6 Comments

CHAPTER 79 LIPID STORAGE DISEASES

CHAPTER 79 LIPID STORAGE DISEASES
Williams Hematology

CHAPTER 79 LIPID STORAGE DISEASES

ERNEST BEUTLER

Definitions and History
Gaucher Disease

History

Etiology and Pathogenesis

Clinical Features

Laboratory Features

Differential Diagnosis

Therapy

Course and Prognosis
Niemann-Pick Disease

History and Classification

Etiology and Pathogenesis

Pathology and Clinical Manifestations

Laboratory Features and Differential Diagnosis

Treatment

Course and Prognosis
Sea-Blue Histiocyte Syndrome

History

Etiology and Pathogenesis

Clinical Features

Therapy, Course, and Prognosis
Chapter References

Gaucher disease and Niemann-Pick disease are the two lipid storage disorders that are most likely to be encountered by the hematologist, because both may cause splenomegaly and cytopenias. Gaucher disease is the most common of the lipid storage diseases. It occurs among Ashkenazi Jews, the population in which it is most prevalent, at a rate of about 1 birth per 1000. Deficiency of the enzyme glucocerebrosidase results in accumulation of the glycolipid glucocerebroside in the cells of the macrophage-monocyte system. Patients with the common type 1 disease have no neurologic symptoms, but the central nervous system is involved in type 2 and type 3 disease. Diagnosis of Gaucher disease depends upon demonstration of a deficiency of glucocerebrosidase, an acid b-glucosidase, or of mutations of the glucocerebrosidase gene. Most patients with type 1 disease do not require treatment, but for those who have sufficiently severe disease manifestations, the replacement of the missing enzyme by infusions given once weekly or more frequently is a very effective but very costly therapy. Splenectomy corrects the thrombocytopenia that commonly occurs in Gaucher disease. The prognosis for patients with type I disease is usually excellent. Niemann-Pick disease is a heterogeneous group of disorders. Types A and B disease are due to deficiency of the enzyme sphingomyelinase, while types C, D, and E are due to a mutation in the NPC1 gene, a gene of unknown function which, however, appears to be involved with cholesterol transport, since not only sphingomyelin but also cholesterol accumulates in these disorders. Type A disease is associated with severe neurologic disease and patients general die during the first few years of life. Type B disease has a later onset and neurologic disease is usually absent. Type C disease is associated with neurologic symptoms as well has hepatosplenomegaly. Types D and E are probably variants of type C disease. There is currently no treatment for Niemann-Pick disease, but some patients have benefitted from liver transplantation. The sea-blue histiocyte syndrome is a heterogeneous group of disorders, characterized by the presence in the marrow of macrophages that contain granules that stain a bright blue color. These cells are found in some patients with Niemann-Pick disease, and are occasionally seen in a variety of hematologic disorders.

DEFINITIONS AND HISTORY
The lipid storage diseases are hereditary disorders in which one or more tissues become engorged with a lipid. The type of lipid and its distribution have a characteristic pattern in each disorder; this chapter will deal only with those disorders in which lipid storage in the macrophages causes major clinical manifestations. These disorders are Gaucher disease, in which glucocerebroside is stored, and Niemann-Pick disease, where the storage material is sphingomyelin and/or cholesterol.
GAUCHER DISEASE
HISTORY
Gaucher disease was first described by Philippe Gaucher, who thought that the peculiar large cells in the spleen were evidence of a primary neoplasm.1 Although it was believed at one time that the glycolipid that accumulated in Gaucher disease was a galactocerebroside, it was shown in 1934 that actually glucocerebroside accumulated.2 In 1965, the primary defect was recognized as the inability to degrade glucocerebroside.3,4
ETIOLOGY AND PATHOGENESIS
ENZYMATIC BASIS OF LYSOSOMAL STORAGE DISEASES
In the course of normal growth, development, and senescence, parts of cells or whole cells are continually replaced in all tissues. Breakdown of the complex constituents of cells requires sequential, enzymatic degradation. Such degradation takes place largely in secondary lysosomes, organelles formed by the fusion of primary lysosomes with the phagocytic vacuole containing the ingested material.
Gaucher disease is the result of a hereditary deficiency in the activity of one of the lysosomal enzymes required for glycolipid degradation, viz. glucocerebrosidase. The parent substance is either a globoside or a ganglioside (Fig. 79-1). In the degradation of globosides and gangliosides it is necessary for the carbohydrate portion to be removed before hydrolysis of the sphingosine-fatty acid complex, ceramide. Removal of carbohydrate always proceeds from the free end of the polysaccharide chain: the distal glycosidic linkage must be cleaved with removal of the terminal sugar before the other glycosidic linkages can be enzymatically hydrolyzed. In the glycolipid storage diseases, the hereditary lack of a lysosomal enzyme required for hydrolysis of one of the glycosidic bonds results in the accumulation of the glycolipid that serves as a substrate for the missing enzyme. As shown in Fig. 79-1, the absence of the b-glucosidase that cleaves glucocerebroside (glucocerebrosidase) will result in accumulation of glucocerebroside. Storage of this glycolipid results in Gaucher disease.

FIGURE 79-1 The structure of some of the lipids involved in lipid storage diseases. The solid squares indicate the bonds that fail to be cleaved in the diseases specified. The globosides are sometimes designated GL-1, GL-2, and so on, the number designating the number of sugar residues attached to ceramide. There are many systems of nomenclature for the gangliosides; the designation GM2 is commonly applied to the ganglioside that accumulates in Tay-Sachs disease.

While Gaucher disease is almost always characterized by a deficiency of the lysosomal b-glucosidase, glucocerebrosidase,5 in very rare instances a severe neuronopathic form of the disease occurs as a result of a deficiency of saposin, a heat-stable glucocerebrosidase cofactor.6
GENETIC BASIS OF GAUCHER DISEASE
The glucocerebrosidase gene is located on chromosome 1. A pseudogene has been identified about 16 kb downstream from the functional gene. Well over 100 mutations causing Gaucher disease have been described7 [see williamshematology.com]. Most of these are point mutations, but one very common mutation represents the insertion of a single guanine at nucleotide (nt) 84 of the cDNA. Deletions, gene fusion events, and gene conversions involving the pseudogene also have been documented. In the Ashkenazi Jewish population the predominant mutation is at cDNA nucleotide 1226, where it causes an Asp®Ser substitution at amino acid 370. This mutation accounts for about 75 percent of the mutant alleles in Jewish patients and about 30 percent of the alleles in non-Jewish patients. It is relatively mild, both with respect to the amount of residual enzyme that can be detected in cells of affected individuals and in its phenotypic effect. A frameshift mutation resulting in the insertion of a guanine nucleotide at nt 84 is also common in the Jewish population and is phenotypically much more severe. The five most common mutations account for about 97 percent of the alleles in the Jewish population, but only for about 75 percent of the alleles in the non-Jewish population.8,9 and 10 The common mutation in the Norrbottnian population (see Incidence) is at nt 1448, and this mutation, which represents the normal pseudogene sequence, is also common in other ethnic groups.
INCIDENCE
Gaucher disease is inherited as an autosomal recessive disorder. It is most common in the Ashkenazi Jewish population where the gene frequency is 0.034.9 Thus, about 6.8 percent of the Jewish population is heterozygous for Gaucher disease and the expected birth frequency is 1:1000. Gaucher disease is also relatively common in a population isolated in Norrbottnia in Northern Sweden.11
Gaucher disease, Niemann-Pick disease, and Tay-Sachs disease all occur with elevated frequencies among Ashkenazi Jews. The high frequency of these genes is almost certainly the result of some advantage enjoyed by heterozygotes, analogous to that found in sickle cell anemia and glucose-6-phosphate dehydrogenase deficiency among African and Mediterranean peoples. The basis for such a possible heterozygote advantage in Gaucher disease is unknown.
CLINICAL FEATURES
Three major types of Gaucher disease have been differentiated clinically.5 All types are characterized by a deficiency of glucocerebrosidase and accumulation of glucocerebroside, but they are genetically and clinically quite distinct. Type 1 (“adult”) Gaucher disease occurs in children as well as in adults, but is clearly differentiated from types 2 (acute infantile neuronopathic) and 3 disease by the absence of neurologic symptoms. Type 2 disease is exceedingly rare, does not occur predominantly in Jewish families, and is characterized by rapid neurologic deterioration and early death. Type 3 (juvenile) Gaucher disease is a less well defined subacute neuronopathic disorder with later onset of neurologic symptoms and a better prognosis than the acute infantile neuronopathic type. The prototype of this type of the disease is the Norrbottnian form of the disorder.11 Type 3 disease has been subdivided into three further subtypes, a, b, and c (see “Clinical Features”).
The clinical manifestations of Gaucher disease are produced by the accumulation of Gaucher cells (Fig. 79-2), glucocerebroside-laden macrophages, in spleen, liver, and marrow. In type 2 and type 3 disease storage of glycolipid also occurs in the brain.

