Disease relevance of Sandhoff Disease

• GINI was tested on colon cancer and Sandhoff disease cell lines, which contained previously characterized nonsense mutations in the MutL homolog 1 (MLH1) and hexosaminidase B (HEXB) genes, respectively [1].
• There were 20 cases of metachromatic leukodystrophy (infantile,14; juvenile, 6), 12 cases of Tay-Sachs disease (infantile, 9; late G(M2-M3) gangliosidoses, 3), 8 cases of Sandhoff's disease, and 1 male case with multiple sulfatase deficiency [2].
• Lysosomal enzymes in ataxia: discovery of two new cases of late onset hexosaminidase A and B deficiency (adult Sandhoff disease) in French Canadians [3].
• The data obtained may be applied to the investigation of the multiple forms of alpha-L-fucosidase and hexosaminidase in chorion biopsy specimens for the prenatal diagnosis of fucosidosis (alpha-L-fucosidase deficiency), Tay-Sachs diseases (hexosaminidase A deficiency) and Sandhoff disease (deficiency of hexosaminidase A and B) [4].

High impact information on Sandhoff Disease

• Mice containing a disruption of the Hexb gene have provided a useful model system for the study of the human lysosomal storage disorder known as Sandhoff disease (SD) [5].
• Both isozyme activities are deficient in Sandhoff disease, owing to mutations of the HEXB gene encoding the common beta-subunit [6].
• Deletion of macrophage-inflammatory protein 1 alpha retards neurodegeneration in Sandhoff disease mice [7].
• We therefore have treated a mouse model of Sandhoff disease with the inhibitor N-butyldeoxynojirimycin [8].
• Hex B (beta beta homodimer) is also defective in Sandhoff disease [9].

Chemical compound and disease context of Sandhoff Disease

• In this study, we treated Sandhoff disease mice with nonsteroidal antiinflammatory drugs (indomethacin, aspirin, and ibuprofen) and antioxidants (L-ascorbic acid and alpha-tocopherol acetate) [10].
• In the present study, a more selective compound, the galactose analogue N-butyldeoxygalactonojirimycin (NB-DGJ), was evaluated in the Sandhoff disease mouse model [11].
• GM2 and GA2 gangliosides from the brain of a patient who died of Sandhoff's disease were purified by solvent partition, silicic acid and silica gel column chromatography, and silica gel preparative thin-layer chromatography [12].
• In a previous study, we reported the beneficial effects of treating Sandhoff disease mice with the glucose analogue N-butyldeoxynojirimycin (NB-DNJ), a compound that inhibits the first step of GSL biosynthesis catalysed by the ceramide specific glucosyltransferase [11].
• The urine of a patient with Sandhoff's disease (GM2 gangliosidosis-variant O) contains 10--12 N-acetylglucosamine-rich oligosaccharides in high amounts [13].

Biological context of Sandhoff Disease

• Deletion of MIP-1alpha expression resulted in a substantial decrease in infiltration and macrophage/microglial-associated pathology together with neuronal apoptosis in Sandhoff disease mice [7].
• Recent advances in determining the neuropathophysiological mechanisms in Sandhoff disease have shown a mechanistic link between GM2 accumulation, neuronal cell death, reduction of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA) activity, and axonal outgrowth [14].
• Compound heterozygosity with two novel mutations in the HEXB gene produces adult Sandhoff disease presenting as a motor neuron disease phenotype [15].
• The technique is applied here to PGD of Sandhoff disease caused by 16-kb deletion of the hexosaminidase B gene for a couple with a religious objection to discarding embryos irrespective of embryo genotype [16].

Anatomical context of Sandhoff Disease

• We have cloned and fully characterized a deletion at the HEXB gene from fibroblasts of a patient with the infantile form of Sandhoff disease [6].
• Levels of total hexosaminidase and hexosaminidase B in plasma, white blood cells, and fibroblasts were decreased, as found in Sandhoff disease [17].
• Bone marrow transplantation (BMT), which augments enzyme levels, and substrate deprivation (using the glycosphingolipid biosynthesis inhibitor N-butyldeoxynojirimycin [NB-DNJ]) independently have been shown to extend life expectancy in a mouse model of Sandhoff disease [18].
• Inhibition of calcium uptake via the sarco/endoplasmic reticulum Ca2+-ATPase in a mouse model of Sandhoff disease and prevention by treatment with N-butyldeoxynojirimycin [19].

Gene context of Sandhoff Disease

• Mutations in the HEXA or HEXB gene resulting in a beta-hexosaminidase deficiency cause Tay-Sachs or Sandhoff disease, respectively [20].
• Two small deletion mutations of the HEXB gene are present in DNA from a patient with infantile Sandhoff disease [21].
• Beta-N-Acetylhexosaminidase is a lysosomal enzyme; mutation in this protein leads to Tay-Sachs or Sandhoff disease [22].
• We isolated primary microglial cells from the neonatal brains of Sandhoff disease model mice (SD mice) produced by disruption of the murine Hex beta-subunit gene allele (Hexb-/-) [23].
• Both GA2 and GM2 were reduced by almost 10% and 50%, respectively, on day 3, and by 60% and 70% on day 7 compared with untreated age-matched Sandhoff disease mice [24].

References