The Experts below are selected from a list of 234 Experts worldwide ranked by ideXlab platform
Marie Vidailhet - One of the best experts on this subject based on the ideXlab platform.
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deep brain stimulation of the globus pallidus for generalized dystonia in gm1 type 3 Gangliosidosis technical case report
Neurosurgery, 2006Co-Authors: Emmanuel Roze, Soledad Navarro, Philippe Cornu, Marielaure Welter, Marie VidailhetAbstract:OBJECTIVE: GM1 Type 3 Gangliosidosis is a lysosomal storage guidance. At follow-up visits, both the patient and the disorder for which no specific treatment is available. It is neurologists who performed the assessment were unaware of characterized by progressive generalized dystonia, which is whether the neurostimulator was on or off. The patient was refractory to pharmacological treatment and results in severe videotaped with a standardized protocol and scored by an disability and life-threatening complications. We performed independent expert. bilateral pallidal stimulation in a patient with GM1 Gangliosidosis, and report the 12-month postoperative course. CONCLUSION: After 1 year of follow-up, double-blind comparison of the patient's status with and without CLINICAL PRESENTATION: A 24-year old woman presented neurostimulation showed a 20% improvement, with a with genetically confirmed GM1 Gangliosidosis, resulting in significant functional benefit but no change in disease severe progressive generalized dystonia. progression. Although further studies are needed to evaluate this therapeutic approach, this report suggests that pallidal INTERVENTION: Leads were implanted bilaterally into the stimulation might be a promising treatment for dystonia internal part of the globus pallidus under stereotactic caused by GM1 Type 3 Gangliosidosis.
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dystonia and parkinsonism in gm1 type 3 Gangliosidosis
Movement Disorders, 2005Co-Authors: Emmanuel Roze, Catherine Caillaud, Eduard Paschke, Nathalie Lopez, Kunihiro Yoshida, Annie Maurelollivier, Diane Doummar, Damien Galanaud, Thierry Billette De Villemeur, Marie VidailhetAbstract:GM1 Gangliosidosis is due to β-galactosidase deficiency. Only patients with type 3 disease survive into adulthood and develop movement disorders. Clinical descriptions of this form are rare, particularly in non-Japanese patients. We describe four new patients and systematically analyze all previous reports found by a literature search and contacts with the authors for additional information. Generalized dystonia remained the predominant feature throughout the disease course and was often associated with akinetic–rigid parkinsonism. GM1 Gangliosidosis must be considered as a cause of early-onset generalized dystonia, particularly in patients with short stature and skeletal dysplasia. © 2005 Movement Disorder Society
Roberto Giugliani - One of the best experts on this subject based on the ideXlab platform.
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Clinical findings in Brazilian patients with adult GM1 Gangliosidosis
JIMD reports, 2019Co-Authors: Luciana Giugliani, Carlos Eduardo Steiner, Charles Marques Lourenço, Mara Lucia Schmitz Ferreira Santos, Carolina Fischinger Moura De Souza, Ana Carolina Brusius-facchin, Guilherme Baldo, Mariluce Riegel, Roberto GiuglianiAbstract:GM1 Gangliosidosis is a lysosomal storage disorder caused by β-galactosidase deficiency. To date, prospective studies for GM1 Gangliosidosis are not available, and only a few have focused on the adult form. This retrospective cross-sectional study focused on clinical findings in Brazilian patients with the adult form of GM1 Gangliosidosis collected over 2 years. Ten subjects were included in the study. Eight were males and two females, with median age at diagnosis of 11.5 years (IQR, 4-34 years). Short stature and weight below normal were seen in five out of the six patients with data available. Radiological findings revealed that the most frequent skeletal abnormalities were beaked vertebrae, followed by hip dysplasia, and platyspondyly. Neurological examination revealed that dystonia and swallowing problems were the most frequently reported. None of the patients presented hyperkinesia, truncal hypertonia, Parkinsonism, or spinal cord compression. Clinical evaluation revealed impairment in activities of cognitive/intellectual development and behavioral/psychiatric disorders in all nine subjects with data available. Language/speech impairment (dysarthria) was found in 8/9 patients, fine motor and gross motor impairments were reported in 7/9 and 5/9 patients, respectively. Impairment of cognition and daily life activities were seen in 7/9 individuals. Our findings failed to clearly identify typical early or late alterations presented in GM1 Gangliosidosis patients, which confirms that it is a very heterogeneous condition with wide phenotypic variability. This should be taken into account in the evaluation of future therapies for this challenging condition.
