Gaucher disease: review of the literature.
Abstract: We present a brief review of Gaucher disease, the most common lysosomal storage disease. Gaucher disease is a rare autosomal recessive disorder characterized by defective function of the catabolic enzyme [beta]-glucocerebrosidase, leading to an accumulation of its substrate, glucocerebroside, in the mononuclear phagocyte system, especially histiocytes in the spleen, lymph nodes, and bone marrow; Kupffer cells in the liver; osteoclasts in bone; microglia in the central nervous system; alveolar macrophages in the lungs; and histiocytes in the gastrointestinal tracts, genitourinary tracts, and the peritoneum. Clinical signs and symptoms include neurologic dysfunctions, bone infarcts and malformations, hepatosplenomegaly and hypersplenism leading to anemia, neutropenia, and thrombocytopenia. Enzyme replacement therapy with recombinant glucocerebrosidase is the mainstay of treatment for Gaucher disease, which became the first successfully managed lipid storage disease. Future treatments may include oral enzyme replacement and/or gene therapy interventions.
Article Type: Disease/Disorder overview
Subject: Gaucher's disease (Diagnosis)
Gaucher's disease (Care and treatment)
Clinical pathology (Research)
Enzymes (Health aspects)
Enzymes (Methods)
Authors: Chen, Mingyi
Wang, Jun
Pub Date: 05/01/2008
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2008 College of American Pathologists ISSN: 1543-2165
Issue: Date: May, 2008 Source Volume: 132 Source Issue: 5
Topic: Event Code: 310 Science & research
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 230247010
Full Text: Gaucher disease (GD) was first described by Philippe Gaucher in his doctoral thesis in 1882, (1) when he hypothesized that infiltration of enlarged cells in a spleen represented a "neoplasm." The biochemical basis for the disease was elucidated 83 years later (1965) by Roscoe Brady's group at the National Institutes of Health. (2) The molecular basis of the disease was elucidated in the late 1980s, when the glucocerebrosidase gene mutations were identified. (3,4) Gaucher disease is inherited in an autosomal recessive fashion. It is most common in the Ashkenazi Jewish population. (4) In a population survey involving 2000 Ashkenazi Jews, the gene frequency was 0.034. Approximately 6.8% of the Jewish population is heterozygous for GD and, based on this, the expected birth frequency is 1 in 1000. (4) The disease is also relatively common among the Norrbottnian population in northern Sweden. The phenotype is usually classified into 3 major types based on clinical signs/symptoms (Table).3 The diagnosis is usually based on identification of Gaucher cells in a bone marrow aspirate. However, enzymatic assay to evaluate [beta]-glucocerebrosidase activity in leukocytes combined with molecular analysis is now considered to be the gold standard for diagnosis.

Genetic studies have shown that the glucocerebrosidase gene (GBA) is located on chromosome 1q21, and more than 200 mutations of this gene have been reported as being associated with GD. (3,4) In the Ashkenazi Jewish population, the predominant point mutation is N370S. This mutation accounts for ~75% of the mutant alleles in Jewish patients and ~30% in non-Jewish patients. It predisposes to type 1 disease and precludes neurologic involvement. (3-5) A frame shift mutation of 84GG is relatively common in the Jewish population. (3,6) The L444P mutation is common in the Norrbottnian population, and the homozygous state has a very high association with the neuronopathic variants of GD. (3,4) Recent genetic analysis suggested that the N370S and 84GG mutations each originated in a single founder/progenitor in the Ashkenazi Jewish population. (3,4) Thus, the founder effect followed by genetic drift rather than an evolutionary advantage for heterozygotes best explains the high frequency of these mutations in Ashkenazi Jews. (3,6) It has been suggested that despite considerable uncertainty about the demographic history of Ashkenazi Jews and their ancestors, the available genetic data are consistent with a founder effect resulting from a severe bottleneck in population size between 1100 AD and 1400 AD and an earlier bottleneck in 75 AD, at the beginning of the Jewish Diaspora. (4) A founder effect could account for the relatively high frequency of alleles causing the lysosomal storage disorders, including Tay-Sachs disease and GD, if the disease-associated alleles are recessive in their effects on reproductive fitness.


