Although previously considered to be related to type A and type B Niemann-Pick disease type C (NPC) is quite distinct at the biochemical and molecular levels and is more common than types A and B combined. Mutations in two related genes, NPC1 and NPC2, can give rise to this disorder, with NPC1 being responsible for a majority of cases. Unlike most other lysosomal storage diseases, NPC results from a primary defect in lipid transport. Affected cells accumulate cholesterol as well as gangliosides such as GM1 and GM2. Both NPC1 and NPC2 are involved in the transport of free cholesterol from the lysosomes to the cytoplasm. NPC is clinically heterogeneous. The most common form manifests in childhood and is marked by ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria, and psychomotor regression.
Gaucher disease results from mutation in the gene that encodes glucocerebrosidase, and the resultant deficiency of this enzyme leads to an accumulation of glucocerebroside, an intermediate in glycolipid metabolism, in the mononuclear phagocytic cells. There are three autosomal recessive variants of Gaucher disease resulting from distinct allelic mutations. Common to all is deficient activity of a glucocerebrosidase that cleaves the glucose residue from ceramide. Normally, macrophages, particularly in the liver, spleen, and bone marrow, sequentially degrade glycolipids derived from the breakdown of senescent blood cells. In Gaucher disease, the degradation stops at the level of glucocerebrosides, which accumulate in macrophages. These cells—the so-called “Gaucher cells”—become enlarged, with some reaching a diameter as great as 100 µm, because of the presence of distended lysosomes, and they acquire a pathognomonic cytoplasmic appearance characterized as “wrinkled tissue paper” (
Fig. 7.11 ). It is evident now that Gaucher disease is caused not just by the burden of storage material but also by activation of the macrophages. High levels of macrophage-derived cytokines, such as interleukins (IL-1, IL-6) and tumor necrosis factor (TNF), are found in affected tissues.
Fig. 7.10 Niemann-Pickdiseaseinliver.ThehepatocytesandKupffercellshaveafoamy,vacuolatedappearanceresultingfromdepositionoflipids.
(Courtesy of Dr. Arthur Weinberg, Department of Pathology, University of Texas Southwestern Medical Center, Dallas,Texas.) http://ebooksmedicine.net