FIGURE 79-2 A Gaucher disease cell from the marrow (×915).

There is enormous variability in the severity of all types of Gaucher disease. Type 1 disease may be entirely asymptomatic, discovered in the course of a population survey9 or accidentally in the course of investigation of an unrelated hematologic disorder. In those patients who do have clinical manifestations the spleen may be barely palpable or it may be massively enlarged and produce symptoms, both as a result of its great bulk and by sequestering formed elements of the blood. Chronic fatigue is a common complaint. Hepatic enlargement, like splenic enlargement, may cause mechanical symptoms and liver fibrosis accompanied by functional abnormalities and varices may develop. In children, growth retardation is common. Severe pulmonary disease with cyanosis and clubbing occurs in some patients with advanced liver involvement, probably because of shunting through the lung secondary to the liver disease. Direct involvement of the lungs with Gaucher cells also has been observed.12,13 Pulmonary hypertension occurs in some patients and has been noted particularly after enzyme replacement therapy has been initiated.14,15,16,17 and 18
Skeletal lesions are often widespread. Patchy areas of bone demineralization and areas of infarction are found, and widening of the distal femur gives rise to a typical “Erlenmeyer flask” deformity (Fig. 79-3). Bone pain is probably the most troublesome clinical manifestation of Gaucher disease. Pain may occur anywhere. It generally has a deep, somewhat dull character and may be very severe. Bone pain may occur in areas with no involvement detectable by x-ray examination. It may last for weeks or months but usually subsides spontaneously, only to reappear later in the same or in another location. Aseptic necrosis of the femoral heads and vertebral collapse are particularly common, crippling complications.19,20

FIGURE 79-3 X-rays of distal femora and pelvis of a 27-year-old woman with Gaucher disease. The distal femur shafts are flared with thinning bone trabeculae, scattered sclerotic zones, and bone infarcts. The most extensive changes are seen in the left tibia proximally. The pelvis and upper femurs demonstrate extensive cystic and sclerotic changes with collapse of both femoral heads and of the right acetabulum. (X-rays courtesy of Dr. Hyman Gildenhorn, City of Hope Medical Center.)

