isolated and sequenced yielding a partial (2060 bp) canine {beta}-galactosidase cDNA with 86% identity to the human {beta}-galactosidase cDNA. Preliminary analysis of a canine genomic library indicated conservation of exon number and size. Analysis by Northern blotting disclosed a single mRNA of 2.4 kb in fibroblasts and liver from normal dogs and dogs affected with GM1 gangliosidosis. Although incomplete, these results indicate canine GM1 gangliosidosis is a suitable animal model of the human disease and should further efforts to devise a gene therapy strategy for its treatment. 20 refs., 2 figs., 1 tab.

Ahern-Rindell, A.J. [Weber State Univ., Ogden, UT (United States)] [Weber State Univ., Ogden, UT (United States); Kretz, K.A. [Recombinant BioCatalysis, Inc., La Jolla, CA (United States)] [Recombinant BioCatalysis, Inc., La Jolla, CA (United States); O`Brien, J.S. [Univ. of California at San Diego, La Jolla, CA (United States)] [Univ. of California at San Diego, La Jolla, CA (United States)

1996-05-17

348

Degradation of blood group A glycolipid A-6-2 by normal and mutant human skin fibroblasts.  

PubMed

The degradation of blood group glycolipid A-6-2 (GalNAc(alpha1-->3)[Fuc alpha1-->2]Gal(beta1-->4)GlcNAc(beta1-->3)Gal(beta1-->4)Glc(beta1-->1')C er, IV2-alpha-fucosyl-IV3-alpha-N-acetylgalactosaminylneolact otetraosylceramide), tritium-labeled in its ceramide moiety, was studied in situ, in skin fibroblast cultures from normal controls, from patients with defects of lysosomal alpha-N-acetylgalactosaminidase, and from patients with other lysosomal storage diseases. Uptake of the glycolipid with apolipoprotein E-coated liposomes was linear with time and with the amount of glycolipid added. In normal cells, the expected array of less polar products and some lipids resulting from re-using the liberated sphingosine, mainly sphingomyelin and phosphatidylcholine, were formed. In alpha-N-acetylgalactosaminidase-deficient cells, the glycolipid was virtually not degraded; product formation was less than 2% of the normal control rate, suggesting that blood group A-active glycolipids contribute as storage compounds to the pathogenesis of this disease. The expected accumulation of degradation intermediates was seen in fucosidosis, and in Sandhoff, Gaucher, and Farber disease cells, whereas normal turnover rates were found in Tay-Sachs disease cells, G(M2) activator-deficient (variant AB of G(M2) gangliosidosis) and in sulfatide activator- (sap-B-) deficient cells. In G(M1) gangliosidosis and in sap precursor-deficient cells, the lysosomal glycolipid catabolism was found to be strongly retarded; accumulation of individual products could not be seen. Skin fibroblasts from patients with alpha-N-acetylgalactosaminidase deficiency (Schindler disease) cannot degrade the major blood group A glycolipid. PMID:9741689

Asfaw, B; Schindler, D; Ledvinová, J; Cerný, B; Smíd, F; Conzelmann, E

1998-09-01

349

Bickerstaff's brainstem encephalitis, Miller Fisher syndrome and Guillain-Barr? syndrome overlap in an asthma patient with negative anti-ganglioside antibodies  

PubMed Central

Background Bickerstaff’s brainstem encephalitis (BBE), together with Miller Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS) were considered to form a continuous clinical spectrum. An anti-GQ1b antibody syndrome has been proposed to underlie the common pathophysiology for the three disorders; however, other studies have found a positive anti-GM1 instead of anti-GQ1b antibody. Case presentation Here we report a 20-year-old male patient with overlapping BBE, MFS and GBS. The patient had a positive family history of bronchial asthma and had suffered from the condition for over 15?years. He developed BBE symptoms nine days after an asthma exacerbation. During the course of illness, he had significantly elevated IgE levels in both serum and cerebrospinal fluid. Serologic analysis of antibodies against ganglioside complexes (anti-GDIa, anti-GDIb, anti-GM1, anti-GM2, anti-GM3, anti-GQIb and anti-GTIb antibodies) showed negative results. Conclusions Since asthma has recently been related to autoimmune disease, our case supports an autoimmune mechanism underlying the clinical spectrum composed of BBE, MFS and GBS. However, contrary to a proposed anti-GQ1b antibody syndrome, we would suggest that pathogenesis of this clinical spectrum is not limited to anti-ganglioside antibodies.

2012-01-01

350

Magnetic resonance findings of the corpus callosum in canine and feline lysosomal storage diseases.  

PubMed

Several reports have described magnetic resonance (MR) findings in canine and feline lysosomal storage diseases such as gangliosidoses and neuronal ceroid lipofuscinosis. Although most of those studies described the signal intensities of white matter in the cerebrum, findings of the corpus callosum were not described in detail. A retrospective study was conducted on MR findings of the corpus callosum as well as the rostral commissure and the fornix in 18 cases of canine and feline lysosomal storage diseases. This included 6 Shiba Inu dogs and 2 domestic shorthair cats with GM1 gangliosidosis; 2 domestic shorthair cats, 2 familial toy poodles, and a golden retriever with GM2 gangliosidosis; and 2 border collies and 3 chihuahuas with neuronal ceroid lipofuscinoses, to determine whether changes of the corpus callosum is an imaging indicator of those diseases. The corpus callosum and the rostral commissure were difficult to recognize in all cases of juvenile-onset gangliosidoses (GM1 gangliosidosis in Shiba Inu dogs and domestic shorthair cats and GM2 gangliosidosis in domestic shorthair cats) and GM2 gangliosidosis in toy poodles with late juvenile-onset. In contrast, the corpus callosum and the rostral commissure were confirmed in cases of GM2 gangliosidosis in a golden retriever and canine neuronal ceroid lipofuscinoses with late juvenile- to early adult-onset, but were extremely thin. Abnormal findings of the corpus callosum on midline sagittal images may be a useful imaging indicator for suspecting lysosomal storage diseases, especially hypoplasia (underdevelopment) of the corpus callosum in juvenile-onset gangliosidoses. PMID:24386203

Hasegawa, Daisuke; Tamura, Shinji; Nakamoto, Yuya; Matsuki, Naoaki; Takahashi, Kimimasa; Fujita, Michio; Uchida, Kazuyuki; Yamato, Osamu

2013-01-01

351

GM1 induces p38 and microtubule dependent ramification of rat primary microglia in vitro  

Microsoft Academic Search

Microglia are immunologically competent cells in the central nervous system and considered to be a key player in brain inflammation. The morphological change of microglia has been shown to be linked to functional phenotypes both in vivo and in vitro. As an attempt to identify factors that regulate microglial morphology, we investigated the effect of gangliosides on microglial ramification in

Ji-Young Park; Hee Young Kim; Ilo Jou; Sang Myun Park

2008-01-01

352

Integrate the GM(1,1) and Verhulst models to predict software stage effort  

Microsoft Academic Search

Software effort prediction clearly plays a crucial role in software project management. In keeping with more dynamic approaches to software development, it is not sufficient to only predict the whole-project effort at an early stage. Rather, the project manager must also dynamically predict the effort of different stages or activities during the software development process. This can assist the project

Yong Wang; Qinbao Song; Stephen G. MacDonell; Martin J. Shepperd; Junyi Shen

2009-01-01

353

Object detection and tracking based on adaptive canny operator and GM(1,1) model  

Microsoft Academic Search

A new method of moving object detection and tracking from dynamical image sequence is proposed in this paper. This method uses information entropy to achieve the adaptive selection of high threshold in Canny operator. The modified Canny operator is used to detect the object contour from difference images. And this detected contour is then used as the template of partial

Zhiyu Zhou; Jianxin Zhang

2007-01-01

354

Bone marrow cytological storage phenomena in lipidoses  

Microsoft Academic Search

The bone marrow cytological storage phenomena in generalized lysosomal lipid storage disorders (Gaucher disease, Niemann-Pick disease, GM1-gangliosidosis, cholesterol ester storage diseases) are reviewed. The value of bone marrow cytology as a pre-screening method in the diagnostic strategy for the different diseases depends on the disease type suspected and the availability of biochemical screening methods. While cytological screening is not necessary

Sargon Ziyeh; Klaus Harzer

1994-01-01

355

The human Purkinje cells  

Microsoft Academic Search

Purkinje cells from five autopsy cases (a premature newborn infant, a GM1-gangliosidosis, an olivo-ponto-cerebellar atrophy, a multisystem atrophy involving the spinal cord and the brain stem, and a woman of 82 years) were studied using the Golgi impregnation technique. The results were the following: (1) the Purkinje cells showed different abnormalities in each case; (2) the dedrite and cell body

K. Fujisawa; A. Nakamura

1982-01-01

356

Niemann-Pick disease associated with nonimmune hydrops fetalis.  