The phenotype has been divided into 3 major types based on the clinical signs/symptoms (Table). Type 1, the most common type of GD, often presents with abdominal pain and/or enlargement due to hepatosplenomegaly (Figure 1, A) as well as a combination of anemia, leukocytopenia, and thrombocytopenia as the most common clinical manifestations. Extensive skeletal disease, such as Erlenmeyer flask deformity of the distal femur, is the typical radiologic finding of GD. Pathologic fracture (Figure 1, B) after falling or minor injury may be an initial presentation in some patients. Neurologic symptoms (in types 2 and 3), such as convulsions, dementia, ocular muscle apraxia, mental retardation, and myoclonus, can be seen, as are osteoporosis, hypertonia, apnea, and yellowish brown skin pigmentation. The demonstrable cardiac, renal, or pulmonary symptoms are usually absent. (1-3,5)





The peripheral blood usually shows a moderate to marked anisopoikilocytosis, mild microcytosis, hypochromia, and moderate thrombocytopenia. Bone marrow aspirate and biopsy reveal cellular marrow admixed with individual as well as clusters and aggregates of large Gaucher cells (Figure 2). The Gaucher cells have abundant granular or fibrillary blue-gray cytoplasm with a wrinkled tissue paper-like appearance with abundant lightly periodic acid-Schiff-positive fibrillary material in the cytoplasm (Figure 3). A CD68 immunohistochemical stain usually highlights the Gaucher cells, as does an iron stain.


Immunophenotyping by flow cytometry may show slightly increased numbers of hematogones and otherwise is unremarkable. Conventional cytogenetic studies usually reveal a normal male or female karyotype. However, an enzyme panel will demonstrate decreased or absent activity of the characteristic lysosomal [beta]-glucosidase (glucocerebrosidase) in leukocytes, whereas enzyme activity for other lysosomal enzymes is usually within normal range.

The targeted mutational analysis can be used to aid diagnosis in the Ashkenazi Jew population, where 4 specific sites (N370S, L444P, 84GG, and IVS2+1) account for approximately 90% of the disease-causing alleles. (4,6-8) Sequence analysis of the GBA coding region can be used to detect mutations in affected individuals in the general population. DNA testing, therefore, currently provides the most reliable means of identifying carriers, and carrier testing is recommended for all close relatives of a confirmed GD patient. Bone marrow biopsy is still an easy and rapid method to identify Gaucher cells for the diagnosis of GD. Heterozygous cannot be identified by this test. False negatives can occur when Gaucher cells are sparsely distributed. Thus, enzymatic assay to evaluate [beta]-glucocerebrosidase activity in leukocytes combined with molecular analysis is now considered to be the gold standard for diagnosis of GD.


The main differential diagnosis of GD includes other lipid accumulation abnormalities, such as Pseudo-Gaucher disease, Niemann-Pick disease, Tay-Sachs disease, and Pompe disease. (5,7-9) Gaucher-like cells can be found in hematologic abnormalities, such as chronic myelogenous leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, multiple myeloma, and idiopathic thrombocytopenia. Although those cells cannot be distinguished from true Gaucher cells on hematoxylin-eosin-stained sections, iron staining is generally negative in these cells but will be positive in true Gaucher cells. Niemann-Pick disease is caused by a deficiency in sphingomyelinase, which leads to accumulation of sphingomyelin in the cytoplasm of macrophages. The globules are small and relatively uniform in size, sometimes described as mulberry-like in appearance. The cytoplasm in these macrophages is foamy and vacuolated as opposed to fibrillary in Gaucher cells. In Tay-Sachs disease (hemoaminidase A deficiency), there is accumulation of GM2 ganglioside in the heart, liver, and spleen. Involvement of the central nervous system with vacuolated neurons is predominant. Patients present at 6 months of age, and the disease is fatal by age 2 to 3 years. Pompe disease (acid maltase deficiency) is characterized by glycogen accumulation in hepatocytes and muscle cells, but the primary pathologic derangement is in skeletal and cardiac muscle, not bone marrow. Sea blue histiocytes may be found in small numbers in disorders associated with massively increased intramedullary cell destruction, such as chronic myelogenous leukemia. The macrophage cytoplasm is filled with insoluble lipid pigment, called ceroid. Compared with Gaucher cells, these cells are stained more intensely blue with Wright-Giemsa, and the inclusions are globular rather than fibrillary.


The infantile form (type 2) of GD may lead to early death. Most affected children die before the age of 5 years. (3,6) In adult form (type 1) of GD, the clinical features are extremely variable in each patient, and even within a family various members can exhibit very different clinical problems and course. Some individuals are very mildly affected and can only be identified by screening or during evaluation for chronic diseases (eg, anemia). For others, GD can be a progressive condition. Close medical follow-up with periodic assessment is appropriate for those with GD throughout their lifetime. With the availability of recombinant enzyme, most patients with the adult-chronic form can look forward to normal or near-normal life expectancy.

