NN'-diacetylchitobiase activity in Tay-Sachs disease and Sandhoff's disease.
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ABSTRACT:
SUBMITTER: Stirling JL
PROVIDER: S-EPMC1168118 | biostudies-other | 1974 Aug
REPOSITORIES: biostudies-other
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Project description:Tay-Sachs disease belongs to the group of autosomal-recessive lysosomal storage metabolic disorders. This disease is caused by ?-hexosaminidase A (HexA) enzyme deficiency due to various mutations in ?-subunit gene of this enzyme, resulting in GM2 ganglioside accumulation predominantly in lysosomes of nerve cells. Tay-Sachs disease is characterized by acute neurodegeneration preceded by activated microglia expansion, macrophage and astrocyte activation along with inflammatory mediator production. In most cases, the disease manifests itself during infancy, the "infantile form," which characterizes the most severe disorders of the nervous system. The juvenile form, the symptoms of which appear in adolescence, and the most rare form with late onset of symptoms in adulthood are also described. The typical features of Tay-Sachs disease are muscle weakness, ataxia, speech, and mental disorders. Clinical symptom severity depends on residual HexA enzymatic activity associated with some mutations. Currently, Tay-Sachs disease treatment is based on symptom relief and, in case of the late-onset form, on the delay of progression. There are also clinical reports of substrate reduction therapy using miglustat and bone marrow or hematopoietic stem cell transplantation. At the development stage there are methods of Tay-Sachs disease gene therapy using adeno- or adeno-associated viruses as vectors for the delivery of cDNA encoding ? and ? HexA subunit genes. Effectiveness of this approach is evaluated in ? or ? HexA subunit defective model mice or Jacob sheep, in which Tay-Sachs disease arises spontaneously and is characterized by the same pathological features as in humans. This review discusses the possibilities of new therapeutic strategies in Tay-Sachs disease therapy aimed at preventing neurodegeneration and neuroinflammation.
| S-EPMC6256099 | biostudies-literature
Project description:Tay-Sachs disease (TSD) is a fatal, recessively inherited neurodegenerative condition of infancy and early childhood. Although rare in most other populations, the carrier frequency is one in 25 in Ashkenazi Jews. Australian high-school-based TSD preconception genetic screening programs aim to screen, educate, and optimize reproductive choice for participants. These programs have demonstrated high uptake, low psychological morbidity, and have been shown to result in fewer than expected Jewish TSD-affected births over 18 years of operation. The majority of Jewish individuals of reproductive age outside of the high school screening program setting in Australia have not accessed screening. Recent recommendations advocate supplementing the community high school screening programs with general practitioner- and obstetrician-led genetic screening of Ashkenazi Jewish individuals for TSD and other severe recessive diseases for which this group is at risk. Massively parallel DNA sequencing is expected to become the testing modality of choice over the coming years.
| S-EPMC4309774 | biostudies-literature
Project description:Lysosomal storage disorders or lipidoses are a wide spectrum of inherited diseases caused by deficiency of a specific lysosomal hydrolase. About 134 mutations have been described so far and this number is gradually increasing with newer mutations being reported. We report a 28-month-old child who presented to us with neurodevelopment regression, seizures and cherry red spot in both eyes. His hexosaminidase A enzyme activity was reduced and genetic testing revealed a homozygous novel variation in HEXA (hexosaminidase A) gene in the DNA sample of the patient.