PubMed

The number of metabolic disorders associated with nonimmune hydrops fetalis is very small and includes only Gaucher disease, GM1 gangliosidosis type 1, Hurler syndrome, and mucolipidosis type I. We report another association of a nonimmune hydrops fetalis with Niemann-Pick disease as evident by electron microscopy, and wish to add this disorder to the list of conditions associated with nonimmune hydrops fetalis. PMID:2375336

Meizner, I; Levy, A; Carmi, R; Robinsin, C

1990-07-01

357

[Differential diagnosis of congenital lipidoses by lipid analyses of body fluids, biopsy and autopsy tissue].  

PubMed

1. Presentation of the commomly used procedures for the extraction and separation of total lipids, glycolipids and phosholipids from fresh and formalin-fixed organs tissues (brain, liver, spleen, kidney) as well as from serum, CSF and urine. II. Description of the qualitative and quantitative analysis of individual lipid fractions (glycolipids, gangliosides, phospholipids, neutral lipids) by thin-layer chromatograhy and photodensitometry. III. Results of investigations performed on biopsy material, autopsy material, serum and urine in the following diseases: 1. Infantile, juvenile and adult Gaucher's disease: accumulation of glucocerebroside in liver and spleen. 2. Infantile and adult Niemann-Pick disease: accumulation of sphingomyelin in liver, spleen, kidney and lung. 3. Fabry's disease: increased urinary excretion of trihexosyl-ceramide and dihexosyl-ceramide. 4. Infantile and adult metachromatic leukodystrophy: accumulation of sulfatides in the central and peripheral nervous system and kidney, increased urinary excretion of sulfatides. 5. Austin's variant of metachromatic leukodystrophy: besides an increase of sulfatides in the white matter of brain accumulation of glycolipids in the cerebral cortex. 6. Tay-Sachs disease (GM2-gangliosidosis): cerebral accumulation of GM2-ganglioside and trihexosylceramide (enzyme variant B), additional visceral accumulation (liver, spleen, kidney) of tetrahexosyl-ceramide = globoside (enzyme variant 0). 7. Infantile generalized GM1-gangliosidosis: cerebral (and visceral) accumulation of GM1-ganglioside and tetrahexosyl-ceramide. 8. Late infantile GM1-gangliosidosis: Cerebral accumulation of GM1-ganlioside and tetrahexosylceramide. 9. GM3-gangliosidosis (lactosyl-ceramidosis): neuronal accumulation of lactosyl-ceramide, GM2-ganglioside and GM3-ganglioside. 10. Refsum's disease: demonstration of phytanic acid esters of cholesterol in serum. PMID:53174

Pilz, H; Heipertz, R

1975-11-01

358

Synthesis of lipophilic 1-deoxygalactonojirimycin derivatives as D-galactosidase inhibitors.  

PubMed

N-Alkylation at the ring nitrogen of the D-galactosidase inhibitor 1-deoxygalactonojirimycin with a functionalised C ?alkyl chain followed by modification with different aromatic substituents provided lipophilic 1-deoxygalactonojirimycin derivatives which exhibit inhibitory properties against ?-glycosidases from E. coli and Agrobacterium sp. as well as green coffee bean ?-galactosidase. In preliminary studies, these compounds also showed potential as chemical chaperones for GM1-gangliosidosis related ?-galactosidase mutants. PMID:20502610

Schitter, Georg; Scheucher, Elisabeth; Steiner, Andreas J; Stütz, Arnold E; Thonhofer, Martin; Tarling, Chris A; Withers, Stephen G; Wicki, Jacqueline; Fantur, Katrin; Paschke, Eduard; Mahuran, Don J; Rigat, Brigitte A; Tropak, Michael; Wrodnigg, Tanja M

2010-01-01

359

Distribution of saposin proteins (sphingolipid activator proteins) in lysosomal storage and other diseases.  

PubMed Central

Saposins (A, B, C, and D) are small glycoproteins required for the hydrolysis of sphingolipids by specific lysosomal hydrolases. Concentrations of these saposins in brain, liver, and spleen from normal humans as well as patients with lysosomal storage disease were determined. A quantitative HPLC method was used for saposin A, C, and D and a stimulation assay was used for saposin B. In normal tissues, saposin D was the most abundant of the four saposins. Massive accumulations of saposins, especially saposin A (about 80-fold increase over normal), were found in brain of patients with Tay-Sachs disease or infantile Sandhoff disease. In spleen of adult patients with Gaucher disease, saposin A and D accumulations (60- and 17-fold, respectively, over normal) were higher than that of saposin C (about 16-fold over normal). Similar massive accumulations of saposins A and D were found in liver of patients with fucosidosis (about 70- and 20-fold, respectively, over normal). Saposin D was the primary saposin stored in the liver of a patient with Niemann-Pick disease (about 30-fold over normal). Moderate increases of saposins B and D were found in a patient with GM1 gangliosidosis. Normal or near normal levels of all saposins were found in patients with Krabbe disease, metachromatic leukodystrophy, Fabry disease, adrenoleukodystrophy, I-cell disease, mucopolysaccharidosis types 2 and 3B, or Jansky-Bielschowsky disease. The implications of the storage of saposins in these diseases are discussed.

Morimoto, S; Yamamoto, Y; O'Brien, J S; Kishimoto, Y

1990-01-01

360

A capillary electrophoresis procedure for the screening of oligosaccharidoses and related diseases.  

PubMed

The most widely used method for the biochemical screening of oligosaccharidoses is the analysis of the urinary oligosaccharide pattern by thin-layer chromatography on silica gel plates. However, this method is not always sensitive enough, and it is extremely time-consuming and laborious. In this work, the analysis of the urine oligosaccharide pattern was standardized for the first time by using capillary electrophoresis with laser-induced fluorescence (CE-LIF) detection (Beckman P/ACE MDQ) with a 488-nm argon ion laser module. All of the analyses were conducted using the Carbohydrate Labeling and Analysis Kit (Beckman-Coulter), which derivatizes samples with 8-aminopyrene-1,3,6-trisulfonate. Urine samples from 40 control subjects (age range, 1 week to 16 years) and from ten patients diagnosed with eight different lysosomal diseases (six of them included in the Educational Oligosaccharide Kit from ERNDIM EQA schemes) were analyzed. Two oligosaccharide excretion patterns were established in our control population according to age (younger or older than 1 year of age). Abnormal peaks with slower migration times than the tetrasaccharide position were observed for fucosidosis, ?-mannosidosis, GM1 gangliosidosis, GM2 gangliosidosis variant 0, Pompe disease, and glycogen storage disease type 3. In conclusion, the first CE-LIF method to screen for oligosaccharidoses and related diseases, which also present oligosacchariduria, has been standardized. In all of the cases, the urine oligosaccharide analysis was strongly informative and showed abnormal patterns that were not present in any of the urine samples from the control subjects. Only urine from patients with aspartylglucosaminuria and Schindler disease displayed normal results. PMID:24788891

Casado, Mercedes; Altimira, Laura; Montero, Raquel; Castejón, Esperanza; Nascimento, Andrés; Pérez-Dueñas, Belén; Ormazabal, Aida; Artuch, Rafael

2014-07-01

361

The value of CT in diagnosis and prognosis of different inborn neurodegenerative disorders in childhood.  

PubMed

Inborn errors of metabolism in 40 children have been investigated by computed tomography to obtain data on the degree of cerebral involvement in neurodegenerative and storage disorders: 20 children had various mucopolysaccharidoses, 8 sphingolipidoses , 3 mucolipidoses, 2 oligosaccharidoses , 3 ceroidlipofuscinoses and 4 had various leucodystrophies . Diagnosis in all patients except Alexander's disease was established by biochemical or histological means. The main findings on CT were cerebral atrophy with enlargement of the ventricles and the subarachnoid spaces and hypodensity of the white matter. The degree of cerebral atrophy seemed to develop according to the age of the patients, as could be seen from the patients with mucopolysaccharidosis III, metachromatic leucodystrophy and GM1-gangliosidosis. Hypodensity of the white matter was found in mucopolysaccharidosis I-H, II-B, VI, in mucolipidosis II and in patients with leucodystrophies . On the other hand, there was great variability in these CT findings even in siblings, as seen in four patients with mucopolysaccharidosis VI. Among the series there were several patients who did not show any abnormalities in CT, so that a negative CT did not exclude these disorders, even the leucodystrophies . CT features such as cerebral atrophy or hypodensity were helpful in the evaluation of these disorders, though a diagnosis could not be made by CT alone. PMID:6429290

Wende, S; Ludwig, B; Kishikawa, T; Rochel, M; Gehler, J

1984-01-01

362

A study on enzyme activities of some sphingolipidoses.  

PubMed

Enzyme activities were determined in fibroblast cell cultures of eight patients suspected of having a type of sphingolipidosis. The patients were 0 to 4 years of age; four were female and four were male. Thirteen age-matched controls were also included in the study. In one of the cases, hexosaminidase A activity was found to be 0% (43-82%), while in two other cases beta-galactosidase activity was found to be 5 nmol/h/mg protein (100-1035 nmol/h/mg protein) and arylsulfatase activity was found to be 12 nmol/h/mg protein (106-990 nmol/h/mg protein), respectively. Two more enzymes, alpha-galactosidase (11-39 nmol/h/mg protein) and cerebroside beta-galactosidase (3.7-6.9 nmol/h/mg protein), were also evaluated but were found to be in the normal ranges in these patients. Therefore, these patients were considered to have Tay-Sachs disease, GM1 gangliosidosis and metachromatic leukodystrophy, respectively. The remaining five patients were normal in respect to the five enzyme activities determined. For the prenatal diagnosis of metachromatic leukodystrophy, arylsulfatase A activity was determined in one amniotic cell culture. The activity found in this case was lower than normal (34 nmol/h/mg protein versus 387 nmol/h/mg protein found in three control amniotic cell cultures. PMID:7974812

Ozkara, H A; Arikan, M C; Topçu, M; Emre, S; Renda, Y

1994-01-01

363

[A program of prevention of hereditary lysosomal diseases in the USSR].  

PubMed

The organization of genetic counselling for the families of patients with lysosomal storage diseases (LSD) was based on the interaction of the genetic counselling units of this country with a laboratory of inherited metabolic diseases of the National Research Center of Medical Genetics, USSR AMS. All the patients from 705 families at risk were examined using biochemical techniques and methods of somatic cell genetics. In total the loci differentiation was performed for 309 patients with mucopolysaccharidoses, glycoproteinoses, mucolipidoses, sphingolipidoses and other LSD. 53 families at risk (of 277) were prenatally diagnosed. 66 fetuses were diagnosed for mucopolysaccharidoses, type I, II, III, A and B, VI, Tay-Sachs disease, Sandhoff's disease, GM1-gangliosidosis, metachromatic leukodystrophy, mannosidosis, and multiple sulfatidosis. In total 18 affected fetuses were diagnosed and aborted. All the prenatal diagnoses were verified. The prevalence of mucopolysaccharidoses in two Central Asian republics was evaluated as 1:15,000. An Uneven ethnic distribution of different mucopolysaccharides in the USSR has also been shown. PMID:1384872

Krasnopol'skaia, K D; Mirenburg, T V; Aronovich, E L; Lebedeva, T V; Akhunov, V S; Odinokova, O N; Chebysheva, M V; Demina, N A; Nikiforova, O K; Kuznetsov, M I

1992-01-01

364

Molecular basis of adult-onset and chronic G sub M2 gangliosidoses in patients of Ashkenazi Jewish origin: Substitution of serine for glycine at position 269 of the. alpha. -subunit of. beta. -hexosaminidase  

SciTech Connect

Chronic and adult-onset G{sub M2} gangliosidoses are neurological disorders caused by marked deficiency of the A isoenzyme of {beta}-hexosaminidase; they occur in the Ashkenazi Jewish population, though less frequently than classic (infantile) Tay-Sachs disease. Earlier biosynthetic studies had identified a defective {alpha}-subunit that failed to associate with the {beta}-subunit. The authors have now found a guanosine to adenosine transition at the 3{prime} end of exon 7, which causes substitution of serine for glycine at position 269 of the {alpha}-subunit. An RNase protection assay was used to localize the mutation to a segment of mRNA from fibroblasts of a patient with the adult-onset disorder. That segment of mRNA (after reverse transcription) and a corresponding segment of genomic DNA were amplified by the polymerase chain reaction and sequenced by the dideoxy method. The sequence analysis, together with an assay based on the loss of a ScrFI restriction site, showed that the patient was a compound heterozygote who had inherited the 269 (Gly {yields} Ser) mutation from his father and an allelic null mutation from his mother. The 269 (Gly {yields} Ser) mutation, in compound heterozygosity with a presumed null allele, was also found in fetal fibroblasts with an association-defective phenotype and in cells from five patients with chronic G{sub M2} gangliosidosis.

Paw, B.H.; Kaback, M.M.; Neufeld, E.F. (Univ. of California, Los Angeles (USA))

1989-04-01

365

Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients  

PubMed Central

Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE) have multiple defects in lymphocyte signaling and function that contribute to disease pathogenesis. Such defects could be attributed to alterations in metabolic processes, including abnormal control of lipid biosynthesis pathways. Here, we reveal that CD4+ T cells from SLE patients displayed an altered profile of lipid raft–associated glycosphingolipids (GSLs) compared with that of healthy controls. In particular, lactosylceramide, globotriaosylceramide (Gb3), and monosialotetrahexosylganglioside (GM1) levels were markedly increased. Elevated GSLs in SLE patients were associated with increased expression of liver X receptor ? (LXR?), a nuclear receptor that controls cellular lipid metabolism and trafficking and influences acquired immune responses. Stimulation of CD4+ T cells isolated from healthy donors with synthetic and endogenous LXR agonists promoted GSL expression, which was blocked by an LXR antagonist. Increased GSL expression in CD4+ T cells was associated with intracellular accumulation and accelerated trafficking of GSL, reminiscent of cells from patients with glycolipid storage diseases. Inhibition of GSL biosynthesis in vitro with a clinically approved inhibitor (N-butyldeoxynojirimycin) normalized GSL metabolism, corrected CD4+ T cell signaling and functional defects, and decreased anti-dsDNA antibody production by autologous B cells in SLE patients. Our data demonstrate that lipid metabolism defects contribute to SLE pathogenesis and suggest that targeting GSL biosynthesis restores T cell function in SLE.

