This is an inherited disease caused by a deficiency of a lysosomal enzyme, beta-glucocerebrosidase. This deficiency leads to accumulation of glucosylceramide within many of the organs of the body. It is present within macrophages which are stuffed with the substance. Patients present with symptoms localized to the involved organs. Pancytopenia resulting from bone marrow involvement or bone pain resulting from bone involvement is common. Other organs commonly involved include the spleen, liver, kidneys, lungs, and lymph nodes.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
EPIDEMIOLOGY CHARACTERIZATION AGE RANGE-MEDIAN Dependent upon the type
DISEASE ASSOCIATIONS CHARACTERIZATION
Gaucher disease and parkinsonism: a phenotypic and genotypic characterization.
Tayebi N, Callahan M, Madike V, Stubblefield BK, Orvisky E, Krasnewich D, Fillano JJ, Sidransky E.
Clinical Neuroscience Branch, NIMH, 49 Convent Drive MSC405, 49/B1EE16, Bethesda, MD 20892-4405, USA.
Mol Genet Metab 2001 Aug;73(4):313-21 Abstract quote
Among the many phenotypes associated with Gaucher disease, the inherited deficiency of glucocerebrosidase, are reports of patients with parkinsonian symptoms. The basis for this association is unknown, but could be due to alterations in the gene or gene region. The human glucocerebrosidase gene, located on chromosome 1q21, has a nearby pseudogene that shares 96% identity. Immediately adjacent to the glucocerebrosidase pseudogene is a convergently transcribed gene, metaxin, which has a pseudogene that is located just downstream to the glucocerebrosidase gene.
We describe a patient with mild Gaucher disease but impaired horizontal saccadic eye movements who developed a tremor at age 42, followed by rapid deterioration of her gait. A pallidotomy at age 47 was unsuccessful. Her motor and cognitive deterioration progressed despite enzyme replacement therapy. Sequencing of the glucocerebrosidase gene identified mutations L444P and D409H. Southern blot analysis using the enzyme SspI showed that the maternal allele had an additional 17-kb band. PCR amplifications and sequencing of this fragment demonstrated a duplication which included the glucocerebrosidase pseudogene, metaxin gene, and a pseudometaxin/metaxin fusion.
Gene alterations associated with this novel rearrangement, resulting from a crossover between the gene for metaxin and its pseudogene, could contribute to the atypical phenotype encountered in this patient.
PATHOGENESIS CHARACTERIZATION Autosomal recessive sphingolipid storage disorder Deficiency of beta-glucocerebrosidase. Gaucher Cells Demonstrate a Distinct Macrophage Phenotype and Resemble Alternatively Activated Macrophages
Leonie A. Boven, PhD, etal.
Am J Clin Pathol 2004;122:359-369 Abstract quote
Although the existence of anti-inflammatory alternatively activated macrophages (aamf) has been accepted widely based on in vitro studies, their in vivo location, phenotype, and function still are debated. Gaucher disease (GD) is caused by a genetic deficiency in the lysosomal enzyme glucocerebrosidase and is characterized by accumulation of glycosphingolipids in so-called Gaucher cells (GCs).
By using immunohistochemical analysis, we investigated whether this results in an aamf phenotype. GCs are macrophage-like cells, expressing acid phosphatase, CD68, CD14, and HLA class II, but not CD11b, CD40, or dendritic cell markers. GCs show infrequent immunoreactivity for mannose receptor. GCs did not express proinflammatory cytokines such as tumor necrosis factor a and monocyte chemoattractant protein 1, but did express the aamf markers CD163, CCL18, and interleukin-1 receptor antagonist. Furthermore, CD36 and signal receptor protein a, involved in lipid uptake, also were observed on GCs.
Thus, GCs represent a distinctive population of myeloid cells that resemble aamf but differ from previously described in vitro aamf.
CHARACTERIZATION ENZYME ASSAY Assay for acid beta-glucocerebrosidase in white blood cells or fibroblasts PCR
Microdissection genotyping of archival fixative treated tissue for Gaucher disease.
Mohan D, Rolston R, Pal R, Swalsky PA, Sasatomi E, Lee RE, Finkelstein SD.
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Hum Pathol. 2004 Apr;35(4):482-7. Abstract quote
The genetic diagnosis of Gaucher disease by molecular methods is complicated by the existence of a highly homologous transcribed pseudogene (96% identity) that is found in close proximity to the true gene on chromosome 1q21. In addition, the pseudogene sequence can mimic disease-causing mutations in the true gene. Selective polymerase chain reaction (PCR) amplification of the true gene can be accomplished in extracted DNA from fresh-frozen samples by designing oligonucleotide primers to hybridize to defined regions that are not present in the pseudogene.
This standard molecular approach, which entails amplification of relatively long segments of intact DNA, is not feasible in archival, paraffin-embedded, solid-tissue specimens in which the negative effects of chemical fixation result in DNA strand scission and breakdown of nucleic acid. A novel approach, specifically created for use with archival, fixative-treated tissue specimens, was developed for detection and characterization of common mutations of Gaucher disease. Three separate robust PCR reactions were formulated, 2 for selective amplification of portions of only the true gene exons 2 and 9, with a third reaction targeting exon 10, wherein both the true and pseudogene were coamplified.
In the latter, DNA sequencing was used to determine the presence of true and pseudogene allele content in addition to identification of base sequence alterations. This method, requiring a single, 4-microm-thick histologic section, was successfully applied to archival paraffin block tissue specimens that had been in storage for up to 75 years. It was capable of accurately genotyping common Gaucher disease mutations as well as discovering a novel mutation and genetic polymorphism.
- We recommend our approach when only fixative-treated tissue is available for molecular genotyping.
CHARACTERIZATION Type 1-Nonneuropathic form Most prevalent genetic disorder among Ashkenazi Jews
Usually presents in adolescence
Symptoms are variable and dependent upon the enzyme activity
No neurologic impairment
Type 2-Infantile or acute neuropathic form First 2 years of life
Rapidly progressive neurodegenerative disorders
Type 3-Juvenile form Presents in infancy or early childhood
Splenomegaly, bone marrow involvement, and neurologic symptoms
HISTOLOGICAL TYPES CHARACTERIZATION Gaucher cell Histiocyte often 20-100 um in diameter
May-Grunwald-Giemsa stain reveals abundant blue staining cytoplasm with crinkled tissue paper appearance
CHARACTERIZATION PAS PAS positive material within the cytoplasm
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES Gaucher-like cells found in several other disorders Chronic myeloproliferative disorders
Chronic dyserythropoietic anemias
PROGNOSIS AND TREATMENT CHARACTERIZATION Prognostic Factors See clinical types 5 Year Survival See clinical types Treatment
Symptomatic and palliation
Bone marrow transplantation
Enzyme replacement with modified placental human glucocerebrosidase (alglucerase) May be used to treat type 1 disease
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Last Updated September 9, 2004
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