CHAPTER 79 LIPID STORAGE DISEASES
CHAPTER 79 LIPID STORAGE DISEASES
Definitions and History
Etiology and Pathogenesis
Course and Prognosis
History and Classification
Etiology and Pathogenesis
Pathology and Clinical Manifestations
Laboratory Features and Differential Diagnosis
Course and Prognosis
Sea-Blue Histiocyte Syndrome
Etiology and Pathogenesis
Therapy, Course, and Prognosis
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 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.
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.
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
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, 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
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.
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.
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 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.
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.
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.
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
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.
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
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
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
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn