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1128 Part VIII: Monocytes and Macrophages Chapter 72: Gaucher Disease and Related Lysosomal Storage Diseases 1129

neurodegeneration in infants. The first adult patients identified had PATHOLOGY AND CLINICAL MANIFESTATIONS
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massive hepatosplenomegaly but no neurologic involvement. The The most characteristic histopathologic feature of the various forms of
predominant phospholipid accumulating in this disorder is sphingo- Niemann-Pick disease is the presence of foam histiocytes (Fig. 72–6),
myelin. In 1966, a deficiency of sphingomyelinase activity was demon- mainly in lymphoid tissues, but these may be present throughout the
strated in a patient with Niemann-Pick disease. Niemann-Pick is body. The foam cells contain largely sphingomyelin and cholesterol, the
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not a single entity; it comprises a group of disorders in which sphin- storage of cholesterol being more prominent in type C disease.
gomyelin storage occurs. Type A and type B disease, the classic forms Type A disease presents in infancy. During the first months of
of the disorder, represent an infantile neuronopathic and a later-onset life, affected infants gain weight at a diminished rate, the abdomen
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nonneuronopathic form, respectively. Type C, the most common enlarges, and development is delayed. The patients usually cannot sit
form of Niemann-Pick disease, is a neuronopathic disorder, usually and lose physical capabilities already achieved and become blind and
with an onset in early childhood, that results from an abnormality deaf. Some infants have a protracted course of jaundice of unknown
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in cholesterol transport. The sphingomyelinase gene is normal in cause. During the second year of life, the child lies still with nearly
type C disease, but mutations occur in one of two genes which have flaccid hyporeflexic extremities; there is massive hepatosplenomeg-
been designated NPC1 and NPC2; the proteins they code may func- aly, mild lymphadenopathy, and often a fine xanthomatous rash. Bone
tion in closely related steps of cholesterol transport. The designation lesions may occur.
type D disease was once applied to a population isolate in Nova Sco- Type B disease usually presents in the first decade of life with
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tia but because these individuals also have an NPC1 mutation, this hepatosplenomegaly, but may not be noted until adulthood. Neuro-
term is no longer used.
logic manifestations are usually absent. Pulmonary infiltrates are com-
mon. The absence of a cherry-red spot in the macula and longer life
EPIDEMIOLOGY expectancy differentiate type B from type A. Sea-blue histiocytes are
sometimes found in the marrow, and a number of patients had been
Niemann-Pick type A and type B diseases, also referred to as diagnosed as having sea-blue histiocytosis before a deficiency in sphin-
acid-sphingomyelinase deficiency, are panethnic disorders. There gomyelinase was demonstrated. 165
is a relatively high prevalence of type A disease among Ashkenazi Patients with type C disease often have neonatal jaundice, normal
Jews with a carrier rate of approximately 1 in 90. Three mutations early childhood, and then develop hypotonia, dementia, ataxia, dys-
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account for 90 percent of Ashkenazi Jewish patients. Type B is com- arthria, dystonia, seizures, gelastic cataplexy, and cognitive decline.
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mon among individuals from the Maghreb region and the Arabian Hepatosplenomegaly is common. Presentation may be at any
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peninsula, with three and two mutations accounting for 75 percent age, even in the seventh decade, but the “classic” description is of
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and 85 percent of Turkish and Arabic patients, respectively. Type C
disease is relatively common in a Nova Scotia isolate, in a Hispanic
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population from the Upper Rio Grande Valley in the United States,
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and in Western Europe. The prevalence of Niemann-Pick type C
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disease in European populations is estimated to be 1 in 120,000 to 1 in
150,000 Europeans. 156
ETIOLOGY AND PATHOGENESIS
Type A and type B are autosomal recessive diseases caused by loss
of function mutations in the gene for sphingomyelinase, which is
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required for cleaving the bond between ceramide and phosphorylcho-
line (see Fig. 72–1). Nonsense mutations seem to cause the more severe
type A disease, while missense mutations are found in the milder type
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B disorder. Although sphingomyelinase is believed to be a part of an
apoptosis-signaling pathway by generating ceramide from sphingomy-
elin, no relationship between disease severity and this pathway has
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been established.
Type C disease also is an autosomal recessive disorder and is
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caused by mutations in either the NPC1 159,160 or NPC2 gene. The func-
tion of the proteins encoded by these genes is unknown, but was sug-
gested to be related to intracellular cholesterol transport. 160,161 The NPC1
gene encodes for a multi-pass transmembrane protein that localizes to
the late endosome. The NPC2 protein is soluble. The NPC1 mutations
account for more than 95 percent of cases. There are only a few cases
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of NPC2 mutations manifested in neonates by severe liver and lung
involvement, and progressive neurologic involvement leading to death
by 4 years of age; there is a juvenile form in which there seems to be
good genotype–phenotype correlation. NPC1 deficiency is associ-
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ated with induction of autophagy by the class III-P13K (phosphatidyli-
nositide 3′-kinase)/beclin-1 complex. A naturally occurring murine Figure 72–6. Typical foam cell from the marrow of a patient with
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model of the disease exists. 164 Niemann-Pick disease.

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