Many organs other than the liver, spleen, and bones may be affected. Brownish masses of Gaucher cells have been reported to occur at the corneoscleral limbus of the eye.21 Gaucher cells have been found in a colonic polyp22 and the maxillary sinus.23 Fever may occur in patients in whom a meticulous search fails to reveal evidence of infection often24,25 but not always26 in connection with bone crises,24,25 and hypermetabolism has been documented.27 Severe neonatal ichthyosis (“collodion babies”) has been described in infants with acute neuronopathic Gaucher disease.28
Neurologic symptoms are the hallmark of type 2 and type 3 disease. Particularly notable are oculomotor abnormalities, hypertonia of the neck muscles with extreme arching of the neck (opistotonus), bulbar signs, limb rigidity, seizures, and sometime choreoathetoid movements. Patients with type 3a29 disease have progressive neurologic disease dominated by myoclonus and dementia; those with 3b29 disease have aggressive visceral and skeletal disease, but with neurologic manifestations largely limited to horizontal supranuclear gaze palsy; those with type 3c disease30,31,32,33 and 34 have neurologic manifestations largely limited to horizontal supranuclear gaze palsy, corneal opacities, and cardiac valve calcification, but generally have little visceral disease.
Neoplastic disorders are somewhat more common in patients with Gaucher disease than in the general population.35 Especially notable are lymphoproliferative diseases including chronic lymphocytic leukemia,24,36,37 and 38 multiple myeloma,39,40,41,42 and 43 lymphoma,44 and Hodgkin disease.45,46 The existence of monoclonal immunoglobulin spikes in the serum also has been documented in a high proportion of patients with Gaucher disease who are more than 50 years of age.47,48,49 and 50 Cohort control studies showed that the risk of hematologic neoplasms in Gaucher disease patients was 14.7 (confidence limits 5.2–41.7) times that of control subjects.51
LABORATORY FEATURES
THE BLOOD
The blood of patients with Gaucher disease may be normal or may manifest effects of hypersplenism. A normocytic, normochromic anemia is frequently present, but hemoglobin levels only uncommonly fall below 8 g/dl. A modest reticulocytosis is often present in anemic patients. The white cell count may be decreased to levels as low as 1000/µl, although milder degrees of leukopenia are much more common. The differential count is normal, but a defect of leukocyte chemotaxis52 that is corrected by enzyme replacement therapy53 has been reported. Thrombocytopenia may become quite severe. If splenectomy has been carried out, severe anisocytosis and poikilocytosis occur, with many target cells, some nucleated red cells, and Howell-Jolly bodies usually being present. In splenectomized patients the white cell count and platelet count may be higher than normal. Biochemical examination of leukocytes for b-glucosidase activity shows a severe deficiency of a pH 4 b-glucosidase and a much milder deficiency of pH 5 b-glucosidase activity.54,55
GAUCHER CELLS
Gaucher cells, found mainly in the marrow, spleen, and liver, have small, usually eccentrically placed nuclei and cytoplasm with characteristic crinkles or striations. The cytoplasm is stained by the periodic acid–Schiff technique. Electron microscopy reveals that the cytoplasm contains spindle- or rod-shaped, membrane-bound inclusion bodies 0.6 to 4 µm in diameter. These bodies appear to consist of numerous small tubules 130 to 750 Å in diameter that are seen to be composed of twisted multilayers in negatively stained preparations.56,57
Most patients with Gaucher disease manifest an increase in serum acid phosphatase activity. Since measurement of acid phosphatase activity can be performed in any clinical laboratory, increased activity of this acid hydrolase is the one most often detected, but activities of other hydrolases such as b-hexosaminidase,58 b-glucuronidase,58 angiotensin-converting enzyme,61 and chitotriosidase59,60 are also increased in the serum of most patients with Gaucher disease. Although it has been suggested that the latter may be a particularly sensitive indicator of disease activity, side-by-side comparison with angiotensin-converting enzyme and acid phosphatase shows it to have no particular advantage.62 When liver involvement is extensive, various biochemical stigmata of liver disease, including clotting factor abnormalities, may be present. Factor IX deficiency may be a laboratory artifact related to the effect of accumulated lipid on the platelet membrane on the assay.63 Factor XI deficiency is common but probably represents a chance association of two disorders, each of which is common in the Ashkenazi Jewish population.64
In older patients with Gaucher disease, monoclonal immunoglobulins are found in the plasma more frequently than expected.47,48
DIFFERENTIAL DIAGNOSIS
DIAGNOSIS
The diagnosis of Gaucher disease should be considered in patients with splenomegaly, particularly if the splenomegaly has been present for an extended period of time. The definitive diagnosis is established by determining leukocyte54 or cultured fibroblast65 b-glucosidase activity or by demonstrating the presence of known Gaucher mutations in the patient’s DNA. The latter method of diagnosis can usually establish the diagnosis in Jewish patients, but cannot exclude it: if the DNA is examined for the five most common mutations, mutations will be detected on both alleles in about 97 percent of the patients,8 but in only about 55 percent of the non-Jewish patients.66,67
Although most patients with Gaucher disease have readily demonstrable Gaucher cells in their marrow, and the diagnosis has often been established by performing a marrow examination, determination of the b-glucosidase activity is the preferred method of diagnosis.66 The number of these cells may be relatively small, and thorough examination of the marrow film under a low-power objective may be required to find them. Cells indistinguishable by light microscopy from typical Gaucher cells are also found in patients with hematologic abnormalities, including those with chronic myelogenous leukemia,68,69 Hodgkin disease,70 multiple myeloma,71 and AIDS.72 These patients do not lack the capacity to catabolize glucocerebroside,73 but the great inflow of globoside into phagocytic cells exceeds their normal capacity to hydrolyze this glycolipid. Prenatal diagnosis of Gaucher disease may be established by examining cultured amniocentesis cells for their b-glucosidase activity65 and examining the DNA for mutations.
Measurement of serum acid phosphatase activity and angiotensin converting activity are useful in confirming the diagnosis of Gaucher disease.
HETEROZYGOTE DETECTION
Heterozygotes for Gaucher disease have neither Gaucher cells in their marrow nor other stigmata of the disease. Existence of a carrier state can be established in many cases by assaying leukocytes54,74,75 or fibroblasts65 for b-glucosidase activity and demonstrating the reduction in the activity of the enzyme to about one-half of normal. However, regardless of the method used, there is an overlap between the measured enzyme activity in heterozygous individuals and the normal range. Definitive diagnosis of the heterozygous state can only be established by DNA analysis.
THERAPY
SYMPTOMATIC TREATMENT
Thrombocytopenia and leukopenia in Gaucher disease are more frequently the consequence of hypersplenism than of marrow replacement by Gaucher cells. These cytopenias respond very satisfactorily to splenectomy. However, the pathophysiology of Gaucher disease suggests that splenectomy be avoided as long as possible. The body must continue to metabolize all of the globoside that is formed; after the spleen has been removed, the glucocerebroside that accumulates as the result of incomplete globoside metabolism is deposited in the liver and marrow. Bone lesions may progress more rapidly following surgical removal of the spleen,76,77 and 78 but this impression is difficult to quantitate and cannot be verified experimentally, and no worsening of bone lesions after splenectomy could be documented in one study.35 Conservatism is advised, however, in recommending splenectomy. Partial splenectomy has been introduced in an attempt to preserve a glycolipid-sequestering site.79 The results of such surgery have been reported in a number of patients80,81,82,83,84,85,86,87,88 and 89 without conclusive data being obtained regarding the merits of the procedure.90
When bone lesions result in fractures, orthopedic procedures may be required. Hip replacement surgery is often successful, allowing some severely incapacitated patients to return to normal activity. Radiation therapy has been credited with relief of bone pain.91,92 However, radiotherapy more often fails to produce a satisfactory response93,94 and is therefore not recommended.
Liver transplantation has been carried out in a few patients with severe hepatic failure.95,96,97 and 98
ENZYME REPLACEMENT
Enzyme replacement therapy for Gaucher disease has been attempted intermittently since the mid-1970s99,100,101 and 102 but did not become successful until the commercial production of enzyme was undertaken. Alglucerase (Ceredase) is a mannose-terminated form of the enzyme extracted from placenta. Imiglucerase (Cerezyme) is the recombinant product. The removal of sugars to expose inner mannose residues was designed to take advantage of the mannose receptor of macrophages to target the enzyme. However, it has been established that alglucerase is inefficiently taken up by macrophages both in vivo and in vitro. Rather a calcium-independent mannose receptor, distinct from the classical mannose receptor found on macrophages, is ubiquitously present in large numbers in many tissues and probably binds most of the enzyme in vivo.103
Nonetheless, the response to enzyme replacement therapy with alglucerase is gratifying.104,105,106,107,108,109,110 and 111 Decrease in the size of the liver and spleen and increases in the hemoglobin levels of anemic patients and of thrombocyte levels of patients with thrombocytopenia occur within 6 months in most of the patients. The platelet count of patients with massively enlarged spleens often requires a longer period of therapy to respond, and in some patients there is sufficient splenic scarring that no appreciable response occurs.112 Response of bony lesions is much slower than that of visceral lesions, but improvement may be evident after treatment for about 2 years, regardless of the dose that is used.62,107,113,114 and 115 However, the expense of the preparation is daunting, particularly when administered by the high-dose/low-frequency schedule (60 units/kg every 2 weeks) recommended by the manufacturer and by some investigators.116 Enzyme alone, given on this schedule to an average adult, costs one-half million dollars per year. Giving enzyme infusions one to three times weekly requires much less enzyme and is therefore much more economical. One unit per kilogram every day or 2.3 units/kg three times weekly has been shown to be fully as effective as a dose more than four times as large given every 2 weeks.117 This greater effectiveness of small doses is expected for a preparation for which a few high-affinity and many lower-affinity receptors compete. Moreover, the intracellular life span of alglucerase is very short, so that infrequent administration provides therapeutic levels for only a very small proportion of the time. Even one-half of this dose was found to be fully effective in most or all patients.118,119 The practicality and effectiveness of frequent administration of alglucerase has been questioned,120,121 but the results obtained have been amply confirmed,107,108 and 109,122,123 and home therapy with alglucerase has been shown to be feasible and safe.124
In view of the very high cost of alglucerase and imiglucerase, the fact that experience with the preparation is, as yet, somewhat limited with unknown risks, and because anaphylaxis has occurred in at least one patient, use of the preparation should be reserved for patients with relatively severe disease. These would include patients with marked organomegaly, severe or moderately severe cytopenias, or patients with extensive skeletal involvement. At present, alglucerase therapy of the many patients who have clinically mild disease cannot be endorsed, even though it is recognized that some of these patients may develop aseptic necrosis of the femoral head in an unpredictable fashion. The normal starting dose for patients who do need treatment is 3.75 to 7.5 units/kg body weight given weekly.
MARROW TRANSPLANTATION
Because the macrophage is a descendant of the hematopoietic stem cell, allogeneic marrow transplantation might be expected to cure Gaucher disease. This has, indeed, been accomplished several times.11,60,125,126,127,128,129,130 and 131 Although some enthusiasm has been expressed for this approach,127 the very considerable short-term risk of marrow transplantation markedly limits the number of patients who might be suitable candidates for this therapeutic approach. The availability of effective enzyme replacement therapy further limits the appropriateness of marrow transplantation. However, because of its lower cost and the potential for cure, transplantation may occasionally be considered for the management of severe Gaucher disease.
GENE THERAPY
Autologous transplantation after gene transfer into hematopoietic cells has received considerable attention as a possible alternative form of therapy.132,133,134,135 and 136 Despite some exaggerated claims, there is no credible evidence of benefit to any patient; in vivo studies showed that, at best, 1:2000 cells carried the transgene.
OTHER THERAPIES
Decreasing globoside inflow by repeated phlebotomy has not yielded clinically significant results,137 probably because most of the glucocerebroside is formed from sequestered white cells. Splenic transplantation was attempted in one patient, without success.138 The possibility that inhibitors of ceramide formation in experimental animals might be effective treatment has been suggested,139,140 and 141 but no clinical trials have been conducted.
COURSE AND PROGNOSIS
The age of onset, severity of clinical manifestations, and degree of progression are related to the genotype of the patient. Patients with the 1226G/1226G genotype tend to have late-onset disease (Fig. 79-4), relatively mild manifestations, and virtually no progression of disease during adult life. In contrast, patients who have the 1226G/84GG, 1226G/1448C, 1226G/IVS2(+1) genotypes tend to have much earlier onset of disease, usually in the first decade of life, and show gradual progression even during adult life.62,142 Patients who are homozygous for the 1448C mutations generally develop neurologic symptoms, but some possible exceptions have been noted.143,144

FIGURE 79-4 The median and second and third quartiles of the distribution of the age of first symptoms of diagnosis of Gaucher disease in patients with three different genotypes. (Permission from Science. Beutler E: Gaucher disease: New molecular approaches to diagnosis and treatment. Science 256:794–799, 1992)