McDonald, Georgia; Deepak, Shantal; Miguel, Laura; Hall, Cleo J.; Isenberg, David A.; Magee, Anthony I.; Butters, Terry; Jury, Elizabeth C.

2014-01-01

366

Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients.  

PubMed

Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE) have multiple defects in lymphocyte signaling and function that contribute to disease pathogenesis. Such defects could be attributed to alterations in metabolic processes, including abnormal control of lipid biosynthesis pathways. Here, we reveal that CD4+ T cells from SLE patients displayed an altered profile of lipid raft-associated glycosphingolipids (GSLs) compared with that of healthy controls. In particular, lactosylceramide, globotriaosylceramide (Gb3), and monosialotetrahexosylganglioside (GM1) levels were markedly increased. Elevated GSLs in SLE patients were associated with increased expression of liver X receptor ? (LXR?), a nuclear receptor that controls cellular lipid metabolism and trafficking and influences acquired immune responses. Stimulation of CD4+ T cells isolated from healthy donors with synthetic and endogenous LXR agonists promoted GSL expression, which was blocked by an LXR antagonist. Increased GSL expression in CD4+ T cells was associated with intracellular accumulation and accelerated trafficking of GSL, reminiscent of cells from patients with glycolipid storage diseases. Inhibition of GSL biosynthesis in vitro with a clinically approved inhibitor (N-butyldeoxynojirimycin) normalized GSL metabolism, corrected CD4+ T cell signaling and functional defects, and decreased anti-dsDNA antibody production by autologous B cells in SLE patients. Our data demonstrate that lipid metabolism defects contribute to SLE pathogenesis and suggest that targeting GSL biosynthesis restores T cell function in SLE. PMID:24463447

McDonald, Georgia; Deepak, Shantal; Miguel, Laura; Hall, Cleo J; Isenberg, David A; Magee, Anthony I; Butters, Terry; Jury, Elizabeth C

2014-02-01

367

Gangliosidoses.  

PubMed

The gangliosidoses comprise a family of lysosomal storage diseases characterized by the accumulation of complex glycosphingolipids in the nervous system and other tissues, secondary to the deficient activity of lysosomal hydrolases or their associated activator proteins. GM1 and GM2 gangliosidosis are associated with deficiency of ?-galactosidase and ?-hexosaminidase respectively. All gangliosidoses are characterized by progressive neurodegeneration, the severity of which is proportional to the residual enzyme activity. The GM1 gangliosidoses are characterized by dysostosis, organomegaly and coarsening in their most severe forms, whereas children with classic infantile GM2 gangliosidosis (Tay-Sachs disease) are usually spared systemic involvement, except in the case of the Sandhoff variant, in which organomegaly may occur. Cherry-red macular spots occur in the early onset forms of the gangliosidoses, but are less frequently seen in the less severe, later onset phenotypes. Macrocephaly, an exaggerated startle response, cognitive decline, seizures, ataxia, and progressive muscular atrophy may occur in different forms of gangliosidosis. The diagnosis is made by assay of enzyme activity, and can be confirmed by mutation analysis. Carrier screening for Tay-Sachs disease has been remarkably successful in reducing the incidence of this disease in the at-risk Ashkenazi population. There are no proven disease-modifying therapies for the gangliosidoses. PMID:23622392

Patterson, Marc C

2013-01-01

368

Fast urinary screening of oligosaccharidoses by MALDI-TOF/TOF mass spectrometry  

PubMed Central

Background Oligosaccharidoses, which belong to the lysosomal storage diseases, are inherited metabolic disorders due to the absence or the loss of function of one of the enzymes involved in the catabolic pathway of glycoproteins and indirectly of glycosphingolipids. This enzymatic deficiency typically results in the abnormal accumulation of uncompletely degraded oligosaccharides in the urine. Since the clinical features of many of these disorders are not specific for a single enzyme deficiency, unambiguous screening is critical to limit the number of costly enzyme assays which otherwise must be performed. Methods Here we provide evidence for the advantages of using a MALDI-TOF/TOF (matrix-assisted laser desorption ionization time-of-flight) mass spectrometric (MS) method for screening oligosaccharidoses. Urine samples from previously diagnosed patients or from unaffected subjects were randomly divided into a training set and a blind testing set. Samples were directly analyzed without prior treatment. Results The characteristic MS and MS/MS molecular profiles obtained allowed us to identify fucosidosis, aspartylglucosaminuria, GM1 gangliosidosis, Sandhoff disease, ?-mannosidosis, sialidosis and mucolipidoses type II and III. Conclusions This method, which is easily run in less than 30 minutes, is performed in a single step, and is sensitive and specific. Invaluable for clinical chemistry purposes this MALDI-TOF/TOF mass spectrometry procedure is semi-automatizable and suitable for the urinary screening of oligosacharidoses.

2014-01-01

369

Clinical and radiological pictures of two newborn babies with manifestations of chondrodysplasia punctata and review of available literature  

PubMed Central

Summary Background: Chondrodysplasia punctata (CDP) is a rare, heterogeneous congenital skeletal dysplasia, characterized by punctate or dot-like calcium deposits in cartilage observed on neonatal radiograms. A number of inborn metabolic diseases are associated with CDP, including peroxisomal and cholesterol biosynthesis dysfunction and other inborn errors of metabolism such as: mucolipidosis type II, mucopolysacharidosis type III, GM1 gangliosidosis. CDP is also related to disruption of vitamin K-dependent metabolism, causing secondary effects on the embryo, as well as fetal alcohol syndrome (FAS), chromosomal abnormalities that include trisomies 18 and 21, Turner syndrome. Case Report: This article presents clinical data and diagnostic imaging findings of two newborn babies with chondrodysplasia punctata. Children presented with skeletal and cartilage anomalies, dysmorphic facial feature, muscles tone abnormalities, skin changes and breathing difficulties. One of the patients demonstrated critical stenosis of spinal canal with anterior subluxation of C1 vertebra relative to C2. The aim of this article is to present cases and briefly describe current knowledge on etiopathogenesis as well as radiological and clinical symptoms of diseases coexisting with CDP. Conclusions: Radiological diagnostic imaging allows for visualization of punctate focal mineralization in bone epiphyses during neonatal age and infancy. Determining the etiology of chondrodysplasia punctata requires performing various basic as well as additional examinations, including genetic studies.

Jurkiewicz, Elzbieta; Marcinska, Beata; Bothur-Nowacka, Joanna; Dobrzanska, Anna

2013-01-01

370

Determination of Acid ?-Galactosidase Activity: Methodology and Perspectives.  

PubMed

Early, accurate diagnosis of lysosomal storage disorders is a major challenge, even for trained specialists. Finding innovative, accurate diagnostic methods, and high throughput, cost-effective tools are crucial to medical progress and will contribute to improved quality of life. The goal of this work was to improve currently used protocols to determine activity of acid ?-galactosidase, and discuss the possibility analysing lysosomal enzymes with microfluidic systems. A principle of the determination of ?-galactosidase activity was fluorometric measurement of a deprotonated form of 4-methylumbelliferone released in the enzymatic reaction. Measurements were performed using Jurkat T cells as a source of the enzyme. We observed the temperature-dependent substrate inhibition effect and determined the substrate (4-MU-?-d-galactopyranoside) concentration which should be used to determine acid ?-galactosidase activity at 37 °C (0.8 mM) and at room temperature (0.6 mM). We proved that the sample incubation time may be significantly reduced to only a few minutes. We also showed that the amount of alkaline buffer used to stop the enzymatic reaction may be minimized and even, in some cases, eliminated. The presented results show how the sensitivity of the available methods to diagnose patients suffer from gangliosidosis GM1 or Morquio B disease can be improved. The proposed method may be easily implemented with microfluidic systems, which currently are promising tools for point-of-care applications. PMID:24478550

Kwapiszewski, Radoslaw; Szczudlowska, Justyna; Kwapiszewska, Karina; Chudy, Michal; Brzozka, Zbigniew

2014-01-01

371

Congenital ocular motor apraxia associated with idiopathic generalized epilepsy in monozygotic twins.  