| S-EPMC6301636 | biostudies-literature
Project description:Antibodies against placental hexosaminidase A and kidney alpha-subunits were raised in rabbits after cross-linking the antigens with glutaraldehyde. Anti-(alpha(n)-subunit) antiserum (anti-alpha(n)) precipitated hexosaminidase A but not hexosaminidase B, whereas anti-(hexosaminidase A) antiserum precipitated both hexosaminidases A and B. Specific anti-(hexosaminidase A) antiserum was prepared by absorbing antiserum with hexosaminidase B. Both anti-alpha(n) and anti-(hexosaminidase A) antisera precipitated the CR (cross-reacting) material from eight unrelated patients with Tay-Sachs disease. Immunotitration, immunoelectrophoresis, double-immunodiffusion and radial-immunodiffusion techniques were used to demonstrate the presence of CR material. The CR-material-antibody complex was enzymically inactive. Antiserum raised against kidney or placental hexosaminidase A, without cross-linking with glutaraldehyde, failed to precipitate the CR material, implying that treatment of the protein with glutaraldehyde exposes antigenic determinants that are hidden in the native protein. Since anti-(hexosaminidase B) antiserum did not precipitate the CR material during the immunoelectrophoresis of Tay-Sachs liver extracts, it is suggested that altered alpha-subunits do not combine with beta-subunits. By using immunotitration we have demonstrated the competition between the hexosaminidase B-free Tay-Sachs liver extract and hexosaminidase A for the common binding sites on monospecific anti-(cross-linked hexosaminidase A) antiserum. The amount of CR material in the liver samples from seven cases of Tay-Sachs desease was found to be in the same range as theoretically calculated alpha-subunits in normal liver samples. Similar results were obtained by the radial-immunodiffusion studies. The present studies therefore suggest that Tay-Sachs disease is caused by a structural-gene mutation.
| S-EPMC1186675 | biostudies-other
Project description:BACKGROUND:Tay-Sachs disease (TSD), or GM2 gangliosidosis, is a lethal autosomal recessive neurodegenerative disorder, which is caused by a deficiency of beta-hexosaminidase A (HEXA), resulting in lysosomal accumulation of GM2 ganglioside. The aim of this study was to identify the TSD-causing mutations in an Iranian population. METHODS:In this study, we examined 31 patients for TSD-causing mutations using PCR, followed by restriction enzyme digestion. RESULTS:Molecular genetics analysis of DNA from 23 patients of TSD revealed mutations that has been previously reported, including four-base duplications c.1274_1277dupTATC in exon 11 and IVS2+1G>A, deletion TTAGGCAAGGGC in exon 10 as well as a few novel mutations, including C331G, which altered Gln>Glu in HEXB, A>G, T>C, and p.R510X in exon 14, which predicted a termination codon or nonsense mutation. CONCLUSION:In conclusion, with the discovery of these novel mutations, the genotypic spectrum of Iranian patients with TSD disease has been extended and could facilitate definition of disease-related mutations.
| S-EPMC3933921 | biostudies-literature
Project description:Tay-Sachs and Sandhoff diseases are lethal inborn errors of acid β-N-acetylhexosaminidase activity, characterized by lysosomal storage of GM2 ganglioside and related glycoconjugates in the nervous system. The molecular events that lead to irreversible neuronal injury accompanied by gliosis are unknown; but gene transfer, when undertaken before neurological signs are manifest, effectively rescues the acute neurodegenerative illness in Hexb-/- (Sandhoff) mice that lack β-hexosaminidases A and B. To define determinants of therapeutic efficacy and establish a dynamic experimental platform to systematically investigate cellular pathogenesis of GM2 gangliosidosis, we generated two inducible experimental models. Reversible transgenic expression of β-hexosaminidase directed by two promoters, mouse Hexb and human Synapsin 1 promoters, permitted progression of GM2 gangliosidosis in Sandhoff mice to be modified at pre-defined ages. A single auto-regulatory tetracycline-sensitive expression cassette controlled expression of transgenic Hexb in the brain of Hexb-/- mice and provided long-term rescue from the acute neuronopathic disorder, as well as the accompanying pathological storage of glycoconjugates and gliosis in most parts of the brain. Ultimately, late-onset brainstem and ventral spinal cord pathology occurred and was associated with increased tone in the limbs. Silencing transgenic Hexb expression in five-week-old mice induced stereotypic signs and progression of Sandhoff disease, including tremor, bradykinesia, and hind-limb paralysis. As in germline Hexb-/- mice, these neurodegenerative manifestations advanced rapidly, indicating that the pathogenesis and progression of GM2 gangliosidosis is not influenced by developmental events in the maturing nervous system.