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genotypic and phenotypic characterization of brazilian patients with gm1 Gangliosidosis
Gene, 2013Co-Authors: Fernanda Sperb, Filippo Pinto E Vairo, Maira Graeff Burin, Fabiana Quoos Mayer, Ursula Matte, Roberto GiuglianiAbstract:Abstract GM1 Gangliosidosis is a lysosomal disorder caused by β-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.
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the natural history of juvenile or subacute gm2 Gangliosidosis 21 new cases and literature review of 134 previously reported
Pediatrics, 2006Co-Authors: Gustavo Maegawa, Roberto Giugliani, Brenda Banwell, Don J Mahuran, Tracy L Stockley, Michael B Tropak, Susan Blaser, Joe T.r. ClarkeAbstract:Juvenile gm2 Gangliosidosis (jGM2), also called subacute GM2 Gangliosidosis (Online Mendelian Inheritance in Man [OMIM] No. 230700), is a rare and heterogeneous autosomal recessive disorder characterized by progressive neurologic deterioration that mainly affects motor and spinocerebellar function. It is a lysosomal storage disease caused by deficiency of β-hexosaminidase A, combined deficiency of β-hexosaminidases A and B, or deficiency of the noncatalytic GM2 activator. The enzyme β-hexosaminidase is comprised of 2 major isoenzymes, β-hexosaminidase A and β-hexosaminidase B. β-Hexosaminidase A is made up of 2 nonidentical subunits, α and β, that are encoded by the genes HEXA (15q23-q24) and HEXB (5q13), respectively, which are associated into the heterodimeric isoenzyme. It catalyzes the removal of the β-N-acetylgalactosamine residue from the nonreducing terminal of the oligosaccharide of GM2 ganglioside. β-Hexosaminidase B comprises 2 identical β subunits (β2). It does not catalyze the degradation of GM2 ganglioside. Mutations of the HEXA gene encoding the α subunit cause deficiency of the β-hexosaminidase A and result in the well-known form of GM2 Gangliosidosis called Tay-Sachs disease (OMIM No. 272800). Mutations of the HEXB gene, encoding the β-subunit, cause deficiency of both enzymes (β-hexosaminidase A and β-hexosaminidase B), leading to Sandhoff disease (OMIM No. 268800), which is, in clinical aspects, virtually indistinguishable from Tay-Sachs disease. Deficiency of the GM2 activator protein, which mediates the interaction between the water-soluble β-hexosaminidase A and its membrane-embedded substrate, GM2 ganglioside, causes the AB variant of GM2 Gangliosidosis (OMIM No. 272750).1,2 In the general population, the Tay-Sachs variant (TSV) of GM2 Gangliosidosis is rare, with a prevalence of 1 in 201 000 live births and incidence of 1 in 222 000 live births.3 The Sandhoff variant (SV) prevalence and incidence rates have been reported as 1 in 384 000 and 1 in 422 000 live births, respectively.3 The TSV carrier frequency is much higher in the Ashkenazi Jewish (1 in 30) and eastern Quebec French Canadian (1 in 14) populations compared with that in the general population (1 in 300).4 Community-based TSV carrier screening programs in these at-risk populations have had a dramatic effect on birth prevalence, which is now lower than that in the general population.5,6 The classical infantile form of GM2 Gangliosidosis is characterized by the onset of symptoms before the age of 6 months and progresses rapidly to death by 3 to 5 years of age.7 Juvenile or subacute and the adult, also called late-onset or chronic, subtypes of this condition present later in childhood or in adulthood and progress more slowly.1,8–22 The juvenile and adult forms of GM2 Gangliosidosis differ from each other primarily by the impact of the disease on intelligence, which is minimal through much of the course of the adult or chronic variant. Several case reports and a small number of case series have been reported.11,13,20,21 However, few studies have provided accurate descriptions of the natural clinical course of jGM2 in larger groups of patients.21,23 We report here a series of 21 cases of juvenile or subacute GM2 Gangliosidosis followed at 2 medical centers. We also review a collection of 134 previously reported cases of jGM2.* The focus of our analysis is on initial symptomatology, age of onset, and severity of symptoms during the course of the disease. We also report on the spectrum of HEXA and HEXB mutations identified in patients with the TSV and SV, respectively, and make some generalizations concerning genotype-phenotype correlations.