PubMed

Identical female twins (age 11 years) with congenital ocular motor apraxia and generalized idiopathic epilepsy are reported. Their presenting symptoms were a long history of abnormal head and eye movements. One twin developed partial sensory seizures. The patients underwent 16-channel EEG, electro-oculographic recordings, MRI of the brain, and genetic and metabolic investigations. EEG findings were consistent with idiopathic generalized epilepsy. Electrooculographic recordings of the saccades confirmed an inability to elicit horizontal saccades without preceding head movement; saccades to the left were better than saccades to the right. MR scans for one twin showed normal findings, however, for the twin who had meningitis they revealed asymmetry between the right and left temporal lobes but no specific abnormality. DNA analysis using a series of autosomal polymorphic markers confirmed the monozygocity of the twins. White blood cell enzyme analysis excluded Sandhoff disease, Tay-Sachs disease, GM1 gangliosidosis, metacromatic leucodystrophy, Gaucher disease, Niemann-Pick disease (A and B), and Krabbe leucodystrophy. Albumin and immunoglobulin (IgA, IgG, and IgM) levels were normal. It is concluded that autosomal recessive inheritance seems the most likely explanation here, as recent studies have found insertion and missense mutations of the aprataxin gene which have been related to an early onset form of ataxia with ocular motor apraxia and hypoalbuminaemia. PMID:15174536

Gonzalez-Martin, J A; Kaye, L C; Brown, M; Ellis, I; Appelton, R; Kaye, S B

2004-06-01

372

Senescence-associated beta-galactosidase is lysosomal beta-galactosidase.  

PubMed

Replicative senescence limits the proliferation of somatic cells passaged in culture and may reflect cellular aging in vivo. The most widely used biomarker for senescent and aging cells is senescence-associated beta-galactosidase (SA-beta-gal), which is defined as beta-galactosidase activity detectable at pH 6.0 in senescent cells, but the origin of SA-beta-gal and its cellular roles in senescence are not known. We demonstrate here that SA-beta-gal activity is expressed from GLB1, the gene encoding lysosomal beta-D-galactosidase, the activity of which is typically measured at acidic pH 4.5. Fibroblasts from patients with autosomal recessive G(M1)-gangliosidosis, which have defective lysosomal beta-galactosidase, did not express SA-beta-gal at late passages even though they underwent replicative senescence. In addition, late passage normal fibroblasts expressing small-hairpin interfering RNA that depleted GLB1 mRNA underwent senescence but failed to express SA-beta-gal. GLB1 mRNA depletion also prevented expression of SA-beta-gal activity in HeLa cervical carcinoma cells induced to enter a senescent state by repression of their endogenous human papillomavirus E7 oncogene. SA-beta-gal induction during senescence was due at least in part to increased expression of the lysosomal beta-galactosidase protein. These results also indicate that SA-beta-gal is not required for senescence. PMID:16626397

Lee, Bo Yun; Han, Jung A; Im, Jun Sub; Morrone, Amelia; Johung, Kimberly; Goodwin, Edward C; Kleijer, Wim J; DiMaio, Daniel; Hwang, Eun Seong

2006-04-01

373

A new form of ovine G M1 -gangliosidosis  

Microsoft Academic Search

neurological signs were observed in 3 lambs at approximately 1 month of age, in a flock of 1 ram and 29 ewes with 43 lambs. Deterioration occurred such that the lambs had either died or been killed by 4 months of age. Necropsies of two of these lambs revealed a diffuse encephalopathy in which the most prominent feature was ballooned

Barbara J. Skelly; Martin Jeffrey; Robin J. M. Franklin; Bryan G. Winchester

1995-01-01

374

Genetics Home Reference: GM2-gangliosidosis, AB variant  

MedlinePLUS

... with the AB variant experience seizures, vision and hearing loss, intellectual disability, and paralysis. An eye abnormality called ... in neurons in the brain and spinal cord. Progressive damage caused by the buildup of GM2 ganglioside ...

375

[Thin-layer chromatography of urine oligosaccharides in diagnosis of some lysosomal storage disorders].  

PubMed

Inherited lysosomal storage disorders are caused by the deficiency or importantly lowered activity of one of the lysosomal enzymes, leading to the storage in the lysosomes the not degraded high-molecular substrates, among others: mucopolysaccharides, glycolipids, oligosaccharides and glycoproteins. Thin-layer chromatography of urine oligosaccharides allows reliable and fast diagnosis of some lysosomal storage disorders e.g. alpha-mannosidosis, fucosidosis, sialidosis, galactosialidosis, Schindler disease, GM1-gangliosidosis, GM2-gangliosidosis (Sandhoff type), Pompe disease, Salla disease, mucolipidosis II and III. We are presenting a modification of the Humbel and Collart's method of TLC of urine oligosaccharides. The principle of our modification is to introduce of the preliminary desalting step of the urine on the columns containing anionit BioRad AG 1 x 8 and cationit Dowex 50 x 8-200. PMID:8649932

Lugowska, A; Tylki-Szyma?ska, A; Sawnor-Korszy?ska, D

1995-10-01

376

GM1 ganglioside administration partially counteracts the morphological changes associated with haloperidol treatment within the dorsal striatum of the rat  

Microsoft Academic Search

Haloperidol, a typical antipsychotic drug, causes an increase in the mean percentage of synapses within the striatum containing a discontinuous, or perforated, postsynaptic density (PSD) following 1 month of treatment (Meshul et al. 1994). This effect is not observed with the atypical antipsychotic drug, clozapine, following subchronic administration (Meshul et al. 1992a). This morphological change is also associated with an

C. K. Meshul; R. K. Stallbaumer; C. Allen

1995-01-01

377

To forecast the investment in the treatment of the environmental pollution of China by Gm (1,1)  

Microsoft Academic Search

The environmental problem is one of the focus problems in the process of the development of society and economy in our country. The treatment of environmental pollution is an effectual way to solve the current environmental pollution in our country. However, the lack of the investment in the treatment of environment pollution becomes the \\

Hongwei Li; Dequn Zhou; Yunlong Sun

2007-01-01

378

Macroautophagy is not directly involved in the metabolism of amyloid precursor protein.  