| S-EPMC3447966 | biostudies-literature
Project description:Treatment of monogenic disorders has historically relied on symptomatic management with limited ability to target primary molecular deficits. However, recent advances in gene therapy and related technologies aim to correct these underlying deficiencies, raising the possibility of disease management or even prevention for diseases that can be treated pre-symptomatically. Tay–Sachs disease (TSD) would be one such candidate, however very little is known about the presymptomatic stage of TSD. To better understand the effects of TSD on brain development, we evaluated the transcriptomes of human fetal brain samples with biallelic pathogenic variants in HEXA. We identified dramatic changes in the transcriptome, suggesting a perturbation of normal development. We also observed a shift in the expression of the sphingolipid metabolic pathway away from production of the HEXA substrate, GM2 ganglioside, presumptively to compensate for dysfunction of the enzyme. However, we do not observe transcriptomic signatures of end-stage disease, suggesting that developmental perturbations precede neurodegeneration. To our knowledge, this is the first report of the relationship between fetal disease pathology in juvenile onset TSD and the analysis of gene expression in fetal TSD tissues. This study highlights the need to better understand the “pre-symptomatic” stage of disease to set realistic expectations for patients receiving early therapeutic intervention.
2023-02-08 | GSE224860 | GEO
Project description:To find a new biomarker of Tay-Sachs disease and Sandhoff disease. The lyso-GM2 ganglioside (lyso-GM2) levels in the brain and plasma in Sandhoff mice were measured by means of high performance liquid chromatography and the effect of a modified hexosaminidase (Hex) B exhibiting Hex A-like activity was examined. Then, the lyso-GM2 concentrations in human plasma samples were determined. The lyso-GM2 levels in the brain and plasma in Sandhoff mice were apparently increased compared with those in wild-type mice, and they decreased on intracerebroventricular administration of the modified Hex B. The lyso-GM2 levels in plasma of patients with Tay-Sachs disease and Sandhoff disease were increased, and the increase in lyso-GM2 was associated with a decrease in Hex A activity. Lyso-GM2 is expected to be a potential biomarker of Tay-Sachs disease and Sandhoff disease.
| S-EPMC3243693 | biostudies-literature
Project description:BACKGROUND:Tay-Sachs disease (TSD) is a rare neurodegenerative disorder caused by autosomal recessive mutations in the HEXA gene on chromosome 15 that encodes ?-hexosaminidase. Deficiency in HEXA results in accumulation of GM2 ganglioside, a glycosphingolipid, in lysosomes. Currently, there is no effective treatment for TSD. RESULTS:We generated induced pluripotent stem cells (iPSCs) from two TSD patient dermal fibroblast lines and further differentiated them into neural stem cells (NSCs). The TSD neural stem cells exhibited a disease phenotype of lysosomal lipid accumulation. The Tay-Sachs disease NSCs were then used to evaluate the therapeutic effects of enzyme replacement therapy (ERT) with recombinant human Hex A protein and two small molecular compounds: hydroxypropyl-?-cyclodextrin (HP?CD) and ?-tocopherol. Using this disease model, we observed reduction of lipid accumulation by employing enzyme replacement therapy as well as by the use of HP?CD and ?-tocopherol. CONCLUSION:Our results demonstrate that the Tay-Sachs disease NSCs possess the characteristic phenotype to serve as a cell-based disease model for study of the disease pathogenesis and evaluation of drug efficacy. The enzyme replacement therapy with recombinant Hex A protein and two small molecules (cyclodextrin and tocopherol) significantly ameliorated lipid accumulation in the Tay-Sachs disease cell model.
| S-EPMC6139903 | biostudies-literature
Project description:Tay-Sachs disease (TSD) is a inherited lysosomal storage disease resulting from mutations in the α-subunits of the lysosomal enzyme, β-hexosaminidase A, and leads to excessive accumulation of GM2 ganglioside. This disease can be presented in infantil, juvenil and adult forms with rapid, progressive neurodegeneration. Although the link between mTOR and autophagy in Taysachs diseases has not been previously examined, it is reasonably to infer that reduced activity of HexA and the consequent intracellular accumulation of undegraded ganglyosides could lead accumulation of lysosomes, other substrates or dysfunctional organelles, similar to other defects detected in other LSD. In the present study, we show that skin fibroblasts derived from PLS patients presented increased p62/SQSTM1 expression levels and autophagosome accumulation suggesting an impaired autophagic flux.
2021-09-30 | GSE184906 | GEO