Although the genotype of the patient does provide a guide to the prognosis, there is, unfortunately, much variability among patients with the same genotype, even between sibs. Other, as yet unknown, genetic or environmental factors are important in determining the actual course of the disease in an individual patient. However, it is important to understand that, whatever the genotype, the severity of the disease does not change after early childhood.62,142,145 Progression, when it does occur, is gradual, except of course, insofar that complications such as aseptic necrosis and collapse of vertebrae may represent acute events.
In severely affected patients with type 1 disease or those with type 3 disease, death may occur as a result of liver disease, bleeding, or sepsis. In type 2 disease death usually is due to the neurologic manifestations and occurs in the first or second year of life. This type of disease can be fatal in the perinatal period.146 The fact that no patient homozygous for the 84GG mutation has ever been encountered, in spite of the relative high frequency with which this mutation occurs in the Jewish population suggests that a total lack of glucocerebrosidase may not be compatible with extrauterine life. This deduction is supported by the fact that a “knockout” mouse that has been deprived of a gene for glucocerebrosidase is not capable of extrauterine life.147
NIEMANN-PICK DISEASE
HISTORY AND CLASSIFICATION
Niemann, a Berlin pediatrician, reported the case of an infant who died at 18 months of age with a disorder that seemed to be unique because of its early onset and rapid course, which seemed atypical for Gaucher disease.148 The predominant phospholipid accumulating in this disorder is sphingomyelin. In 1966 a deficiency of sphingomyelinase activity was demonstrated in a patient with Niemann-Pick disease.149 However, it has become apparent that there is not a single Niemann-Pick disease, but rather a group of disorders that are related in that sphingomyelin storage occurs. Types A and B disease, the classical forms of the disorder, are the results of mutations in the sphingomyelinase gene and represent an infantile neuropathic and a later-onset non-neuronopathic form, respectively.150 Type C, the most common form of Niemann-Pick disease is a neuronopathic disorder, usually with onset in early childhood, that is due to an abnormality in cholesterol transport.151 The sphingomyelinase gene is normal in type C disease, but mutations occur in another gene that has been designated NPC1. Type D disease is very similar to type C disease and is found in a population isolate in Nova Scotia.151
ETIOLOGY AND PATHOGENESIS
Types A and B disease are autosomal recessive diseases caused by mutations of the gene for sphingomyelinase152,153 required to cleave the bond between ceramide and phosphorylcholine (see Fig. 79-1). Nonsense mutations seem to cause the more severe type A disease while missense mutations are found in the milder type B disorder.152 Although sphingomyelinase is believed to be a part of an apoptosis-signaling pathway by generating ceramide from sphingomyelin,154 no relationship between the disease manifestations and this pathway has been established.
Types C and D disease also show autosomal recessive inheritance and are caused by mutations in a gene that has been designated NPC1,155 the function of which is not fully understood, but that presumably plays a role in cholesterol transport and homeostasis.156 A naturally occurring murine model of the disease exists.157
PATHOLOGY AND CLINICAL MANIFESTATIONS
The most characteristic histopathologic feature of the various forms of Niemann-Pick disease is the presence of foam histiocytes (Fig. 79-5). These cells are found mainly in lymphoid tissues, but they may be present throughout the body. The foam cells contain largely sphingomyelin and cholesterol, the storage of cholesterol being more prominent in type C disease.

FIGURE 79-5 A foam cell from the marrow of a patient with Niemann-Pick disease (×875).

Type A Niemann-Pick disease is an affliction of infancy. During the first months of life, affected infants gain weight poorly, the abdomen enlarges, and development is delayed. They usually do not learn to sit and lose those capabilities already achieved. They may become blind and deaf. Some infants have a protracted course of jaundice of unknown cause. During the second year of life, the child lies still with nearly flaccid hyporeflexic extremities, an abdomen enlarged with enormous spleen and liver, mild lymphadenopathy, and often a fine xanthomatous rash. Bone lesions may be present but are less prominent than in Gaucher disease. Patients with type B disease generally present in the first decade of life with hepatosplenomegaly, but in mild cases abnormalities may not be noted until adult life. Neurologic manifestations are usually absent; pulmonary infiltrates are common. Sea-blue histiocytes are sometimes found in the marrow, and a number of patients have been diagnosed as having sea-blue histiocytosis before a deficiency in sphingomyelinase was demonstrated to be present.158 Patients with type C disease often have neonatal jaundice, develop normally in early childhood, and then develop dementia, ataxia, dysarthria, dystonia, and seizures. Hepatosplenomegaly is often, but not always, present.151
LABORATORY FEATURES AND DIFFERENTIAL DIAGNOSIS
The hemoglobin concentration of the blood may be normal, or mild anemia may be present. Typically, approximately 75 percent of the blood lymphocytes contain one to nine vacuoles. These measure approximately 2 µm in diameter. Electron microscopy reveals that these vacuoles are lipid-filled lysosomes.159
The marrow contains typical foam cells ranging in size from 20 to 100 µm in diameter and containing small droplets throughout the cytoplasm (Fig. 79-5). The cytoplasm of these cells stains only very faintly with the periodic acid–Schiff reagent. Phase microscopy of unstained preparations clearly reveals droplets in the cytoplasm of Niemann-Pick foam cells that distinguishes them from Gaucher cells. In polarized light the droplets may be birefringent, and in ultraviolet light they manifest a greenish-yellow fluorescence.160 Foam cells resembling those seen in Niemann-Pick disease also are observed in generalized gangliosidosis, and foamy histiocytes, primarily involving the bone, are seen in the rare Erdheim-Chester disease, a non-Langerhans form of histiocytosis.161 Occasionally the storage cells in Gaucher disease may present a somewhat vacuolated appearance and thereby be misinterpreted. The occurrence of sea-blue histiocytes in the spleen and marrow has been documented.158,162,163 and 164
Types A and B Niemann-Pick disease can be distinguished from other disorders by identification of the lipid as sphingomyelin and by demonstration of sphingomyelinase deficiency in leukocytes or in cultured fibroblasts. Heterozygotes may be detected by measurement of sphingomyelinase activity of cultured fibroblasts.165 Prenatal diagnosis by amniocentesis has been achieved.165,166 An artificial substrate that is very useful for the measurement of sphingomyelinase activity has been introduced.167,168 In type C disease studies of cholesterol uptake by cultured fibroblasts is diagnostic169 but cumbersome and not readily available. The identification of the NPC1 gene,155 the diagnosis of this type of disease, should be facilitated.
TREATMENT
There is no effective treatment for Niemann-Pick disease. Splenectomy is only rarely required, because death usually occurs from other manifestations of the disease before hypersplenism becomes clinically important. Liver transplantation was carried out with encouraging results.97 Repeated implantations of amniotic epithelial cells as a source of exogenous sphingomyelinase has been claimed to be associated with clinical improvement.170
COURSE AND PROGNOSIS
The prognosis in type A Niemann-Pick disease is very poor; death nearly always occurs before the third year of life.150 Patients with type B disease may survive into childhood or adult life.150 Patients with type C disease usually die in the second decade of life.151
SEA-BLUE HISTIOCYTE SYNDROME
HISTORY
According to Sawitsky et al,171 Moeschlin, in his 1947 book on splenic puncture, described a 29-year-old man with unexplained splenomegaly whose spleen contained macrophages with closely packed granules colored deep azure blue with May-Grünwald stain. He named these blauen pigmentmakrophagen (blue pigment macrophages). These cells have subsequently been found in marrow as well as spleen, and in 1954 Sawitsky et al172 suggested that two cases they observed and Moeschlin’s might represent a syndrome.
ETIOLOGY AND PATHOGENESIS
Although sea-blue histiocytes are found in Niemann-Pick disease, presumably and particularly in the type B disorder, sea-blue histiocytes are also found in patients who do not have any well-defined disorder. They have been reported in the marrow of patients with immune thrombocytopenic purpura,173 in patients receiving parenteral nutrition,174 and in patients with chronic myelogenous leukemia,175 as well as patients with Niemann-Pick disease.162,163 and 164,176
CLINICAL FEATURES
In patients without other underlying disorders, the sea-blue histiocyte syndrome is often characterized by hepatosplenomegaly and thrombocytopenia and usually by a mild chronic course. Most patients are below the age of 40 when diagnosed, and there is usually not a clear family history.171
THERAPY, COURSE, AND PROGNOSIS
There is no treatment except that which can be offered for the underlying disease. In cases associated with parenteral nutrition, there has been improvement when the dose was decreased. In those cases in which there is no known cause the course is generally a chronic, stable one.171
CHAPTER REFERENCES

1.
Gaucher PCE: De l’epithelioma primitif de la rate, hypertrophie idiopathique del la rate san leucémie. Thesis, Paris 1882.

2.
Aghion H: La maladie de Gaucher dans l’enfance. PhD thesis, Paris, 1934.

3.
Brady RO, Kanfer JN, Shapiro D: Metabolism of glucocerebrosides: II. Evidence of an enzymatic deficiency in Gaucher’s disease. Biochem Biophys Res Commun 18:221, 1965.

4.
Patrick AD: Short communications: A deficiency of glucocerebrosidase in Gaucher’s disease. Biochem J 97:17C, 1965.

5.
Beutler E, Grabowski G: Gaucher disease, in Scriver CR, et al. The Metabolic and Molecular Bases of Inherited Disease, 8th ed, McGraw-Hill, New York, 2000.

6.
Schnabel D, Schröder M, Sandhoff K: Mutation in the sphingolipid activator protein 2 in a patient with a variant of Gaucher disease. FEBS Lett 284:57, 1991.