PubMed

Alterations in the metabolism of amyloid precursor protein (APP) are believed to play a central role in Alzheimer disease pathogenesis. Burgeoning data indicate that APP is proteolytically processed in endosomal-autophagic-lysosomal compartments. In this study, we used both in vivo and in vitro paradigms to determine whether alterations in macroautophagy affect APP metabolism. Three mouse models of glycosphingolipid storage diseases, namely Niemann-Pick type C1, GM1 gangliosidosis, and Sandhoff disease, had mTOR-independent increases in the autophagic vacuole (AV)-associated protein, LC3-II, indicative of impaired lysosomal flux. APP C-terminal fragments (APP-CTFs) were also increased in brains of the three mouse models; however, discrepancies between LC3-II and APP-CTFs were seen between primary (GM1 gangliosidosis and Sandhoff disease) and secondary (Niemann-Pick type C1) lysosomal storage models. APP-CTFs were proportionately higher than LC3-II in cerebellar regions of GM1 gangliosidosis and Sandhoff disease, although LC3-II increased before APP-CTFs in brains of NPC1 mice. Endogenous murine A?40 from RIPA-soluble extracts was increased in brains of all three mice. The in vivo relationship between AV and APP-CTF accumulation was also seen in cultured neurons treated with agents that impair primary (chloroquine and leupeptin + pepstatin) and secondary (U18666A and vinblastine) lysosomal flux. However, A? secretion was unaffected by agents that induced autophagy (rapamycin) or impaired AV clearance, and LC3-II-positive AVs predominantly co-localized with degradative LAMP-1-positive lysosomes. These data suggest that neuronal macroautophagy does not directly regulate APP metabolism but highlights the important anti-amyloidogenic role of lysosomal proteolysis in post-secretase APP-CTF catabolism. PMID:20864542

Boland, Barry; Smith, David A; Mooney, Declan; Jung, Sonia S; Walsh, Dominic M; Platt, Frances M

2010-11-26

379

Chronic Cyclodextrin Treatment of Murine Niemann-Pick C Disease Ameliorates Neuronal Cholesterol and Glycosphingolipid Storage and Disease Progression  

PubMed Central

Background Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder caused most commonly by a defect in the NPC1 protein and characterized by widespread intracellular accumulation of unesterified cholesterol and glycosphingolipids (GSLs). While current treatment therapies are limited, a few drugs tested in Npc1?/? mice have shown partial benefit. During a combination treatment trial using two such compounds, N-butyldeoxynojirimycin (NB-DNJ) and allopregnanolone, we noted increased lifespan for Npc1?/? mice receiving only 2-hydroxypropyl-?-cyclodextrin (CD), the vehicle for allopregnanolone. This finding suggested that administration of CD alone, but with greater frequency, might provide additional benefit. Methodology/Principal Findings Administration of CD to Npc1?/? mice beginning at either P7 or P21 and continuing every other day delayed clinical onset, reduced intraneuronal cholesterol and GSL storage as well as free sphingosine accumulation, reduced markers of neurodegeneration, and led to longer survival than any previous treatment regime. We reasoned that other lysosomal diseases characterized by cholesterol and GSL accumulation, including NPC disease due to NPC2 deficiency, GM1 gangliosidosis and mucopolysaccharidosis (MPS) type IIIA, might likewise benefit from CD treatment. Treated Npc2?/? mice showed benefits similar to NPC1 disease, however, mice with GM1 gangliosidosis or MPS IIIA failed to show reduction in storage. Conclusions/Significance Treatment with CD delayed clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan of both Npc1?/? and Npc2?/? mice. In contrast, CD failed to ameliorate cholesterol or glycosphingolipid storage in GM1 gangliosidosis and MPS IIIA disease. Understanding the mechanism(s) by which CD leads to reduced neuronal storage may provide important new opportunities for treatment of NPC and related neurodegenerative diseases characterized by cholesterol dyshomeostasis.

Davidson, Cristin D.; Ali, Nafeeza F.; Micsenyi, Matthew C.; Stephney, Gloria; Renault, Sophie; Dobrenis, Kostantin; Ory, Daniel S.; Vanier, Marie T.; Walkley, Steven U.

2009-01-01

380

Selective screening for lysosomal storage diseases with dried blood spots collected on filter paper in 4,700 high-risk colombian subjects.  

PubMed

Lysosomal storage disorders (LSDs) are a very heterogeneous group of hereditary disorders. The diagnostic process usually involves complex sampling, processing, testing, and validation procedures, performed by specialized laboratories only, which causes great limitations in reaching a diagnosis for patients affected by these diseases.There are few studies about LSDs in Colombia. The diagnostic limitations often make medical practitioners disregard the possibility of these disorders while diagnosing their patients. The current study documents the results of a 7-year screening in high-risk patients, aimed to detect LSDs using dried blood spots (DBS) collected on filter paper, with a micromethodology that facilitates diagnosis even with a large number of samples.The activities of ?-galactosidase A, ? glucosidase, ?-L-iduronidase, arylsulfatase B, ?-galactosidase, ?-glucosidase, total hexosaminidase, iduronate sulfatase, and chitotriosidase were analyzed in high-risk patients for lysosomal disease. The catalytic activity was evaluated with fluorometric micromethods using artificial substrates marked with 4-methylumbelliferone.The reference values for a control population were established for the enzymes listed above, and 242 patients were found to have an enzyme deficiency, guiding to the following diagnoses: Fabry disease (n = 31), Pompe disease (n = 16), Hurler Syndrome (n = 15), Maroteaux-Lamy Syndrome (n = 34), GM1 Gangliosidosis (n = 10), Morquio B (n = 1), Gaucher disease (n = 101), Sandhoff disease (n = 1), Mucolipidosis (n = 2), and Hunter Syndrome (n = 31). In conclusion, this protocol provides a comprehensive diagnostic approach which could be carried out in Colombia and made it available to medical services spread around the country, enabling the identification of a large number of patients affected by LSDs, which could potentially benefit from the therapeutic tools already available for many of these diseases. PMID:23609959

Uribe, Alfredo; Giugliani, Roberto

2013-01-01

381

Lectin histochemistry and ultrastructure of feline kidneys from six different storage diseases  

Microsoft Academic Search

Summary  We have compared the pattern of lectin staining with the ultrastructural features of kidneys from normal cats and 19 cats\\u000a with 6 different lysosomal storage diseases. The diseases studied include GM1 and GM2 gangliosidosis, mucopolysaccharidosis (MPS)-I and MPS-VI, sphingomyelinlipidosis (i.e., Niemann-Pick disease) and mannosidosis.\\u000a Ten different biotinylated lectins were used as histochemical probes for carbohydrate residues and avidin-biotin-peroxidase\\u000a complex as

Massimo Castagnaro; Joseph Alroy; Angelo A. Ucci; Robert H. Glew

1987-01-01

382

[The progress and strategy of molecular diagnosis for human genetic diseases].  

PubMed

Recently, the human genome project has progressed and the responsible genes for many diseases have been discovered. Molecular diagnosis based on gene analysis techniques has developed. In this paper, the methods in molecular diagnosis were explained, taking as examples of several pediatric neurological diseases such as GM1- gangliosidosis, fragile X syndrome and congenital myotonic dystrophy. Next, we stressed the importance of the study on the gene function in related to the gene mutation. Finally the strategy to establish the molecular diagnosis of polygenic diseases, such as mental retardation and autism, was considered. PMID:9545776

Nanba, E

1998-03-01

383

Crystal Structure of Human ?-Galactosidase  

PubMed Central

GM1 gangliosidosis and Morquio B are autosomal recessive lysosomal storage diseases associated with a neurodegenerative disorder or dwarfism and skeletal abnormalities, respectively. These diseases are caused by deficiencies in the lysosomal enzyme ?-d-galactosidase (?-Gal), which lead to accumulations of the ?-Gal substrates, GM1 ganglioside, and keratan sulfate. ?-Gal is an exoglycosidase that catalyzes the hydrolysis of terminal ?-linked galactose residues. This study shows the crystal structures of human ?-Gal in complex with its catalytic product galactose or with its inhibitor 1-deoxygalactonojirimycin. Human ?-Gal is composed of a catalytic TIM barrel domain followed by ?-domain 1 and ?-domain 2. To gain structural insight into the molecular defects of ?-Gal in the above diseases, the disease-causing mutations were mapped onto the three-dimensional structure. Finally, the possible causes of the diseases are discussed.

Ohto, Umeharu; Usui, Kimihito; Ochi, Toshinari; Yuki, Kenjiro; Satow, Yoshinori; Shimizu, Toshiyuki

2012-01-01

384

Prevalence and Novel Mutations of Lysosomal Storage Disorders in United Arab Emirates : LSD in UAE.  

