Diagnosis and treatment: A specific sphingolipidosis can be diagnosed by measuring enzyme activity in cultured fibroblasts or peripheral leukocytes or by analyzing DNA (see Chapter 34). Histologic examination of the affected tissue is also useful. [Note: Shell-like inclusion bodies are seen in Tay-Sachs, and a crumpled tissue paper appearance of the cytosol is seen in Gaucher disease (Fig. 17.19).] Prenatal diagnosis, using cultured amniocytes or chorionic villi, is available. Gaucher disease, in which macrophages become engorged with glucocerebroside, and Fabry disease, in which globosides accumulate in the vascular endothelial lysosomes of the brain, heart, kidneys, and skin, are treated by recombinant human enzyme replacement therapy, but the monetary cost is extremely high. Gaucher has also been treated by bone marrow transplantation (because macrophages are derived from hematopoietic stem cells) and by substrate reduction therapy through pharmacologic reduction of glucosylceramide, the substrate for the deficient enzyme.
VIII. EICOSANOIDS: PROSTAGLANDINS, THROMBOXANES, AND LEUKOTRIENES
Prostaglandins (PG), thromboxanes (TX), and leukotrienes (LT) are collectively known as eicosanoids to reflect their origin from ω-3 and ω-6 polyunsaturated FA with 20 carbons (eicosa = 20). They are extremely potent compounds that elicit a wide range of responses, both physiologic (inflammatory response) and pathologic (hypersensitivity). They insure gastric integrity and renal function, regulate smooth muscle contraction (the intestine and uterus are key sites) and blood vessel diameter, and maintain platelet homeostasis. Although they have been compared to hormones in terms of their actions, eicosanoids differ from endocrine hormones in that they are produced in very small amounts in almost all tissues rather than in specialized glands and act locally rather than after transport in the blood to distant sites. Eicosanoids are not stored, and they have an extremely short half-life, being rapidly metabolized to inactive products. Their biologic actions are mediated by plasma membrane GPCR (see p. 94), which are different in different organ systems and typically result in changes in cyclic adenosine monophosphate production. Examples of eicosanoid structures are shown in Figure 17.21.
life. Cer = ceramide; Gal = galactose; Glc = glucose; GalNAc = Nacetylgalactosamine; NANA = N-acetylneuraminic acid; CNS = central nervous system. = sulfate; ERT = enzyme replacement therapy.
known as prostacyclin. Thromboxanes are designated by TX and leukotrienes by LT.]
A. Prostaglandin and thromboxane synthesis