197,182 research outputs found
Iminosugar-based GCS inhibitors improve Sandhoff mouse function.
No full text<p>(<b>A</b>) Mice were evaluated in an open-field assay at 112 days of age. Total distance traversed (ambulatory distance) and the number of times the mice raised onto their hind legs (rearing events) over 30 min are shown. (n = 15/group. Statistics are between untreated and treated Sandhoff mice, and were determined using the Graphpad Prism software t test; ** = p<0.01, *** = p<0.001. Error bars indicate SEM). (<b>B</b>) Mice were evaluated for motor coordination using the rotarod assay. The amount of time (in secs) the mice remained on the rotarod is reported as the latency. Latency is shown for wild-type mice, Genz-529468- and <i>N</i>B-DNJ-treated Sandhoff mice and untreated Sandhoff mice. (n = 15/group). Statistics compared untreated Sandhoff to Genz-529468-treated Sandhoff mice, and were determined using the Graphpad Prism software t test; * = p<0.05, ** = p<0.01, *** = p<0.001. Error bars indicate SEM.</p
A novel HEXB mutation and its structural effects in juvenile Sandhoff disease
No full textMutations in HEXB, encoding the β-subunit common to hexosaminidases A and B, cause the neurodegenerative condition, Sandhoff disease. A homozygous missense HEXB mutation (p. D459A) was discovered in six patients with a rare juvenile variant: we show that this disrupts a salt bridge between aspartate D459 and arginine 505 at the subunit interface; R505 mutations are reported in late-onset Sandhoff disease. Identification of D459A contributes to diagnosis and molecular understanding of attenuated Sandhoff disease variants. Crown Copyright © 2008
An inducible mouse model of late onset Tay-Sachs disease
No full textMouse models of the GM2 gangliosidoses, Tay–Sachs and Sandhoff disease, are null for the hexosaminidase ? and ? subunits respectively. The Sandhoff (Hexb?/?) mouse has severe neurological disease and mimics the human infantile onset variant. However, the Tay–Sachs (Hexa?/?) mouse model lacks an overt phenotype as mice can partially bypass the blocked catabolic pathway and escape disease. We have investigated whether a subset of Tay–Sachs mice develop late onset disease. We have found that not, vert, similar65% of the mice develop one or more clinical signs of the disease within their natural life span (n = 52, P < 0.0001). However, 100% of female mice with repeat breeding histories developed late onset disease at an earlier age (n = 21, P < 0.0001) and displayed all clinical features. Repeat breeding of a large cohort of female Tay–Sachs mice confirmed that pregnancy induces late onset Tay–Sachs disease. Onset of symptoms correlated with reduced up-regulation of hexosaminidase B, a component of the bypass pathway
Sandhoff disease in the Turkish population
No full textEighteen cases affected by Sandhoff disease were investigated by an enzymatic study of serum and leukocytes during the period 1988-1996, the clinical expression and enzymatic study were reported and discussed, An indirect minimum disease incidence was calculated in the Turkish population. Hexosaminidase activity in serum and leukocytes was severely deficient when measured by synthetic substrate 4-MU-N-acetylglucosaminide using the thermolabile fractionation procedure, Fractionation of hexosaminidase revealed different levels of isoenzymes A and B. Clinically, organomegaly was not found in 11 out of 18 infantile Sandhoff disease patients, while the remaining seven had mild organomegaly. Organomegaly was not found in patients with relatively high % hexosaminidase B activities. These results suggested that patients with different percent heat-stable enzyme activity may have a different type of mutation which is related to the underlying molecular heterogeneity in the Turkish population where 21% of marriages are found to be consanguineous. (C) 1997 Elsevier Science B.V
Bone marrow transplantation prolongs life span and ameliorates neurologic manifestations in Sandhoff disease mice.
No full textThe GM2 gangliosidoses are a group of severe, neurodegenerative conditions that include Tay-Sachs disease, Sandhoff disease, and the GM2 activator deficiency. Bone marrow transplantation (BMT) was examined as a potential treatment for these disorders using a Sandhoff disease mouse model. BMT extended the life span of these mice from approximately 4.5 mo to up to 8 mo and slowed their neurologic deterioration. BMT also corrected biochemical deficiencies in somatic tissues as indicated by decreased excretion of urinary oligosaccharides, and lower glycolipid storage and increased levels of beta-hexosaminidase activity in visceral organs. Even with neurologic improvement, neither clear reduction of brain glycolipid storage nor improvement in neuronal pathology could be detected, suggesting a complex pathogenic mechanism. Histological analysis revealed beta-hexosaminidase-positive cells in the central nervous system and visceral organs with a concomitant reduction of colloidal iron-positive macrophages. These results may be important for the design of treatment approaches for the GM2 gangliosidoses
Iminosugar-based GCS inhibitors increase Sandhoff mouse survival.