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six novel beta galactosidase gene mutations in brazilian patients with gm1 Gangliosidosis
Human Mutation, 1999Co-Authors: Claudia Maria Dornelles Da Silva, Alessandra Dazzo, Marcia Ha Severini, Andreia Maria Ida Sopelsa, Janice Carneiro Coelho, Arnaldo Zaha, Roberto GiuglianiAbstract:GM1-Gangliosidosis is a lysosomal storage disease caused by a deficiency of acid β-galactosidase. Three clinical forms are recognized—infantile, juvenile, and adult—based on age of onset and severity of the symptoms. We have performed molecular analysis of a large cohort of GM1 patients (19 Brazilian and one Uruguayan), using nonradioactive single-strand conformation polymorphism (SSCP) and restriction enzyme analysis of genomic DNA. Six novel mutations (R121S, V240M, D491N, 638–641insT, 895–896insC, 1622–1627insG) and two previously described point mutations (R59H, R208C) were identified. Together they accounted for 90% of the disease alleles of the patients. Two mutations, 1622–1627insG and R59H, were present in 18 of 20 patients. In addition, four polymorphisms (L10P, L12L, R521C, S532G) were identified. All cases reported are infantile GM1 Gangliosidosis. This report constitutes the most comprehensive molecular study to date of this disorder in infantile patients. Since GM1-Gangliosidosis is the most common lysosomal storage disorder in Southern Brazil, molecular diagnosis will be important for genetic counseling, carrier detection and prenatal diagnosis in index families. Hum Mutat 13:401–409, 1999. © 1999 Wiley-Liss, Inc.
Cynthia J Tifft - One of the best experts on this subject based on the ideXlab platform.
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the natural history of type 1 infantile gm1 Gangliosidosis a literature based meta analysis
Molecular Genetics and Metabolism, 2020Co-Authors: Frederick M Lang, Paul Korner, Mark Harnett, Ajith Karunakara, Cynthia J TifftAbstract:Abstract Introduction Type 1 GM1 Gangliosidosis is an ultra-rare, rapidly fatal lysosomal storage disorder, with life expectancy of Objectives The objectives of this study were to establish a large sample of patients from the literature in order to identify: 1) clinically distinguishing factors between Type 1 and Type 2 GM1 Gangliosidosis, 2) age at first symptom onset, first hospital admission, diagnosis, and death, 3) time to onset of common clinical findings, and 4) timing of developmental milestone loss. Methods PubMed was searched with the keyword “GM1 Gangliosidosis” and for articles from the year 2000 onwards. A preliminary review of these results was conducted to establish subtype classification criteria for inclusion of only Type 1 patients, resulting in 44 articles being selected to generate the literature dataset of 154 Type 1 GM1 Gangliosidosis patients. Key clinical events of these patient cases were recorded from the articles. Results Comprehensive subtyping criteria for Type 1 GM1 Gangliosidosis were created, and clinical events, including onset, diagnosis, death, and symptomology, were mapped over time. In this dataset, average age of diagnosis was 8.7 months, and average age of death was 18.9 months. Discussion This analysis demonstrates the predictable clinical course of this disease, as almost all patients experienced significant multi-organ system dysfunction and neurodevelopmental regression, particularly in the 6- to 18-month age range. Patients were diagnosed at a late age relative to disease progression, indicating the need for improved public awareness and screening. Conclusion This study highlights the significant burden of illness in this disease and provides critical natural history data to drive earlier diagnosis, inform clinical trial design, and facilitate family counseling.