Macrophage-targeted glucocerebrosidase was approved as a specific treatment for GD by the federal Food and Drug Administration on April 5, 1991. Enzyme replacement therapy with a recombinant glucocerebrosidase known as imiglucerase (Cerezyme) given intravenously is the mainstay of treatment for GD, which became the first successfully managed lipid storage disease. (10) Hepatosplenomegaly, anemia, and thrombocytopenia usually improve within 6 months. Unfortunately, it is not effective on neurologic symptoms, because it does not cross the blood-brain barrier. More recently, an oral therapy was developed (Genzyme), and a phase 2 clinical trial is being performed for the treatment of GD. Future treatments may include gene therapy and intervention with chemical chaperones.

We gratefully acknowledge Donald Chase, MD, for critical review of the manuscript.


(1.) Gaucher PCE. De l'epithelioma primitif de la rate, hypertrophie idiopathique de la rate sans leucemie [academic thesis]. Paris, France; 1 882.

(2.) Brady RO, Kanfer JN, Shapiro D. Metabolism of glucocerebrosides, II: evidence of an enzymatic deficiency in Gaucher's disease. Biochem. Biophys. Res. Commun. 1 965;1 8:221-225.

(3.) Jmoudiak M, Futerman AH. Gaucher disease: pathological mechanisms and modern management. Br J Haemtol. 2005;129:178-188.

(4.) Beutler E, Nguyen NJ, Henneberger MW, et al. Gaucher disease: gene frequencies in the Ashkenazi Jewish population. Am J Hum Genet. 1993;52:85-88.

(5.) Lysosomal storage diseases. In: Hoffbrand AV, PettitJE, eds. Color Atlas of Clinical Hematology. 3rd ed. St Louis, Mo: Mosby; 2000:303-307.

(6.) Elstein D, Abrahamov A, Hadas-Halpern I, Zimran A. Gaucher's disease. Lancet. 2001;358:324-327.

(7.) Zimran A, Altarescu G, Rudensky B, Abrahamov A, Elstein D. Survey of hematological aspects of Gaucher disease. Hematology. 2005;10:151-156.

(8.) Shiran A, Brenner B, Laor A, Tatarsky I. Increased risk of cancer in patients with Gaucher disease. Cancer. 1993;72:219-224.

(9.) Aerts JMFG, Hollak CEM, van Breeman M, Maas M, Groener JEM, Boot RG. Identification and use of biomarkers in Gaucher disease and other lysosomal storage diseases. Acta Paediatrica. 2005;94:43-46.

(10.) Brady RO. Enzyme replacement for lysosomal diseases. Ann Rev Med. 2006;57:283-296.

Mingyi Chen, MD, PhD; Jun Wang, MD

Accepted for publication November 9, 2007.

From the Department of Pathology and Laboratory Medicine, Loma Linda University Medical Center, Loma Linda, Calif.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Mingyi Chen, MD, PhD, Department of Pathology and Laboratory Medicine, Loma Linda University Medical Center, Loma Linda, CA 92350 (e-mail:
Clinical Classification of Gaucher Disease

                                                Type 2: Acute
                     Type 1: Nonneuronopathic   Neuronopathic
                     (Adult)                    (Infantile)

Whom it strikes      Young adults/adults;       Infants rarely, with
                     most common in Ashkenazi   no ethnicity
                     Jewish population
                     (1 in 450)

                     1 in 100 000 general       1 in 100 000 live
                     population                 births

Distinguishing       Liver, spleen, and bone;   Early nervous system
symptom              no nervous                 problems, brainstem
                     system problems            abnormalities

Effects of disease   Varies from mild           Death in infancy
                     to severe                  (age < 2 y)

Glucocerebrosidase   Some activity, but         Very little activity
activity             much less
                     than normal

                     Type 3: Chronic/Subacute
                     Neuronopathic (Juvenile)

Whom it strikes      Children/young adults, with no
                     ethnicity; 1 in 50 000
                     live births

                     Norrbottnian variant: Sweden;
                     until early adulthood

Distinguishing       Later onset of nervous system
symptom              problems: incoordination, mental
                     deterioration, myoclonic seizures

Effects of disease   Slowly progressive; becomes severe
                     later in childhood

Glucocerebrosidase   Little activity
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