No full text<p>Mice were monitored daily from 80 days of age and euthanized when they became moribund and were unable to right themselves from a supine position within 30 sec. Untreated mice displayed a median survival of 135 days; Sandhoff mice treated with Genz-5294468 or <i>N</i>B-DNJ had median survivals of 181 days and 191 days, respectively. Both iminosugar-based GCS inhibitors significantly (p<0.0001) increased survival relative to that of untreated Sandhoff mice. (n = 15/group).</p
Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation
No full textSandhoff disease, one of the GM2 gangliosidoses, is a lysosomal storage disorder characterized by the absence of beta-hexosaminidase A and B activity and the concomitant lysosomal accumulation of its substrate, GM2 ganglioside. It features catastrophic neurodegeneration and death in early childhood. How the lysosomal accumulation of ganglioside might affect the early development of the nervous system is not understood. Recently, cerebral organoids derived from induced pluripotent stem (iPS) cells have illuminated early developmental events altered by disease processes. To develop an early neurodevelopmental model of Sandhoff disease, we first generated iPS cells from the fibroblasts of an infantile Sandhoff disease patient, then corrected one of the mutant HEXB alleles in those iPS cells using CRISPR/Cas9 genome-editing technology, thereby creating isogenic controls. Next, we used the parental Sandhoff disease iPS cells and isogenic HEXB-corrected iPS cell clones to generate cerebral organoids that modeled the first trimester of neurodevelopment. The Sandhoff disease organoids, but not the HEXB-corrected organoids, accumulated GM2 ganglioside and exhibited increased size and cellular proliferation compared with the HEXB-corrected organoids. Whole-transcriptome analysis demonstrated that development was impaired in the Sandhoff disease organoids, suggesting that alterations in neuronal differentiation may occur during early development in the GM2 gangliosidoses
Glycosphingolipid storage leads to the enhanced degradation of the B cell receptor in Sandhoff disease mice.
No full textGlycosphingolipid storage diseases are a group of inherited metabolic diseases in which glycosphingolipids accumulate due to their impaired lysosomal breakdown. Splenic B cells isolated from NPC1, Sandhoff, GM1-gangliosidosis and Fabry disease mouse models showed large (20- to 30-fold) increases in disease specific glycosphingolipids and up to a 4-fold increase in cholesterol. The magnitude of glycosphingolipid storage was in the order NPC1 > Sandhoff approximately GM1 gangliosidosis > Fabry. Except for Fabry disease, glycosphingolipid storage led to an increase in the lysosomal compartment and altered glycosphingolipid trafficking. In order to investigate the consequences of storage on B cell function, the levels of surface expression of B cell IgM receptor and its associated components were quantitated in Sandhoff B cells, since they are all raft-associated on activation. Both the B cell receptor, CD21 and CD19 had decreased cell surface expression. In contrast, CD40 and MHC II, surface receptors that do not associate with lipid rafts, were unchanged. Using a pulse chase biotinylation procedure, surface B cell receptors on a Sandhoff lymphoblast cell line were found to have a significantly decreased half-life. Increased co-localization of fluorescently conjugated cholera toxin and lysosomes was also observed in Sandhoff B cells. Glycosphingolipid storage leads to the enhanced formation of lysosomal lipid rafts, altered endocytic trafficking and increased degradation of the B cell receptor
GM2-Gangliosidosis (Sandhoff and Tay Sachs disease): Diagnosis and Neuroimaging Findings (An Iranian Pediatric Case Series)
No full textHow to Cite This Article: Karimzadeh P, Jafari N, Nejad Biglari H, Jabbeh Dari S, Ahmad Abadi F, Alaee MR, Nemati H, Saket S,Tonekaboni SH, Taghdiri MM, Ghofrani M. GM2-Gangliosidosis (Sandhoff and Tay Sachs disease): Diagnosis and Neuroimaging Findings (An Iranian Pediatric Case Series) Iran J Child Neurol. 2014 Summer;8(3): 55-60. AbstractObjectiveGM2-Gangliosidosis disease is a rare autosomal recessive genetic disorder that includes two disorders (Tay–Sachs and Sandhoff disease).These disorders cause a progressive deterioration of nerve cells and inherited deficiency in creatinghexosaminidases A, B, and AB.Materials & MethodsPatients who were diagnosed withGM2-Gangliosidosis in the Neurology Department of Mofid Children’s Hospital in Tehran, Iran from October 2009 to February 2014were included in our study. The disorder was confirmed by neurometabolic and enzyme level detection of hexosaminidases A, B, and ABin reference to Wagnester Laboratory in Germany. We assessed age, gender, past medical history, developmental status, clinical manifestations, and neuroimaging findings of 9 patients with Sandhoff disease and 9 with Tay Sachs disease.Results83% of our patients were the offspring of consanguineous marriages. All of them had a developmental disorder as a chief complaint.38%of patients had a history of developmental delay or regression and 22% hadseizures. The patients with Sandhoff and Tay Sachs disease were followed for approximately 5 years and the follow-up showed all patients were bedridden or had expired due to refractory seizures, pneumonia aspiration, or swallowingdisorders.Neuro-imaging findings included bilateral thalamic involvement, brain atrophy, and hypo myelination in near half of our patients (48%). 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