PubMed

Lysosomal storage disorders (LSD) are rare entities of recessive inheritance. The presence of a "founder" mutation in isolated communities with a high degree of consanguinity (e.g., tribes in the Middle East North Africa, MENA, region) is expected to lead to unusually high disease prevalence. The primary aim of this study was to estimate the prevalence of LSD and report their mutation spectrum in UAE. Between 1995 and 2010, 119 patients were diagnosed with LSD (65 Emiratis and 54 non-Emiratis). Genotyping was performed in 59 (50 %) patients (39 Emirati from 17 families and 20 non-Emiratis from 17 families). The prevalence of LSD in Emiratis was 26.9/100,000 live births. Sphingolipidoses were relatively common (9.8/100,000), with GM1-gangliosidosis being the most prevalent (4.7/100,000). Of the Mucopolysaccharidoses VI, IVA and IIIB were the predominant subtypes (5.5/100,000). Compared to Western countries, the prevalence of fucosidosis, Batten disease, and ?-mannosidosis was 40-, sevenfold, and fourfold higher in UAE, respectively. The prevalence of Pompe disease (2.7/100,000) was similar to The Netherlands, but only the infantile subtype was found in UAE. Sixteen distinct LSD mutations were identified in 39 Emirati patients. Eight (50 %) mutations were reported only in Emirati, of which three were novel [c.1694G>T in the NAGLU gene, c.1336 C>T in the GLB1 gene, and homozygous deletions in the CLN3 gene]. Twenty-seven (42 %) patients were clustered in five of the 70 Emirati tribes. These findings highlight the need for tribal-based premarital testing and genetic counseling. PMID:23430803

Al-Jasmi, Fatma A; Tawfig, Nafisa; Berniah, Ans; Ali, Bassam R; Taleb, Mahmoud; Hertecant, Jozef L; Bastaki, Fatma; Souid, Abdul-Kader

2013-01-01

385

Patient Rights  

MedlinePLUS

... keep them private. Many states have additional laws protecting patients, and healthcare facilities often have a patient bill of rights. An important patient right is informed consent. This means that if you ...

386

Patient Satisfaction  

PubMed Central

Patient satisfaction is an important and commonly used indicator for measuring the quality in health care. Patient satisfaction affects clinical outcomes, patient retention, and medical malpractice claims. It affects the timely, efficient, and patient-centered delivery of quality health care. Patient satisfaction is thus a proxy but a very effective indicator to measure the success of doctors and hospitals. This article discusses as to how to ensure patient satisfaction in dermatological practice.

Prakash, Bhanu

2010-01-01

387

Neural autoantibodies and neurophysiologic abnormalities in patients exposed to molds in water-damaged buildings.  

PubMed

Adverse health effects of fungal bioaerosols on occupants of water-damaged homes and other buildings have been reported. Recently, it has been suggested that mold exposure causes neurological injury. The authors investigated neurological antibodies and neurophysiological abnormalities in patients exposed to molds at home who developed symptoms of peripheral neuropathy (i.e., numbness, tingling, tremors, and muscle weakness in the extremities). Serum samples were collected and analyzed with the enzyme-linked immunosorbent assay (ELISA) technique for antibodies to myelin basic protein, myelin-associated glycoprotein, ganglioside GM1, sulfatide, myelin oligodendrocyte glycoprotein, alpha-B-crystallin, chondroitin sulfate, tubulin, and neurofilament. Antibodies to molds and mycotoxins were also determined with ELISA, as reported previously. Neurophysiologic evaluations for latency, amplitude, and velocity were performed on 4 motor nerves (median, ulnar, peroneal, and tibial), and for latency and amplitude on 3 sensory nerves (median, ulnar, and sural). Patients with documented, measured exposure to molds had elevated titers of antibodies (immunoglobulin [Ig]A, IgM, and IgG) to neural-specific antigens. Nerve conduction studies revealed 4 patient groupings: (1) mixed sensory-motor polyneuropathy (n = 55, abnormal), (2) motor neuropathy (n = 17, abnormal), (3) sensory neuropathy (n = 27, abnormal), and (4) those with symptoms but no neurophysiological abnormalities (n = 20, normal controls). All groups showed significantly increased autoantibody titers for all isotypes (IgA, IgM, and IgG) of antibodies to neural antigens when compared with 500 healthy controls. Groups 1 through 3 also exhibited abnormal neurophysiologic findings. The authors concluded that exposure to molds in water-damaged buildings increased the risk for development of neural autoantibodies, peripheral neuropathy, and neurophysiologic abnormalities in exposed individuals. PMID:15259425

Campbell, Andrew W; Thrasher, Jack D; Madison, Roberta A; Vojdani, Aristo; Gray, Michael R; Johnson, Al

2003-08-01

388

Patient Advocacy  

Cancer.gov

CPTAC recognizes the important role that patients, patient advocates, and other members outside of the traditional science community play in advancing cancer research, and is actively involved in dialogue with such communities.  To this end the consortium

389

Intermittent horizontal saccade failure ('ocular motor apraxia') in children.  

PubMed Central

BACKGROUND: Ocular motor apraxia (OMA) in childhood is a poorly understood condition involving a failure of horizontal saccades. OMA is thought to be rare but the literature indicates wide clinical associations. OMA is often identified by abnormal head movements, but failure of reflexive quick phases has been reported in all but a few patients. The extent of this oculomotor disorder was examined in a large group of children with diverse clinical backgrounds. METHODS: The degree of quick phase failure during horizontal vestibular and optokinetic nystagmus was measured using DC electro-oculography and video in 74 affected children, aged 17 days to 14 years. RESULTS: All children showed an intermittent failure of nystagmic quick phases, except for total failure in one case. Other visuomotor abnormalities were common including saccadic hypometria (85%), low gain smooth pursuit (70%), neurological nystagmus (28%), strabismus (22%), and vertical abnormalities (11%). Non-ocular abnormalities were common including infantile hypotonia (61%), motor delay (77%), and speech delay (87%). There was a wide range of clinical associations including agenesis of the corpus callosum, Joubert syndrome, Dandy-Walker malformation, microcephaly, hydrocephalus, vermis hypoplasia, porencephalic cyst, megalocephaly, Krabbe leucodystrophy, Pelizaeus Merzbacher disease, infantile Gaucher disease, GM1 gangliosidosis, infantile Refsum's disease, propionic acidaemia, ataxia telangiectasia, Bardet-Biedl syndrome, vermis astrocytoma, vermis cyst, carotid fibromuscular hypoplasia, Cornelia de Lange syndrome, and microphthalmos. Perinatal and postnatal problems were found in 15% including perinatal hypoxia, meningitis, periventricular leucomalacia, athetoid cerebral palsy, perinatal septicaemia and anaemia, herpes encephalitis, and epilepsy. Only 27% were idiopathic. CONCLUSION: Quick phase failure is a constant feature of OMA, whereas abnormal head movements were detected in only about half, depending on the underlying diagnosis. This oculomotor sign is better described as an intermittent saccade failure rather than as a true apraxia. It indicates central nervous system involvement, has wide clinical associations, but it is not a diagnosis.

Harris, C M; Shawkat, F; Russell-Eggitt, I; Wilson, J; Taylor, D

1996-01-01

390

Juvenile-onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene.  

