Secondary Schizophrenia by Perminder S. Sachdev

Author:Perminder S. Sachdev [Sachdev, Perminder S.]
Language: eng
Format: epub
ISBN: 9780521856973
Amazon: 0521856973
Publisher: Cambridge University Press
Published: 2010-03-14T16:00:00+00:00

Chapter 16 – Storage disorders and psychosis

Niemann-Pick Disease type C

Niemann-Pick Disease type C (NPC) is an autosomal recessive neurovisceral disorder of lipid storage, with a frequency of 1 in 100,000 live births [38]. It is characterized by variable degrees of cognitive decline, behavioral disturbance, and neurological impairment, predominantly ataxia, and vertical supranuclear opthalmoplegia [39]. It is biochemically and pheno-typically distinct from Niemann-Pick Disease types A and B, which result from a deficiency of lysosomal sphingomyelinase [40, 41]. Genetic analysis reveals two distinct genetic foci, with 95% of the disease caused by aberrations in the NPC1 gene on 18q11–12

[42], coding for the lysosomal NPC1 protein [43]. The less common NPC2 variant is caused by mutations in the NPC2 gene, mapping to chromosome 14q24.3

Figure 16.1 Filipin staining of cultured fibroblasts in Niemann-Pick [44] and whose product resides in the Golgi apparatus Disease type C. Top left shows normal cells with minimal staining; top right and bottom left and right show staining of perinuclear and late endosomes. These proteins are involved in cholesterol in three NPC-sufferers who presented with psychosis in cyclical movement of sterols within cells [45, 46, 47],

adulthood and are described in Walterfang et al., 2006 [86].

performing cholesterol trafficking and homeostatic functions [48, 49].

Mutation and dysfunction of NPC1 and NPC2

The diagnosis of NPC can be confirmed by demon-appear to result in late endosomal accumulation of strating a low esterification rate of exogenous choles-cholesterol, some glycolipids, and selected ganglio-terol in cultured skin fibroblasts (Figure 16.1), or by sides [50, 51] leading to Alzheimer-like neurofibrillary testing for lysosomal accumulation of free cholesterol tangles (NFTs), neuronal degeneration, neuroaxonal by filipin staining [67]. The “classical” biochemical dystrophy, and demyelination [47, 52, 53, 54]. This phenotype shows markedly reduced esterification and intracellular cholesterol “traffic jam” impairs the trans-greater than 70% to 80% of cells staining positive for port of endogenously synthesized cholesterol to dis-filipin, whereas the “variant” phenotype shows near-tal axons, where it is required for membrane mainte-normal esterification rates and lower filipin-positive nance [55] and response to axonal injury [56]. Axonal cell counts while still demonstrating clinical symptoms structures are therefore particularly vulnerable and [67].

are affected early with axonal spheroid formation, NPC may present in infancy, adolescence, or adult-hypomyelination, and eventual demyelination [57]. As hood [68] with a clinically variable picture, although a result, white-matter tracts are severely affected [51,

its core features include dementia, dysarthria, ataxia, 58, 59] , with the corpus callosum showing the most vertical supranuclear opthalmoplegia, and hep-striking axonal loss [60].

atosplenomegaly. It may also commonly present The neuronal cells most vulnerable to NFT accu-with dystonia and choreoathetosis [68, 69]. Seizures, mulation are the Purkinje cells of the cerebellum, dysphagia, and pyramidal signs may appear with basal ganglia, and thalamus followed by neurons in disease progression. The range of NPC1 and NPC2

hippocampal and cortical regions [59, 61, 62, 63].

mutations results in marked heterogeneity of clinical Affected neurons often show ectopic dendritogene-presentations [70].

sis with stunted dendrites and greatly reduced den-Structural imaging in NPC commonly shows dritic arborization [64]. Altered phosphorylation of diffuse cerebral and/or

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