2010 - Secondary Schizophrenia by Sachdev & Keshavan

Author:Sachdev & Keshavan
Language: eng
Format: mobi
Published: 2014-08-01T19:55:10.593000+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 cerebellar atrophy [68, 71,

the microtubule-associated protein MAP2 results in

72, 73, 74] or callosal pathology [58, 75] (Figure

dendritic microtubule depolymerization [65], and a

16.2). Occasionally, white matter hyperintensities may

reduced availability of arborization-promoting neu-

present [68, 74, 75, 76, 77], which may radiologically

rosteroids secondary to cholesterol unavailability

mimic multiple sclerosis [75].

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