PubMed

Progressive proximal muscle weakness is present both in spinal muscular atrophy (SMA) type III (Kugelberg-Welander disease) and in GM2 gangliosidosis, diseases that segregate in an autosomal recessive fashion. The SMN gene for SMA and the HEXA gene for GM2 gangliosidosis were investigated in a woman with progressive proximal muscle weakness, long believed to be SMA type III (Kugelberg-Welander type). She and her family underwent biochemical studies for GM2 gangliosidosis. Analysis of SMN excluded SMA. Biochemical studies on GM2 gangliosidosis showed deficiency in hexosaminidase A activity and increased GM2 ganglioside accumulation in the patient's fibroblasts. The HEXA gene was first analyzed for the Gly269-->Ser mutation characteristic for adult GM2 gangliosidosis. Since the patient was carrying the adult mutation heterozygously, all 14 exons and adjacent intron sequences were analyzed. A novel mutation in exon 1 resulting in an A-to-T change in the initiation codon (ATG to TTG) was identified. The adult patient is a compound heterozygote, with each allele containing a different mutation. Although mRNA was transcribed from the novel mutant allele, expression experiments showed no enzyme activity, suggesting that neither the TTG nor an alternative codon serve as an initiation codon in the HEXA gene. PMID:9153525

Navon, R; Khosravi, R; Melki, J; Drucker, L; Fontaine, B; Turpin, J C; N'Guyen, B; Fardeau, M; Rondot, P; Baumann, N

1997-05-01

391

Designed Fluorescent Probes Reveal Interactions between Amyloid ?(1–40) Peptides and G M1 Gangliosides in Micelles and Lipid Vesicles  

Microsoft Academic Search

A hallmark of the common Alzheimer's disease (AD) is the pathological conversion of its amphiphatic amyloid-? (A?) peptide into neurotoxic aggregates. In AD patients, these aggregates are often found to be tightly associated with neuronal GM1 ganglioside lipids, suggesting an involvement of GM1 not only in aggregate formation but also in neurotoxic events. Significant interactions were found between micelles made

I. Mikhalyov; A. Olofsson; G. Gröbner; L. B.-Å. Johansson

2010-01-01

392

Patient monitoring.  

PubMed

Optimum results are obtained in the care of the critically ill patient if efforts are directed to maintaining the internal environment in a state as near normal as possible. This cannot be done without the use of basic monitoring procedures. Complex investigations may have a legitmate and necessary role as research tools. There is, however, a real risk of complex procedures becoming an end in themselves in general intensive therapy units, where they are apt to distract overworked nurses and medical attendants from the care of their patients. It is important, therfore, for clearcut indications for various monitoring procedures to be defined, and in this paper an attempt has been made to outline alogical approach to the monitoring of critically ill genral surgical patients admitted intensive therapy units. PMID:1071552

Morton, A

1976-11-01

393

Naturally occurring G M2 gangliosidosis in two Muntjak deer with pathological and biochemical features of human classical Tay-Sachs disease (type B G M2 gangliosidosis)  

Microsoft Academic Search

Two juvenile sibling male Muntjak deer (Muntiacus muntjak) with histories of depression, ataxia, circling and visual deficits were studied. Cerebrospinal fluid analyses revealed vacuolated\\u000a macrophages that contained long parallel needle-like intracytoplasmic inclusions. Light microscopically, nerve cell bodies\\u000a throughout the brain, ganglion cells within the retina and neurons in the myenteric plexuses were variably swollen and had\\u000a pale granular to finely

J. Fox; Y.-T. Li; G. Dawson; A. Alleman; J. Johnsrude; J. Schumacher; B. Homer

1999-01-01

394

Patient Monitoring  

NASA Technical Reports Server (NTRS)

In photo above, the electrocardiogram of a hospitalized patient is being transmitted by telemetry. Widely employed in space operations, telemetry is a process wherein instrument data is converted to electrical signals and sent to a receiver where the signals are reconverted to usable information. In this instance, heart readings are picked up by the electrode attached to the patient's body and delivered by wire to the small box shown, which is a telemetry transmitter. The signals are relayed wirelessly to the console in the background, which converts them to EKG data. The data is displayed visually and recorded on a printout; at the same time, it is transmitted to a central control station (upper photo) where a nurse can monitor the condition of several patients simultaneously. The Patient Monitoring System was developed by SCI Systems, Inc., Huntsville, Alabama, in conjunction with Abbott Medical Electronics, Houston, Texas. In developing the system, SCI drew upon its extensive experience as a NASA contractor. The company applied telemetry technology developed for the Saturn launch vehicle and the Apollo spacecraft; instrumentation technology developed for heart, blood pressure and sleep monitoring of astronauts aboard NASA's Skylab long duration space station; and communications technology developed for the Space Shuttle.

1978-01-01

395

"Patient Zero":  

PubMed Central

Summary This article contextualizes the production and reception of And the Band Played On, Randy Shilts’s popular history of the initial recognition of the American AIDS epidemic. Published over twenty-five years ago, the book and its most notorious character, “Patient Zero,” are in particular need of a critical historical treatment. The article presents a more balanced consideration—a “patient’s view”—of Gaétan Dugas’s experience of the early years of AIDS. I oppose the assertion that Dugas, the so-called Patient Zero, ignored incontrovertible information about the condition and was intent on spreading his infection. Instead I argue that scientific ideas in 1982 and 1983 about AIDS and the transmissibility of a causative agent were later portrayed to be more self-evident than they were at the time. The article also traces how Shilts’s highly selective—and highly readable—characterization of Dugas rapidly became embedded in discussions about the need to criminalize the reckless transmission of HIV.

McKay, Richard A.

2014-01-01

396

Carrier rates of four single-gene disorders in Croatian Bayash Roma.  

PubMed

To assess how specific population history, different migration routes, isolation, and endogamy practices contributed to the distribution of several rare diseases found in specific Roma groups, we conducted a population-based research study of rare disease mutations in Croatian Vlax Roma. We tested a total of 427 subjects from Baranja and Me?imurje for the presence of four mutations causing hereditary motor and sensory neuropathy type Lom (HMSNL), GM1 gangliosidosis (GM1), congenital cataracts, facial dysmorphism and neuropathy (CCFDN), and limb girdle muscle dystrophy type 2C (LGMD2C), using the RFLP-PCR method to estimate carrier frequencies. We identified a total of four individuals heterozygous for the mutation causing HMSNL in the Baranja population, with a carrier rate amounting to 1.5%. Carriers for other three mutations causing GM1, CCFDN, and LGMD2C were not found in our sample. The carrier rate for the HMSNL mutation in Baranja is lower than in other Vlax Roma groups. In addition, distinct differences in carrier rates between the Croatian Vlax groups point to different genetic history, despite their belonging to the same Roma migration category and subgroup. The difference in carrier rates is either the result of admixture or the reflection of a greater extent of genetic drift since recent founding, maintained by a high degree of endogamy. PMID:24180318

Bareši?, Ana; Peri?i? Salihovi?, Marijana

2014-02-01

397

Savannah River Site's macro encapsulation processing of Less Than 3700 BQ/GM1 tru isotopic mixed waste for disposal at the Nevada Test Site  

SciTech Connect

During the Fiscal Year of 2006 (FY2006) the Savannah River Site (SRS) made a commitment with the South Carolina Department of Health and Environmental Control (SC-DHEC) to remove 1000 cubic meters of Transuranic (TRU) waste from its TRU inventory. As SRS has been generating TRU waste for many years, there was a multi-thousand drum inventory of waste designated as TRU waste. After characterization, a large inventory of TRU designated waste was determined to have a TRU radiological content of less than 3700 Becquerels per gram. This created an inventory of containers that could not be shipped to the Waste Isolation Pilot Plant (WIPP) due to being below the TRU waste threshold. A substantial portion of this debris waste was also known to contain RCRA constituents, making the waste Mixed Low Level Waste (MLLW). In order to safely and economically dispose of this waste inventory the SRS developed a process to characterize, inspect, and repackage this MLLW for disposal at the Nevada Test Site (NTS). (authors)

Siry, G.W.; Reid, L.T. [Washington Savannah River Company (United States)

2007-07-01