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natural history of infantile gm2 Gangliosidosis
Pediatrics, 2011Co-Authors: Annette Bley, Ourania Giannikopoulos, Doug Hayden, Kim Kubilus, Cynthia J Tifft, Florian EichlerAbstract:+OBJECTIVE: G M2 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 G M2 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. Pediatrics 2011;128:e1233–e1241
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mice lacking both subunits of lysosomal β hexosaminidase display Gangliosidosis and mucopolysaccharidosis
Nature Genetics, 1996Co-Authors: Kazunori Sango, Cynthia J Tifft, Michael P Mcdonald, Jacqueline N Crawley, Michelle L Mack, Elisa Skop, Christopher M Starr, Alexander Hoffmann, Konrad SandhoffAbstract:Mice lacking both subunits of lysosomal β–hexosaminidase display Gangliosidosis and mucopolysaccharidosis
Henry J. Baker - One of the best experts on this subject based on the ideXlab platform.
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molecular consequences of the pathogenic mutation in feline gm1 Gangliosidosis
Molecular Genetics and Metabolism, 2008Co-Authors: Douglas R Martin, Misako Hwang, John W. Callahan, Barbara K Krum, G S Varadarajan, Bruce F Smith, Brigitte Rigat, Polly Foureman, Don J Mahuran, Henry J. BakerAbstract:Abstract G M1 Gangliosidosis is an inherited, fatal neurodegenerative disease caused by deficiency of lysosomal β- d -galactosidase (EC 3.2.1.23) and consequent storage of undegraded G M1 ganglioside. To characterize the genetic mutation responsible for feline G M1 Gangliosidosis, the normal sequence of feline β-galactosidase cDNA first was defined. The feline β-galactosidase open reading frame is 2010 base pairs, producing a protein of 669 amino acids. The putative signal sequence consists of amino acids 1–24 of the β-galactosidase precursor protein, which contains seven potential N-linked glycosylation sites, as in the human protein. Overall sequence homology between feline and human β-galactosidase is 74% for the open reading frame and 82% for the amino acid sequence. After normal β-galactosidase was sequenced, the mutation responsible for feline G M1 Gangliosidosis was defined as a G to C substitution at position 1448 of the open reading frame, resulting in an amino acid substitution at arginine 483, known to cause G M1 Gangliosidosis in humans. Feline β-galactosidase messenger RNA levels were normal in cerebral cortex, as determined by quantitative RT-PCR assays. Although enzymatic activity is severely reduced by the mutation, a full-length feline β-galactosidase cDNA restored activity in transfected G M1 fibroblasts to 18-times normal. β-Galactosidase protein levels in G M1 tissues were normal on Western blots, but immunofluorescence analysis demonstrated that the majority of mutant β-galactosidase protein did not reach the lysosome. Additionally, G M1 cat fibroblasts demonstrated increased expression of glucose-related protein 78/BiP and protein disulfide isomerase, suggesting that the unfolded protein response plays a role in pathogenesis of feline G M1 Gangliosidosis.
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an inversion of 25 base pairs causes feline gm2 Gangliosidosis variant 0
Experimental Neurology, 2004Co-Authors: Douglas R Martin, Barbara K Krum, G S Varadarajan, Terri Hathcock, Bruce F Smith, Henry J. BakerAbstract:Abstract In GM2 Gangliosidosis variant 0, a defect in the β-subunit of lysosomal β-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 a 25-base-pair inversion at the extreme 3′ end of the β-subunit (HEXB) coding sequence, which introduces three amino acid substitutions at the carboxyl terminus of the protein and a translational stop that is eight amino acids premature. Cats homozygous for the 25-base-pair inversion express levels of β-subunit mRNA approximately 190% of normal and protein levels only 10–20% of normal. Because the 25-base-pair inversion is similar to mutations in the terminal exon of human HEXB, the domestic shorthair cat should serve as an appropriate model to study the molecular pathogenesis of human GM2 Gangliosidosis variant 0 (Sandhoff disease).
