Disease relevance of Sphingolipidoses

• Gaucher disease, the most common of the sphingolipidoses, results from the inherited deficiency of the enzyme glucocerebrosidase (EC 3.2.1.45) [1].
• Fibroblasts of four patients affected with mucosulfatidosis (multiple sulfatase deficiency, Austin variant of metachromatic leukodystrophy) were assayed for activities of the five sulfatases known to degrade mucopolysaccharides [2].
• HCT alone does not correct skeletal dysplasia in MPSs and may not prevent development or progression of the peripheral neuropathy in sphingolipidoses and ALD [3].

High impact information on Sphingolipidoses

• These two sphingolipidoses are characterized by a heritable absence of beta-hexosaminidase A resulting in defective GM2 ganglioside degradation [4].
• Cholesterol modulates membrane traffic along the endocytic pathway in sphingolipid-storage diseases [5].
• A novel mutation in the coding region of the prosaposin gene leads to a complete deficiency of prosaposin and saposins, and is associated with a complex sphingolipidosis dominated by lactosylceramide accumulation [6].
• Glycosphingolipids are endocytosed and targeted to the Golgi apparatus, but are mistargeted to lysosomes in numerous sphingolipidoses [7].
• These results may indicate that a caspase-3 independent signaling pathway is involved in the lysosphingolipid-induced apoptosis and suggest that accumulation of lysosphingolipids, but not parental sphingolipids, triggers the apoptotic cascade in neuronal cells of patients with sphingolipidoses [8].

Chemical compound and disease context of Sphingolipidoses

• The effects of congenic hematopoietic cell transplantation (HCT; transplantation of bone marrow and spleen cells) after graded doses of busulfan (BU), a myeloablative but nonimmunosuppressive alkylating agent, were evaluated in the twitcher mouse model of human galactosylceramidase deficiency, a demyelinating sphingolipid storage disease [9].
• Together with earlier reports of the deficiencies of arylsulfatases A and C, cholesteryl sulfatase, and dehydroepiandrosterone sulfatae, mucosulfatidosis is now characterized by the deficiency of nine different sulfatases [2].
• With this DE MALDI-TOF-MS method, ceramide or monohexosylceramide accumulating in cultured fibroblasts from cases of sphingolipidoses, such as FD and GD, respectively, can be easily detected [10].
• Sphingolipid metabolism and function was investigated using sphingoid analogs, cells from human sphingolipidoses patients, and knockout animals [11].
• In cells from patients with sphingolipidoses and adult forms of storage diseases, however, methylamine accumulation was not significantly increased [12].

Biological context of Sphingolipidoses

• Other sphingolipid storage diseases such as Niemann-Pick type C which have normal acid sphingomyelinase activity would also be expected to show the same phenotype [13].

Gene context of Sphingolipidoses

• Gaucher disease, the most prevalent sphingolipidosis, is caused by the deficient activity of acid beta-glucosidase, mainly due to mutations in the GBA gene [14].
• The tear enzymes were assayed in most of the cases and demonstrated a profound deficiency of arylsulfatase A, or of arylsulfatase A and B, in the classical MLD and in mucosulfatidosis, respectively [15].
• Lipid storage disease: Part II. Ultrastructural pathology of lipid storage cells in sphingolipidoses [16].

Analytical, diagnostic and therapeutic context of Sphingolipidoses

• Since lysosphingolipids have been implicated in the biochemical pathogenesis of other genetic lysosomal sphingolipidoses, the occurrence of sphingosylphosphorylcholine (lysosphingomyelin) was specifically investigated in brain and extraneural tissues, using an HPLC method with fluorescent detection of orthophtalaldehyde derivatives [17].

References