7.
Beutler E, Gelbart T: Hematologically important mutations: Gaucher disease. Blood Cell Mol Dis 24:2, 1998.

8.
Beutler E, Gelbart T, Kuhl W, Zimran A, West C: Mutations in Jewish patients with Gaucher disease. Blood 79:1662, 1992.

9.
Beutler E, Nguyen NJ, Henneberger MW, et al: Gaucher disease: Gene frequencies in the Ashkenazi Jewish population. Am J Hum Genet 52:85, 1993.

10.
Beutler E, Gelbart T: Gaucher disease mutations in non-Jewish patients. Br J Haematol 85:401, 1993.

11.
Svennerholm L, Erikson A, Groth CG, Ringdén O, Månsson J-E: Norrbottnian type of Gaucher disease: Clinical, biochemical and molecular biology aspects: Successful treatment with bone marrow transplantation. Dev Neurosci 13:345, 1991.

12.
Smith RL, Hutchins GM, Sack GH Jr, Ridolfi RL: Unusual cardiac, renal and pulmonary involvement in Gaucher’s disease. Interstitial glucocerebroside accumulation, pulmonary hypertension and fatal bone marrow embolization. Am J Med 65:352, 1978.

13.
Schneider EL, Epstein CJ, Kaback MJ, Brandes D: Severe pulmonary involvement in adult Gaucher’s disease. Am J Med 63:475, 1977.

14.
Belmatoug N, Launay O, Carbon C, Comité Évaluat Traitement Malad Gaucher: Pulmonary hypertension in type 1 Gaucher’s disease. Lancet 352:240, 1998.

15.
Elstein D, Klutstein MW, Lahad A, et al: Echocardiographic assessment of pulmonary hypertension in Gaucher’s disease. Lancet 351:1544, 1998.

16.
Harats D, Pauzner R, Elstein D, et al: Pulmonary hypertension in two patients with type I Gaucher disease while on alglucerase therapy. Acta Haematol (Basel) 98:47, 1997.

17.
Dawson A, Elias DJ, Rubenson D, et al: Development of pulmonary hypertension after alglucerase therapy in two patients with hepatopulmonary syndrome complicating type 1 Gaucher disease. Ann Intern Med 125:901, 1996.

18.
Kerem E, Elstein D, Abrahamov A, et al: Pulmonary function abnormalities in type I Gaucher disease. Eur Respir J 9:340, 1996.

19.
Elstein D, Itzchaki M, Mankin HJ: Skeletal involvement in Gaucher’s disease. Baillieres Clin Haematol 10:793, 1997.

20.
Lachiewicz PF: Gaucher’s disease. Orthop Clin North Am 15:765, 1984.

21.
Petrohelos M, Tricoulis D, Kotsiras I, Vouzoukos A: Ocular manifestations of Gaucher’s disease. Am J Ophthalmol 80:1006, 1975.

22.
Henderson JM, Gilinsky NH, Lee EY, Greenwood MF: Gaucher’s disease complicated by bleeding esophageal varices and colonic infiltration by Gaucher cells. Am J Gastroenterol 86:346, 1991.

23.
Schwartz MR, Weycer JS, McGavran MH: Gaucher’s disease involving the maxillary sinuses. Arch Otolaryngol Head Neck Surg 114:203, 1988.

24.
Amstutz HC, Carey EJ: Skeletal manifestations and treatment of Gaucher’s disease. J Bone Joint Surg Am] 48:670, 1966.

25.
Draznin SZ, Singer K: Legg-Perthes’ disease: A syndrome of many etiologies? With clinical and roentgenographic findings in a case of Gaucher’s disease. Am J Roentgenol 60:490, 1948.

26.
Billings AA, Post M, Shapiro CM: Febrile reaction of Gaucher’s disease. Ill Med J 145:222, 1973.

27.
Barton DJ, Ludman MD, Benkov K, Grabowski GA, LeLeiko NS: Resting energy expenditure in Gaucher’s disease type 1: Effect of Gaucher’s cell burden on energy requirements. Metabolism 38:1238, 1989.

28.
Fujimoto A, Tayebi N, Sidransky E: Congenital ichthyosis preceding neurologic symptoms in two sibs with type 2 Gaucher disease. Am J Med Genet 59:356, 1995.

29.
Patterson MC, Horowitz M, Abel RB, et al: Isolated horizontal supranuclear gaze palsy as a marker of severe systemic involvement in Gaucher’s disease. Neurology 43:1993, 1993.

30.
Uyama E, Takahashi K, Owada M, et al: Hydrocephalus, corneal opaci-ties, deafness, valvular heart disease, deformed toes and leptomeningeal fibrous thickening in adult siblings: A new syndrome associated with beta-glucocerebrosidase deficiency and a mosaic population of storage cells. Acta Neurol Scand 86:407, 1992.

31.
Abrahamov A, Elstein D, Gross-Tsur V, et al: Gaucher’s disease variant characterised by progressive calcification of heart valves and unique genotype. Lancet 346:1000, 1995.

32.
Chabas A, Cormand B, Grinberg D, et al: Unusual expression of Gaucher’s disease: Cardiovascular calcifications in three sibs homozygous for the D409H mutation. J Med Genet 32:740, 1995.

33.
Beutler E, Kattamis C, Sipe J, Lipson M: The 1342C mutation in Gaucher’s disease. Lancet 346:1637, 1995.

34.
Mistry PK: Genotype/phenotype correlations in Gaucher’s disease. Lancet 346:982, 1995.

35.
Lee RE: The Pathology of Gaucher Disease, in Gaucher Disease: A Century of Delineation and Research, p 177. Alan R. Liss, New York, 1982.

36.
Chang-Lo M, Yam LT, Rubenstone AI, Schwartz SO: Gaucher’s disease associated with chronic lymphocytic leukaemia, gout and carcinoma. J Pathol 116:203, 1975.

37.
Mark T, Dominguez C, Rywlin AM: Gaucher’s disease associated with chronic lymphocytic leukemia. South Med J 75:361, 1982.

38.
Kaufman S, Rozenfeld V, Yona R, Varon M: Gaucher’s disease associated with chronic lymphocytic leukaemia. Clin Lab Haematol 8:321, 1986.

39.
Garfinkel D, Sidi Y, Ben-Bassat M, et al: Coexistence of Gaucher’s disease and multiple myeloma. Arch Intern Med 142:2229, 1982.

40.
Lamon J, Miller W, Tavassoli M, Longmire R, Beutler E: Specialty conference: Multiple myeloma complicating Gaucher’s disease. West J Med 136:122, 1982.

41.
Ruestow PC, Levinson DJ, Catchatourian R, et al: Coexistence of IgA myeloma and Gaucher’s disease. Arch Intern Med 140:1115, 1980.

42.
Benjamin D, Joshua H, Djaldetti M, Hazaz B, Pinkhas J: Nonsecretory IgD-kappa multiple myeloma in a patient with Gaucher’s disease. Scand J Haematol 22:179, 1979.

43.
Gal R, Gukovsky-Oren S, Floru S, Djaldetti M, Kessler E: Sequential appearance of breast carcinoma, multiple myeloma and Gaucher’s disease. Haematologica (Pavia) 73:63, 1988.

44.
Paulson JA, Marti GE, Fink JK, et al: Richter’s transformation of lymphoma complicating Gaucher’s disease. Hematol Pathol 3:91, 1989.

45.
Bruckstein AH, Karanas A, Dire JJ: Gaucher’s disease associated with Hodgkin’s disease. Am J Med 68:610, 1980.

46.
Cho SY, Sastre M: Coexistence of Hodgkin’s disease and Gaucher’s disease. Am J Clin Pathol 65:103, 1976.

47.
Shoenfeld Y, Berliner S, Pinkhas J, Beutler E: The association of Gaucher’s disease and dysproteinemias. Acta Haematol (Basel) 64:241, 1980.

48.
Pratt PW, Estren F, Kochwa S: Immunoglobulin abnormalities in Gaucher’s disease: Report of 16 cases. Blood 31:633, 1968.

49.
Turesson I, Rausing A: Gaucher’s disease and benign monoclonal gammopathy: A case report with immunofluorescence study of bone marrow and spleen. Acta Med Scand 197:507, 1975.

50.
Liel Y, Hausmann MJ, Mozes M: Case report: Serendipitous Gaucher’s disease presenting as elevated erythrocyte sedimentation rate due to monoclonal gammopathy. Am J Med Sci 301:393, 1991.