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Phorbol ester receptors in cerebral cortex of cats with GM_1 Gangliosidosis
Neurochemical Research, 1991Co-Authors: Gouri Shanker, Henry J. BakerAbstract:The pathogenesis of neuronal dysfunction in the gangliosidoses is poorly understood. Studies of the feline gangliosidoses and in vitro experiments implicate ganglioside inhibition of protein kinase C (PKC) in the pathogenesis of these neurological diseases. Therefore, in the present study, the binding of [^3H]phorbol-12, 13 dibutyrate was measured to determine the levels of PKC in cerebral cortex of cats with GM_1 Gangliosidosis (mutant) and age matched normal siblings. This binding of ([^3H]PDB) to cerebral cortex homogenates in both normal and mutant cats was highly specific. The specificity of receptors was ascertained also from displacement studies using nonradioactive phorbol ester analogues to displace [^3H]PDB bound to its receptors. In both mutant and normal cat brain, phorbol 12, 13-dibutyrate (PDB), 4-β-phorbol 12,13-didecanoate (β-PDA) and 4-β-phorbol 12,13-dibenzoate (β-PDBz) were highly potent (approximately to same degree) and effective in displacing [^3H]PDB. On the other hand, 4-β phorbol 12,13-diacetate (β-PDA) was a weak displacer and 4-α-phorbol did not displace the bound [^3H]PDB in either normal or mutant brain. Scatchard analysis of the binding data indicated a homogenous single class of binding sites in normal and mutant brain (Normal: K_d=1.42×10^−7 M, B_max=8.40 pmoles/mg protein. Mutant: K_d=1.60×10^−7 M, B_max=10.00 pmoles/mg protein). Sphingosine inhibited the binding to approximately the same extent in normal and mutant cortex. These studies demonstrate the presence of highly specific, homogenous, single type phorbol ester receptors in cerebral cortex of cats with GM_1 Gangliosidosis which are qualitatively and quantitatively similar to normal cat brain.
John S Obrien - One of the best experts on this subject based on the ideXlab platform.
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bone marrow transplantation in canine gm1 Gangliosidosis
Clinical Genetics, 2008Co-Authors: John S Obrien, Rainer Storb, R F Raff, Jane Harding, Frederick R Appelbaum, Satoshi Morimoto, Yasuo Kishimoto, Ted C Graham, Amelia J Ahernrindell, Susan ObrienAbstract:Allogeneic bone marrow transplantation was carried out in an 81-day-old Portuguese water dog with GM1 Gangliosidosis using a DLA identical sibling as donor. Engraftment was complete and β-galactosidase activity in leukocytes of the transplanted dog were similar to those in the donor. Over the next 2.5 months neurological deterioration in the transplanted dog was similar to that in untreated dogs with GM1 Gangliosidosis. Cerebral ganglioside GM1 concentrations were not diminished by bone marrow transplantation and cerebral β-galactosidase activity was negligible. We conclude that allogeneic bone marrow transplantation early in life is ineffective in canine GM1 Gangliosidosis.
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juvenile gm1 Gangliosidosis clinical pathological chemical and enzymatic studies
Clinical Genetics, 2008Co-Authors: John S Obrien, M W Ho, M L Veath, J F Wilson, G Myers, J M Opitz, Gabriele M Zurhein, J W Spranger, Henrik A HartmannAbstract:Clinical, histological, chemical and enzymatic studies are reported in five patients in two families with juvenile GM1 Gangliosidosis (GM1 Gangliosidosis, Type 2). The clinical picture includes onset of mental and motor retardation beginning at about one year of age and progressive neurological decline with death usually within the first decade. Bony deformities, although mild, are often present and are diagnostically helpful. Ganglioside GM1 and a galactose-containing polysaccharide (similar to keratan sulfate) are stored, β-galactosidase activities are reduced in tissues and cultured skin fibroblasts; both homozygotes and heterozygotes can be detected by this method. The differentiation of juvenile GM1 Gangliosidosis from generalized Gangliosidosis (GM1 Gangliosidosis, Type 1) is discussed.
