Chapter 145

## Abstract

1. Niemann-Pick disease type C (NP-C) is an autosomal recessive lipidosis with protean clinical manifestations, distinguished biochemically by a unique error in cellular trafficking of exogenous cholesterol that is associated with lysosomal accumulation of unesterified cholesterol. A majority of patients with this phenotype are linked genetically to chromosome 18, the locus of Niemann-Pick disease type 1 gene (NPC1). NPC1 is a novel gene whose predicted protein product contains between 13 and 16 transmembrane domains, and a sterol-sensing domain with homologies to Patched, HMG-CoA reductase, and sterol regulatory element binding protein [SREBP] cleavage-activating protein (SCAP). A region designated the NPC domain, conserved in yeast, nematode, and mouse, contains a leucine zipper. NP-C is distinct at clinical, biochemical, and molecular levels from the primary sphingomyelin lipidoses (Niemann-Pick disease types A [NP-A] and Niemann-Pick disease types B [NP-B], respectively]), with which it has traditionally been grouped. Niemann-Pick disease type D (NP-D) is allelic with NP-C, and should be regarded as a variant phenotype associated with a genetic isolate, rather than a distinct entity. A small group of patients belong to a second genetic complementation group that does not link to chromosome 18. These individuals are believed to have mutations in a gene provisionally designated Niemann-Pick disease type 2 gene (NPC2).

2. The clinical manifestations of NP-C are heterogeneous. Most patients with NP-C have progressive neurologic disease, although hepatic damage is prominent in certain cases, and may be lethal in some. Variable hepatosplenomegaly, vertical supranuclear ophthalmoplegia, progressive ataxia, dystonia, and dementia characterize the “classic” phenotype. These children present in childhood, and die in the second or third decade. Other phenotypes include presentations with fetal ascites, fatal neonatal liver disease, early infantile onset with hypotonia and delayed motor development, and adult variants in which psychiatric illness and dementia predominate.

3. NP-C is panethnic. Genetic isolates have been described in Nova Scotia (formerly Niemann-Pick disease type D) and southern Colorado. Complementation studies have demonstrated two distinct groups. About 95 percent of patients link to chromosome 18q11, and thus to NPC1 ; the remainder are believed to have mutations in a second gene, provisionally designated NPC2 .

4. NP-C has an estimated prevalence of approximately 1:150,000, making it a more common phenotype than NP-A and NP-B combined. It is likely that the true prevalence of the disease has been underestimated because of confusing terminology, the lack of a definitive diagnostic test prior to the discovery of the abnormalities of cellular cholesterol processing, and failure to recognize the clinical phenotypes.

5. Foam cells or sea-blue histiocytes are found in many tissues. Such cells are not specific for NP-C and may be absent, particularly in cases lacking visceromegaly. Characteristic inclusions (polymorphous cytoplasmic bodies) may be identified in skin and conjunctival biopsies. Neuronal storage with cytoplasmic ballooning and a variety of inclusions is present throughout the nervous system. Neurofibrillary tangles, meganeurites, and axonal spheroids are also seen.

6. In most cases of NP-C, the primary molecular defect lies in NPC1 . Unesterified cholesterol, sphingomyelin, phospholipids, and glycolipids are stored in excess in the liver and spleen. Glycolipids are elevated in the brain, the principal target of this disease. There is no overt increase in cholesterol in the brain in human NP-C or its animal models. Partial sphingomyelinase deficiency, observed only in cultured cells (and never in leukocytes or solid tissues), represents a variable, secondary consequence of lysosomal cholesterol sequestration. Cultured fibroblasts show a unique disorder of cellular cholesterol processing, in which delayed homeostatic responses to exogenous cholesterol loading are impaired in association with cholesterol accumulation in lysosomes.

7. The diagnosis of NP-C requires both documentation of a characteristic pattern of filipin-cholesterol staining and measurement of cellular cholesterol esterification in cultured fibroblasts during LDL uptake. Candidates for such testing are identified chiefly by clinical presentation with or without supportive findings from neurophysiological tests and tissue biopsies. There is considerable variability in the degree of impairment of cholesterol trafficking in NP-C. Consequently, antenatal diagnosis has been restricted to families in which the biochemical abnormalities are pronounced. Molecular diagnosis will offer a desirable alternative in families where mutations in NPC1 have been identified in the index case.

8. Symptomatic treatment of seizures, dystonia, and cataplexy is effective in many patients with NP-C. Combination drug regimens have been shown to lower hepatic and plasma cholesterol levels in human NP-C. There is no evidence that such therapy alters the progression of the disease in humans or murine models.

9. Animal models with clinical, pathologic, and biochemical features resembling NP-C have been described in two species of mice, as well as in the cat and boxer dog. The murine ortholog of NPC1 is mutated in the C57BLKS/J and BALB/c models.

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