51.
Shiran A, Brenner B, Laor A, Tatarsky I: Increased risk of cancer in patients with Gaucher disease. Cancer 72:219, 1993.

52.
Aker M, Zimran A, Abrahamov A, Horowitz M, Matzner Y: Abnormal neutrophil chemotaxis in Gaucher disease. Br J Haematol 83:187, 1993.

53.
Zimran A, Abrahamov A, Aker M, Matzner Y: Correction of neutrophil chemotaxis defect in patients with Gaucher disease by low-dose enzyme replacement therapy. Am J Hematol 43:69, 1993.

54.
Beutler E, Kuhl W: The diagnosis of the adult type of Gaucher’s disease and its carrier state by demonstration of deficiency of beta-glucosidase activity in peripheral blood leukocytes. J Lab Clin Med 76:747, 1970.

55.
Beutler E: Gaucher disease: New developments, in Fairbanks VF (ed): Current Hematology and Oncology, p 1–25. Year Book Medical Publishers, Chicago, 1988.

56.
Brady RO, King FM: Gaucher’s disease, in Lysosomes and Storage Diseases, p 381. Academic Press, New York, 1973.

57.
Naito M, Takahashi K, Hojo H: An ultrastructural and experimental study on the development of tubular structures in the lysosomes of Gaucher cells. Lab Invest 58:590, 1988.

58.
Öckerman PA, Köhlin P: Acid hydrolases in plasma in Gaucher’s disease. Clin Chem 15:61, 1969.

59.
Aerts JM, Hollak CE: Plasma and metabolic abnormalities in Gaucher’s disease. Baillieres Clin Haematol 10:691, 1997.

60.
Young E, Chatterton C, Vellodi A, Winchester B: Plasma chitotriosidase activity in Gaucher disease patients who have been treated either by bone marrow transplantation or by enzyme replacement therapy with alglucerase. J Inherit Metab Dis 20:595, 1997.

61.
Lieberman J, Beutler E: Elevation of serum angiotensin-converting enzyme in Gaucher’s disease. N Engl J Med 294:1442, 1976.

62.
Beutler E, Demina A, Laubscher K, et al: The clinical course of treated and untreated Gaucher disease. A study of 45 patients. Blood Cell Mol Dis 21:86, 1995.

63.
Boklan BF, Sawitsky A: Factor IX deficiency in Gaucher disease. An in vitro phenomenon. Arch Intern Med 136:489, 1976.

64.
Berrebi A, Malnick SDH, Vorst EJ, Stein D: High incidence of factor XI deficiency in Gaucher’s disease. Am J Hematol 40:153, 1992.

65.
Beutler E, Kuhl W, Trinidad F, Teplitz R, Nadler H: Beta-glucosidase activity in fibroblasts from homozygotes and heterozygotes for Gaucher’s disease. Am J Hum Genet 23:62, 1971.

66.
Beutler E, Saven A: Misuse of marrow examination in the diagnosis of Gaucher disease. Blood 76:646, 1990.

67.
Beutler E: Modern diagnosis and treatment of Gaucher’s disease. Am J Dis Child 147:1175, 1993.

68.
Rosner F, Dosik H, Kaiser SS, Lee SL, Morrison AN: Gaucher cell in leukemia. JAMA 209:935, 1969.

69.
Hopfner C, Potron G, Adnet JJ, Caulet AT, Boy J: Histiocytes bleus et “cellules de Gaucher” avec surcharges splenique et ganglionnaire au cours d’une leucemie myeloide chronique. Nouv Rev Fr Hematol 14:607, 1974.

70.
Zidar BL, Hartsock RJ, Lee RE, et al: Pseudo-Gaucher cells in the bone marrow of a patient with Hodgkin’s disease. Am J Clin Pathol 87:533, 1987.

71.
Scullin DC Jr, Shelburne JD, Cohen HJ: Pseudo-Gaucher cells in multiple myeloma. Am J Med 67:347, 1979.

72.
Solis OG, Belmonte AH, Ramaswamy G, Tchertkoff V: Pseudo-Gaucher cells in Mycobacterium avium intracellulare infections in acquired immune deficiency syndrome (AIDS). Am J Clin Pathol 85:233, 1986.

73.
Kattlove HE, Williams JC, Gaynor E, et al: Gaucher cells in chronic myelocytic leukemia: An acquired abnormality. Blood 33:379, 1969.

74.
Beutler E, Kuhl W, Matsumoto F, Pangalis G: Acid hydrolases in leukocytes and platelets of normal subjects and in patients with Gaucher’s and Fabry’s disease. J Exp Med 143:975, 1976.

75.
Raghavan SS, Topol J, Kolodny EH: Leukocyte beta-glucosidase in homozygotes and heterozygotes for Gaucher disease. Am J Hum Genet 32:158, 1980.

76.
Silverstein MN, Kelly PJ: Osteoarticular manifestations of Gaucher’s disease. Am J Med Sci 253:569, 1967.

77.
Ashkenazi A, Zaizov R, Matoth Y: Effect of splenectomy on destructive bone changes in children with chronic (type I) Gaucher disease. Eur J Pediatr 145:138, 1986.

78.
Shiloni E, Bitran D, Rachmilewitz E, Durst AL: The role of splenectomy in Gaucher’s disease. Arch Surg 118:929, 1983.

79.
Beutler E: Newer aspects of some interesting lipid storage diseases: Tay-Sachs and Gaucher’s diseases. West J Med 126:46, 1977.

80.
Stellin GP, Lilly JR, Githens JH: On partial splenectomy in Gaucher’s disease. Pediatrics 77:618, 1986.

81.
Rubin M, Yampolski I, Lambrozo R, Zaizov R, Dintsman M: Partial splenectomy in Gaucher’s disease. J Pediatr Surg 21:125, 1986.

82.
Rodgers BM, Tribble C, Joob A: Partial splenectomy for Gaucher’s disease. Ann Surg 205:693, 1987.

83.
Guzzetta PC, Connors RH, Fink J, Barranger JA: Operative technique and results of subtotal splenectomy for Gaucher disease. Surg Gynecol Obstet 164:359, 1987.

84.
Morgenstern L, Phillips EH, Fermelia D, Weinstein IM: Near-total splenectomy for massive splenomegaly due to Gaucher disease: A new surgical approach. Mt Sinai J Med 53:501, 1986.

85.
Kyllerman M, Conradi N, Månsson J-E, Percy AK, Svennerholm L: Rapidly progressive type III Gaucher disease: Deterioration following partial splenectomy. Acta Paediatr Scand 79:448, 1990.

86.
Guzzetta PC, Ruley EJ, Merrick HFW, Verderese C, Barton N: Elective subtotal splenectomy: Indications and results in 33 patients. Ann Surg 211:34, 1990.

87.
Thomas WEG, Winfield DA: Partial splenectomy for massive splenomegaly secondary to Gaucher’s disease. Postgrad Med J 67:1072, 1991.

88.
Zer M, Freud E: Subtotal splenectomy in Gaucher’s disease: Towards a definition of critical splenic mass. Br J Surg 79:742, 1992.

89.
Cohen IJ, Katz K, Freud E, Zer M, Zaizov R: Long-term follow-up of partial splenectomy in Gaucher’s disease. Am J Surg 164:345, 1992.

90.
Zimran A, Elstein D, Schiffmann R, et al: Outcome of partial splenectomy for type I Gaucher disease. J Pediatr 126:596, 1995.

91.
Amstutz HC: The hip in Gaucher’s disease. Clin Orthop 90:83, 1973.

92.
Davies FWT: Gaucher’s disease in bone. J Bone Joint Surg [Br] 34B:454, 1952.

93.
Schein AJ, Arkin AM: The classic: Hip-joint involvement in Gaucher’s disease. Clin Orthop 90:4, 1973.

94.
Moore M Jr, Coley BL: Bone lesions in Gaucher’s disease. J Tenn Med Assoc 40:101, 1947.

95.
Carlson DE, Busuttil RW, Giudici TA, Barranger JA: Orthotopic liver transplantation in the treatment of complications of type I Gaucher disease. Transplantation 49:1192, 1990.

96.
DuCerf C, Bancel B, Caillon P, et al: Orthotopic liver transplantation for type 1 Gaucher’s disease. Transplantation 53:1141, 1992.

97.
Smanik EJ, Tavill AS, Jacobs GH, et al: Orthotopic liver transplantation in two adults with Niemann- Pick and Gaucher’s diseases: Implications for the treatment of inherited metabolic disease. Hepatology 17:42, 1993.

98.
Starzl TE, Demetris AJ, Trucco M, et al: Chimerism after liver transplantation for type IV glycogen storage disease and type 1 Gaucher’s disease. N Engl J Med 328:745, 1993.

99.
Brady RO, Pentchev PG, Gal AE, Hibbert SR, Dekaban AS: Replacement therapy for inherited enzyme deficiency: Use of purified glucocerebrosidase in Gaucher’s disease. N Engl J Med 291:989, 1974.

100.
Beutler E, Dale GL: Enzyme replacement therapy, in Atkinson D, Fox CF (eds): Covalent and Non-covalent Modulation of Protein Function, p 449. Academic Press, Inc., New York, 1979.

101.
Beutler E, Dale GL, Guinto E, Kuhl W: Enzyme replacement therapy in Gaucher’s disease: Preliminary clinical trial of a new enzyme preparation. Proc Natl Acad Sci USA 74:4620, 1977.

102.
Belchetz PE, Crawley JCW, Braidman IP, Gregoriadis G: Treatment of Gaucher’s disease with liposome-entrapped glucocerebroside: Beta-glucosidase. Lancet 2:116, 1977.

103.
Sato Y, Kuhl W, Beutler E: Binding, internalization and degradation of mannose-terminated glucocerebrosidase by macrophages. Blood 80 (suppl 1):100a, 1992.

104.
Barton NW, Brady RO, Dambrosia JM, et al: Replacement therapy for inherited enzyme deficiency: Macrophage-targeted glucocerebrosidase for Gaucher’s disease. N Engl J Med 324:1464, 1991.

105.
Beutler E, Kay A, Saven A, et al: Enzyme replacement therapy for Gaucher disease. Blood 78:1183, 1991.

106.
Zimran A, Elstein D, Kannai R, et al: Low-dose enzyme replacement therapy for Gaucher’s disease: Effects of age, sex, genotype, and clinical features on response to treatment. Am J Med 97:3, 1994.

107.
Elstein D, Hadas-Halpern I, Itzchaki M, et al: Effect of low-dose enzyme replacement therapy on bones in Gaucher disease patients with severe skeletal involvement. Blood Cell Mol Dis 22:104, 1996.

108.
Beutler E: Enzyme replacement therapy for Gaucher disease. Baillieres Clin Haematol 10:711, 1997.

109.
Elstein D, Abrahamov A, Hadas-Halpern I, Meyer A, Zimran A: Low-dose low-frequency imiglucerase as a starting regimen of enzyme replacement therapy for patients with type I Gaucher disease. Q J Med 91:483, 1998.

110.
Petrides PE: Mobus Gaucher: Aktueller Stand der Therapie. Arzneimitteltherapie 2:49, 1998.

111.
McCabe ERB, Fine BA, Golbus MS, et al: Gaucher disease—Current issues in diagnosis and treatment. JAMA 275:548, 1996.

112.
Krasnewich D, Dietrich K, Bauer L, et al: Splenectomy in Gaucher Disease: New management dilemmas. Blood 91:3085, 1998.

113.
Beutler E: Effect of low-dose enzyme replacement therapy on bones in Gaucher disease patients with severe skeletal involvement–[commentary]. Blood Cells Mol Dis 22:113, 1996.

114.
Rosenthal DI, Doppelt SH, Mankin HJ, et al: Enzyme replacement therapy for Gaucher disease: Skeletal responses to macrophage-targeted glucocerebrosidase. Pediatrics 96 (part 1):629, 1995.

115.
Cohen IJ, Katz K, Kornreich L, et al: Low-dose high-frequency enzyme replacement therapy prevents fractures without complete suppression of painful bone crises in patients with severe juvenile onset type I Gaucher disease. Blood Cells Mol Dis 24:296, 1998.

116.
Barton NW, Brady RO, Murray GJ, et al: Enzyme-replacement therapy for Gaucher’s disease: Reply. N Engl J Med 325:1811, 1991.

117.
Figueroa ML, Rosenbloom BE, Kay AC, et al: A less costly regimen of alglucerase to treat Gaucher’s disease. N Engl J Med 327:1632, 1992.

118.
Hollak CEM, Aerts JMFG, Goudsmit R, et al: Individualised low-dose alglucerase therapy for type 1 Gaucher’s disease. Lancet 345:1474, 1995.

119.
Beutler E: Treatment regimens in Gaucher’s disease. Lancet 346:581, 1995.

120.
Barton NW, Brady RO, Dambrosia JM: Treatment of Gaucher’s disease. N Engl J Med 328:1564, 1993.

121.
Moscicki RA, Taunton-Rigby A: Treatment of Gaucher’s disease. N Engl J Med 328:1564, 1993.

122.
Zimran A, Hadas-Halpern I, Zevin S, Levy-Lahd E, Abrahamov A: Low dose high frequency enzyme replacement therapy for very young children with Gaucher disease. Br J Haematol 85:783, 1993.

123.
Hollak CEM, Aerts JMFG, van Oers MHJ: Treatment of Gaucher’s disease. N Engl J Med 328:1565, 1993.

124.
Zimran A, Hollak CEM, Abrahamov A, et al: Home treatment with intravenous enzyme replacement therapy for Gaucher disease: An international collaborative study of 33 patients. Blood 82:1107, 1993.

125.
Rappeport JM, Ginns EI: Bone-marrow transplantation in severe Gaucher disease. N Engl J Med 311:84, 1984.

126.
Groth CG, Ringden O: Transplantation in relation to the treatment of inherited disease. Transplantation 38:319, 1984.

127.
Hobbs JR, Shaw PJ, Jones KH, Lindsay I, Hancock M: Beneficial effect of pre-transplant splenectomy on displacement bone marrow transplantation for Gaucher’s syndrome. Lancet 1:1111, 1987.

128.
Tsai P, Lipton JM, Sahdev I, et al: Allogenic bone marrow transplantation in severe Gaucher disease. Pediatr Res 31:503, 1992.

129.
Gluckman E, Esperou H, Devergie A, et al: Pediatric bone marrow transplantation for leukemia and aplastic anemia: Report of 222 cases transplanted in a single center. Nouv Rev Fr Hematol 31:111, 1989.

130.
Ringén O, Groth CG, Erikson A, et al: Ten years’ experience of bone marrow transplantation for Gaucher disease. Transplantation 59:864, 1995.

131.
Chan KW, Wong LTK, Applegarth D, Davidson AGF: Bone marrow transplantation in Gaucher’s disease: Effect of mixed chimeric state. Bone Marrow Transplant 14:327, 1994.

132.
Takiyama N, Mohney T, Swaney W, et al: Comparison of methods for retroviral mediated transfer of glucocerebrosidase gene to CD34+ hematopoietic progenitor cells. Eur J Haematol 61:1, 1998.

133.
Schuening F, Longo WL, Atkinson ME, Zaboikin M: Retrovirus-mediated transfer of the cDNA for human glucocerebrosidase into peripheral blood repopulating cells of patients with Gaucher’s disease. Hum Gene Ther 8:2143, 1997.

134.
Dunbar C, Kohn D, Karlsson S, et al: Retroviral mediated transfer of the cDNA for human glucocerebrosidase into hematopoietic stem cells of patients with Gaucher disease: A phase I study. Hum Gene Ther 7:231, 1996.

135.
Nolta JA, Sender LS, Barranger JA, Kohn DB: Expression of human glucocerebrosidase in murine long-term bone marrow cultures after retroviral vector-mediated transfer. Blood 75:787, 1990.

136.
Sorge J, Kuhl W, West C, Beutler E: Gaucher disease: Retrovirus-mediated correction of the enzymatic defect in cultured cells. Cold Spring Harbor Symp Quant Biol 60:1041, 1986.

137.
Beutler E, Southgate MT: Clinical pathological conference: Hepatosplenomegaly, abdominal pain, anemia, and bone lesions. JAMA 224:502, 1973.

138.
Groth CG, Dreborg S, Öckerman PA, et al: Splenic transplantation in a case of Gaucher’s disease. Lancet 1:1260, 1971.

139.
Lev M, Sundaram KS: Gaucher’s disease. N Engl J Med 317:572, 1987.

140.
Platt FM, Neises GR, Reinkensmeier G, et al: Prevention of lysosomal storage in Tay-Sachs mice treated with N-butyldeoxynojirimycin. Science 276:428, 1997.

141.
Radin NS: Treatment of Gaucher disease with an enzyme inhibitor. Glycoconjugate J 13:153, 1996.

142.
Balicki D, Beutler E: Gaucher disease. Medicine (Baltimore) 74:305, 1995.

143.
Sidransky E, Tsuji S, Martin BM, Stubblefield B, Ginns EI: DNA mutation analysis of Gaucher patients. Am J Med Genet 42:331, 1992.

144.
Masuno M, Tomatsu S, Sukegawa K, Orii T: Non-existence of a tight association between a 444leucine to proline mutation and phenotypes of Gaucher disease: High frequency of a NciI polymorphism in the non-neuronopathic form. Hum Genet 84:203, 1990.

145.
Zimran A, Kay AC, Gelbart T, et al: Gaucher disease: Clinical, laboratory, radiologic and genetic features of 53 patients. Medicine (Baltimore) 71:337, 1992.

146.
Ginsburg SJ, Groll M: Hydrops fetalis due to infantile Gaucher’s disease. J Pediatr 82:1046, 1973.

147.
Tybulewicz VLJ, Tremblay ML, LaMarca ME, et al: Animal model of Gaucher’s disease from targeted disruption of the mouse glucocerebrosidase gene. Nature 357:407, 1992.

148.
Niemann A: Ein unbekanntes Krankheitsbild. Jahr Kinderheilkd 79:1, 1914.

149.
Brady RO, Kanfer JN, Mock MB, Fredrickson DS: The metabolism of sphingomyelin II. Evidence of an enzymatic deficiency in Niemann-Pick disease. Proc Natl Acad Sci USA 55:366, 1966.

150.
Schuchman EH, Desnick RJ: Niemann-Pick disease types A and B: Acid sphingomyelinase deficiencies, in Scriver, et al. The Metabolic and Molecular Bases of Inherited Disease, 7th ed, p 2601. McGraw-Hill, New York, 1995.

151.
Pentchev PG, Vanier MT, Suzuki K, Patterson MC: Niemann-Pick disease type C: A cellular cholesterol lipidosis, in Scriver et al, The Metabolic and Molecular Bases of Inherited Disease, 7th ed, p 2625. McGraw-Hill, New York, 1995.

152.
Takahashi T, Suchi M, Desnick RJ, Takada G, Schuchman EH: Identification and expression of five mutations in the human acid sphingomyelinase gene causing types A and B Niemann-Pick disease. Molecular evidence for genetic heterogeneity in the neuronopathic and non-neuronopathic forms. J Biol Chem 267:12552, 1992.

153.
Ida H, Rennert OM, Maekawa K, Eto Y: Identification of three novel mutations in the acid sphinogomyelinase gene of Japanese patients with Niemann-Pick disease type A and B. Hum Mutat 7:65, 1996.

154.
De Maria R, Rippo MR, Schuchman EH, Testi R: Acidic sphingomyelinase (ASM) is necessary for fas-induced GD3 ganglioside accumulation and efficient apoptosis of lymphoid cells. J Exp Med 187:897, 1998.

155.
Carstea ED, Morris JA, Coleman KG, et al: Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277:228, 1997.

156.
Liscum L, Klansek JJ: Niemann-Pick disease type C. Curr Opin Lipidol 9:131, 1998.

157.
Loftus SK, Morris JA, Carstea ED, et al: Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene. Science 277:232, 1997.

158.
Golde DW, Schneider EL, Bainton EL, et al: Pathogenesis of one variant of sea-blue histiocytosis. Lab Invest 33:371, 1975.

159.
Lazarus SS, Vethamany VG, Schneck L, Volk B: Fine structure and histochemistry of peripheral blood cells in Niemann-Pick disease. Lab Invest 17:155, 1967.

160.
Brady RO: Sphingomyelin lipidoses: Niemann-Pick disease, in Stanbury, et al (eds): The Metabolic Bases of Inherited Disease, 5th ed, p 831. McGraw-Hill, New York, 1983.

161.
Veyssier-Belot C, Cacoub P, Caparros-Lefebvre D, et al: Erdheim-Chester disease: Clinical and radiologic characteristics of 59 cases. Medicine (Baltimore) 75:157, 1996.

162.
Landas S, Foucar K, Sando GN, Ellefson R, Hamilton HE: Adult Niemann-Pick disease masquerading as sea blue histiocyte syndrome: Report of a case confirmed by lipid analysis and enzyme assays. Am J Hematol 20:391, 1985.

163.
Briere J, Calman F, Lageron A, et al: Maladie de Niemann-Pick de l’adulte suivie de la naissance a l’age de 26 ans: Forme viscerale pure avec surcharge en sphingomyeline et deficit en sphingomyelinase. Nouv Rev Fr Hematol 16:185, 1976.

164.
Dewhurst N, Besley GTN, Finlayson NDC, Parker AC: Sea blue histiocytosis in a patient with chronic non-neuropathic Niemann-Pick disease. J Clin Pathol 32:1121, 1979.

165.
Brady RO, King FM: Niemann Pick disease, in Hers HG, Van Hoof F (eds): Lysosomes and Storage Diseases, p 439. Academic Press, New York, 1973.

166.
Epstein CJ, Brady RO, Schneider EL, Bradley RM, Shapiro D: In utero diagnosis of Niemann-Pick disease. Am J Hum Genet 23:533, 1971.

167.
Gal AE, Brady RO, Hibberg SR, Pentchev PG: A practical chromogenic procedure for the detection of homozygotes and heterozygous carriers of Niemann-Pick disease. N Engl J Med 293:632, 1975.

168.
Levade T, Salvayre R, Douste-Blazy L: Sphingomyelinases and Niemann-Pick disease. J Clin Chem Clin Biochem 24:205, 1986.

169.
Roff CF, Goldin E, Comly ME, et al: Niemann-Pick type-C disease: Deficient intracellular transport of exogenously derived cholesterol. Am J Med Genet 42:593, 1992.

170.
Bembi B, Comelli M, Scaggiante B, et al: Treatment of sphingomyelinase deficiency by repeated implantations of amniotic epithelial cells. Am J Med Genet 44:527, 1992.

171.
Sawitsky A, Rosner F, Chodsky S: The sea-blue histiocyte syndrome, a review: genetic and biochemical studies. Semin Hematol 9:285, 1972.

172.
Sawitsky A, Hyman GA, Hyman JB: An unidentified reticuloendothelial cell in bone marrow and spleen: Report of two cases with histochemical studies. Blood 9:977, 1954.

173.
Baumgartner C, Bucher U: Blaue Pigmentmakrophagen (sea blue histiocytes) and Gaucher-aehnliche Zellen. Vorkommen und Bedeutung. Blut 30:309, 1975.

174.
Bigorgne C, Le Tourneau A, Vahedi K, et al: Sea-blue histiocyte syndrome in bone marrow secondary to total parenteral nutrition. Leuk Lymphoma 28:523, 1998.

175.
Kelsey PR, Geary CG: Sea-blue histiocytes and Gaucher cells in bone marrow of patients with chronic myeloid leukaemia. J Clin Pathol 41:960, 1988.

176.
Zelingher J, Shouval D: Liver failure and the sea-blue histiocyte/adult Niemann-Pick disease: Case report and review of the literature. J Clin Gastroenterol 2:146, 1992.
Books@Ovid
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

Advertisements

6 comments on “CHAPTER 79 LIPID STORAGE DISEASES

  1. […] CHAPTER 79 LIPID STORAGE DISEASES | Free Medical Textbook However, regardless of the method used, there is an overlap between the measured enzyme activity in heterozygous individuals and the normal range. Definitive diagnosis of the heterozygous state can only be established by . […]

  2. Execelent info my friend, afiliados elite I just didn’t know what you published, excellent share. afiliados elite

  3. ttbegkhlw wddhv gimfyxm xpne kbyxmgiedocduzn

  4. I did however expertise a few technical issues using this website, since I experienced to reload the website a lot of times previous to I could get it to load properly. I had been wondering if your web host is OK? Not that I’m complaining, but slow loading instances times will often affect your placement in google and can damage your high-quality score if advertising and marketing with Adwords. Anyway I am adding this RSS to my e-mail and can look out for much more of your respective fascinating content. Make sure you update this again very soon..

  5. I have bookmarked you contactos con mujeres , this is excelent information my friends, nicely done contactos con mujeres

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

%d bloggers like this: