DiagnosisClinical DiagnosisGaucher disease (referred to as GD in this entry) is suspected in individuals with characteristic bone lesions, hepatosplenomegaly and hematologic changes, or signs of CNS involvement [Mistry et al 2011]. Clinical findings alone are not diagnostic. TestingAssay of acid β-glucosylceramidase enzyme activity Affected individuals. The most efficient and reliable method of establishing the diagnosis of GD is the assay of acid β-glucosylceramidase enzyme activity in peripheral blood leukocytes or other nucleated cells. The test is a fluorometric assay and uses the substrate 4-methylumbelliferyl-β-D-glucopyranoside. In affected individuals, glucosylceramidase enzyme activity in peripheral blood leukocytes is 0%-15% of normal activity.
Note: The results of biochemical testing do not reliably enable prediction of disease severity or subtype.Carriers. Glucosylceramidase enzyme activity is unreliable for carrier detection given the overlap in enzyme activity levels between carriers and non-carriers. Bone marrow examination. Affected individuals may first be suspected of having GD following bone marrow examination for GD-related manifestations (e.g., anemia, thrombocytopenia, and/or splenomegaly) [Beutler 2006]. Bone marrow examination reveals the presence of lipid-engorged macrophages ('Gaucher cells'), characterized by a fibrillary, 'crumpled silk' appearance to the cytoplasm and an eccentrically placed nucleus. This material stains positively with periodic acid-Schiff (PAS) reagent. Note: The changes described are nonspecific, and bone marrow examination is not a reliable diagnostic test. Molecular Genetic Testing Gene. GBA is the only gene in which mutations are known to cause GD. Clinical testing Targeted mutation analysis Four mutations account for approximately 90% of the disease-causing alleles in the Ashkenazi Jewish population (Table 1). In non-Jewish populations, the same four alleles account for approximately 50%-60% of disease-causing alleles. Non-Jewish individuals with GD tend to be compound heterozygotes with one common and one 'rare' mutation (Table 1) or a unique mutation. Targeted mutation analysis identifies the four common mutations as well as other rarer mutations. Note: The 55-bp deletion (exon 9) overlaps with the N370S mutation. Thus, individuals who are compound heterozygotes with N370S and the 55-bp deletion may appear to be homozygous for the N370S mutation. In practice, these individuals are recognized when parents are tested simultaneously and the N370S allele is confirmed in only one parent (except for cases of alternate paternity), and/or by specifically testing for the 55-bp deletion in all individuals homozygous for N370S. Sequence analysis. Sequence analysis of the GBA coding region may be used to detect mutations in affected individuals in whom mutation analysis has identified only a single mutation. Table 1. Summary of Molecular Genetic Testing Used in Gaucher DiseaseView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityGBATargeted mutation analysisFour common mutations 2 89% 3 Clinical Other mutations 4 ~98%Sequence analysis Sequence variants 5~99%1. The ability of the test method used to detect a mutation that is present in the indicated gene2. N370S, L444P, 84GG, IVS2+1. Historical names for mutations are given in the text. See Table 5 for mutation names according to the current standards of nomenclature.3. See Table 2.4. Mutation panel may vary by laboratory.5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.Table 2. Proportion of Individuals with GBA Mutations Using the Panel of Four Common MutationsView in own windowMutations 1 % of Affected Individuals 2, 3 N370S/N370S29%N370S/? 20%N370S/L444P 16%N370S/84GG 12%L444P/L444P 4 6%L444P/? 3%N370S/IVS2+1 3%1. Table 5 provides the mutation name and nucleotide changes according to current nomenclature guidelines.2. Based on data from 1097 individuals in the Gaucher Registry [International Collaborative Gaucher Group (October 1999)]. In this population, 94% of individuals had type 1, 1% had type 2, and 5% type 3. 3. GD mutation detection rates based on sequence analysis available through the ICGG Registry Program4. Recombinant (Rec) alleles (i.e., the RecNciI allele; see Molecular Genetics) contain two to four point mutations (including L444P) that arise as a result of gene rearrangements between exons 9 and 10 of the functional gene and pseudogene. Thus, testing for the L444P mutation alone does not allow distinction of the isolated L444P allele from Rec alleles, and may lead to an error in genotype designation [Tayebi et al 2003a].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a probandAssay of glucosylceramidase enzyme activity in leukocytes or other nucleated cells is the confirmatory diagnostic test. Molecular genetic testing and the identification of two disease-causing alleles provides additional confirmation of the diagnosis but should not be used in place of biochemical testing. As the diagnosis of GD can be confirmed through biochemical testing performed on peripheral blood leukocytes, it is not necessary to perform a bone marrow examination. Molecular genetic testing of a proband originally diagnosed by biochemical testing may be considered for genetic counseling purposes, primarily to identify the disease-causing mutations to permit carrier detection among at-risk relatives. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes have been associated with GBA mutations. Parkinsonian features have been reported in a few individuals with type 1 GD; although studies suggest a possible cause-and-effect relationship rather than mere coincidence, the underlying basis remains to be established [Tayebi et al 2001, Bembi et al 2003]. The following findings suggest that GBA mutations and/or alterations in glucosylceramide metabolism may be a risk factor for parkinsonism [Sidransky 2005]; however, only a few cases have been identified and other factors may predispose to parkinsonian features in these individuals with type 1 GD. Brain pathology in a few individuals with type 1 GD (with and without parkinsonism and dementia) revealed astrogliosis as well as changes in the hippocampal regions. Brain pathology in individuals with type 2 and type 3 GD additionally revealed neuronal loss [Wong et al 2004]. Immunofluorescence studies on brain tissue samples from persons with parkinsonism associated with GBA mutations showed that glucosylceramidase was present in 32%-90% of Lewy bodies, some ubiquitinated and others non-ubiquitinated [Goker-Alpan et al 2010].Family studies suggest that the incidence of parkinsonism may be higher in obligate heterozygotes for GD [Tayebi et al 2003b, Halperin et al 2006]. GBA mutations have been identified in cohorts with Parkinson disease from centers around the world [Sidransky et al 2009].}

Natural HistoryGaucher disease (GD) encompasses a spectrum of clinical findings from a perinatal-lethal form to an asymptomatic form. However, for the purposes of determining prognosis and management, the classification of GD by clinical subtype is still useful in describing the wide range of clinical findings and broad variability in presentation. Three major clinical types are delineated by the absence (type 1) or presence (types 2 and 3) of primary central nervous system involvement (Table 3).Table 3. Gaucher Disease: Clinical SubtypesView in own windowSubtype Primary CNS Involvement Bone Disease Other Type 1 No Yes Splenomegaly
Hepatomegaly
Cytopenia
Pulmonary disease Type 2
(acute or infantile) Bulbar signs
Pyramidal signs
Cognitive impairment No Hepatomegaly
Splenomegaly
Cytopenia
Pulmonary disease
Dermatologic changes Type 3
(subacute; juvenile) Oculomotor apraxia
Seizures
Progressive myoclonic epilepsy Yes Hepatomegaly
Splenomegaly
Cytopenia
Pulmonary disease Perinatal-lethal formPyramidal signs No Ichthyosiform or collodion skin changes
Nonimmune hydrops fetalis Cardiovascular form Oculomotor apraxia Yes Calcification of mitral and aortic valves
Corneal opacity
Mild splenomegaly Type 1 GD Bone disease. Clinical or radiographic evidence of bone disease occurs in 70%-100% of individuals with type 1 GD. Bone disease ranges from asymptomatic osteopenia to focal lytic or sclerotic lesions and osteonecrosis [Wenstrup et al 2002]. Bone involvement, which may lead to acute or chronic bone pain, pathologic fractures, and subchondral joint collapse with secondary degenerative arthritis, is often the most debilitating aspect of type 1 GD [Pastores et al 2000]. Acute bone pain manifests as 'bone crises' or episodes of deep bone pain that are usually confined to one extremity or joint [Cohen 2003] and are often accompanied by fever and leukocytosis but sterile blood culture. The affected region may be swollen and warm to touch; imaging studies may reveal signal abnormalities consistent with localized edema or hemorrhage; x-rays may show periosteal elevation ('pseudo-osteomyelitis') [Pastores & Meere 2005].Conventional radiographs (x-rays) may reveal undertubulation (Erhlenmeyer flask configuration) noted in the distal femur and endosteal scalloping as a sign of bone marrow infiltration. MRI reveals the extent of marrow involvement and the presence of fibrosis and/or infarction. In general, marrow infiltration extends from the axial to the appendicular skeleton, and greater involvement is often seen in the lower extremities and proximal sites of an affected bone. The epiphyses are usually spared, except in advanced cases. Bone densitometry studies enable quantitative assessment of the degree of osteopenia. Bone disease in GD may not correlate with the severity of hematologic or visceral problems. Secondary neurologic disease in type 1 GD. Although individuals with type 1 GD do not have primary CNS disease, neurologic complications (spinal cord or nerve root compression) may occur secondary to bone disease (e.g., severe osteopenia with vertebral compression; emboli following long bone fracture), or coagulopathy (e.g., hematomyelia) [Pastores et al 2003]. The incidence of peripheral neuropathy may be higher than previously recognized [Capablo et al 2008, Halperin et al 2007].Hepatosplenomegaly. The spleen is enlarged (i.e., 1500-3000 cc in size, compared to 50-200 cc in the average adult) with resultant hypersplenism associated with pancytopenia (i.e., anemia, leukopenia, and thrombocytopenia). Infarction of the spleen can result in acute abdominal pain. Rarely, acute surgical emergencies may arise because of splenic rupture [Stone et al 2000b]. Liver enlargement is common, although cirrhosis and hepatic failure are rare. Cytopenias. Cytopenia is almost universal in untreated GD. Anemia, thrombocytopenia, and leukopenia may be present simultaneously or independently [Zimran et al 2005]. The pattern of cytopenia in GD is dependent on spleen status. Low platelet count may result from hypersplenism, splenic pooling of platelets, or marrow infiltration or infarction. Immune thrombocytopenia has also been reported and should be excluded in individuals with persistent thrombocytopenia despite GD-specific therapy. Thrombocytopenia may be associated with easy bruising or overt bleeding, particularly with trauma, surgery, or pregnancy. The risk for bleeding may be increased in the presence of clotting abnormalities. Anemia may result from hypersplenism, hemodilution (e.g., pregnancy), iron deficiency or B₁₂ deficiency and, in advanced disease, decreased erythropoiesis as a result of bone marrow failure from Gaucher cell infiltration or medullary infarction.Leukopenia is rarely severe enough to require intervention. Deficient neutrophil function has been reported.Coagulation abnormalities. Acquired coagulation factor deficiencies include low-grade disseminated intravascular coagulation and specific inherited coagulation factor deficiencies (e.g., factor XI deficiency among Ashkenazi Jews). An investigation of Egyptian individuals with type 1 GD revealed a wide variety of coagulation factor abnormalities (fibrinogen, factor II, VII, VIII, X, XII) [Deghady et al 2006]. Abnormal platelet aggregation may contribute to bleeding diathesis in the presence of normal platelet counts. Pulmonary involvement. The following can be observed: Interstitial lung disease Alveolar/lobar consolidation Pulmonary hypertension; well documented in individuals with liver disease and presumably the result of inability to detoxify gut-derived factors, which somehow adversely affect the pulmonary endothelium with resultant pulmonary hypertension. Pulmonary hypertension can also occur in individuals with GD without liver disease [Mistry et al 2002]. Dyspnea and cyanosis with digital clubbing attributed to hepatopulmonary syndrome have been described in individuals with liver dysfunction, often caused by an intercurrent disease (e.g., viral hepatitis).Those individuals with type 1 GD without evident lung involvement who limit physical exertion because of easy fatigability may have impaired circulation [Miller et al 2003].Pregnancy and childbirth. Except in women with significant pulmonary hypertension, pregnancy is not contraindicated in GD. Pregnancy may affect the course of GD both by exacerbating preexisting symptoms and by triggering new features such as bone pain. Women with severe thrombocytopenia and/or clotting abnormalities may have an increased risk of bleeding around the time of delivery [Elstein et al 2004b]. In some women the diagnosis of GD is first made in pregnancy because of exacerbation of hematologic features.Other. Cholelithiasis occurs in a significant proportion of adults with GD (21/66 cases) [Rosenbaum & Sidransky 2002]. Cardiac and renal complications are rare.Malignancy. Epidemiologic studies have suggested elevated risk of certain malignancies in GD including the following: Multiple myeloma [Rosenbloom et al 2005] Hepatocellular carcinoma [de Fost et al 2006] Non-Hodgkins lymphoma, malignant melanoma, and pancreatic cancer [Landgren et al 2007] Other reports have failed to find these associations.Immunologic abnormalities. Children or adults may have polyclonal gammopathy [Wine et al 2007]. An increased incidence of monoclonal gammopathy has been reported in adults [Brautbar et al 2004]. Affected individuals also exhibit altered cellular immune profiles with increased peripheral blood NKT lymphocytes and reduced numbers of functionally normal dendritic cells [Lalazar et al 2006, Micheva et al 2006]. Metabolic abnormalities. GD is associated with metabolic abnormalities including high resting energy expenditures (possibly the result of elevated cytokine levels) and low circulating adiponectin and peripheral insulin. The hypermetabolic state is not associated with altered thyroid hormone resistance [Langeveld et al 2007a, Langeveld et al 2007b, Langeveld et al 2008]. Serum concentrations of angiotensin-converting enzyme, tartrate-resistant acid phosphatase, ferritin, chitotriosidase, and PARC/CCL18 are usually elevated. Serum concentrations of total and HDL cholesterol are often low. Abnormalities in the concentration of certain bone markers have been found in some individuals with GD in serum (e.g., osteocalcin, bone-specific alkaline phosphatase, macrophage inhibitory protein-1 alpha and beta) and urine (e.g., urinary hydroxyproline, free deoxypyridinoline, calcium); however, the utility of these findings in clinical practice is undetermined [Drugan et al 2002, Ciana et al 2003, van Breemen et al 2007]. Psychological complications. Persons with GD exhibit moderate to severe psychological complications including somatic concerns and depressed mood [Packman et al 2006]. Type 2 GD / Type 3 GD (Primary Neurologic Disease)Neurologic disease. Previously, affected individuals were classified into type 2 or type 3 GD based on the age of onset of neurologic signs and symptoms and the rate of disease progression. Children with onset before age two years with a rapidly progressive course, limited psychomotor development, and death by age two to four years were classified as having type 2 GD. Individuals with type 3 GD may have onset before age two years but often have a more slowly progressive course, with life span extending into the third or fourth decade in some cases. However, these distinctions are not absolute and it is increasingly recognized that neuropathic GD represents a phenotypic continuum, ranging from abnormalities of horizontal ocular saccades at the mild end to hydrops fetalis at the severe end [Goker-Alpan et al 2003]. Bulbar signs include stridor, squint, and swallowing difficulty.Pyramidal signs include opisthotonus, head retroflexion, spasticity, and trismus.Oculomotor apraxia, saccadic initiation failure, and opticokinetic nystagmus are common [Harris et al 1999]. Oculomotor involvement may be found as an isolated sign of neurologic disease in individuals with a chronic progressive course and severe systemic involvement (e.g., massive hepatosplenomegaly).Generalized tonic-clonic seizures and progressive myoclonic epilepsy have been observed in some individuals [Verghese et al 2000, Frei & Schiffmann 2002].Dementia and ataxia have been observed in the later stages of chronic neurologic disease. Brain stem auditory evoked response (BAER) testing may reveal abnormal wave forms (III and IV). MRI of the brain may show mild cerebral atrophy. (A normal EEG, BAER, or brain MRI does not exclude neurologic involvement.) Perinatal-lethal form. The perinatal-lethal form is associated with hepatosplenomegaly, pancytopenia, and microscopic skin changes (i.e., abnormalities in the stratum corneum attributed to altered glucosylceramide-to-ceramide ratio) and may present clinically with ichthyosiform or collodion skin abnormalities or as nonimmune hydrops fetalis [Orvisky et al 2002]. Arthrogryposis and distinctive facial features are seen in 35%-43% [Mignot et al 2003].Another rare severe variant of GD is associated with hydrocephalus, corneal opacities, deformed toes, gastroesophageal reflux, and fibrous thickening of splenic and hepatic capsules [Stone et al 2000c, Inui et al 2001]. Cardiovascular form. Individuals homozygous for the D409H allele present with an atypical phenotype dominated by cardiovascular disease with calcification of the mitral and aortic valves [Bohlega et al 2000]. Additional findings include mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia [George et al 2001].

Genotype-Phenotype CorrelationsThe amount of residual glucosylceramidase enzyme activity as measured in vitro from extracts of nucleated cells does not correlate with disease type or severity. Genotype-phenotype correlations in GD are imperfect. Significant overlap in the clinical manifestations found between individuals with the various genotypes precludes specific counseling about prognosis in individual cases. At present the factors that influence disease severity or progression within particular genotypes are not known. Discordance in phenotype has been reported even among monozygotic twins [Lachmann et al 2004, Biegstraaten et al 2011]. The following observations apply: Type 1 GD Individuals with at least one N370S allele do not develop primary neurologic disease [Koprivica et al 2000]. In general, individuals who are homozygous for the N370S mutation tend to have milder disease than those who are compound heterozygous. It is suspected that a significant proportion of Ashkenazi Jewish individuals with this genotype may be asymptomatic and thus do not come to the attention of medical professionals [Azuri et al 1998]. However, surveillance is critical, as a proportion of these individuals do develop progressive disease [Taddei et al 2009]. Primary neurologic disease Individuals who are homozygous for the L444P mutation tend to have severe disease, often with neurologic complications (i.e., types 2 and 3), although several individuals (including adults) with this genotype have had no overt neurologic problems. This mutation results in an unstable enzyme with little or no residual activity. In a study of 31 individuals with type 2 GD, L444P accounted for 25 alleles (40%) [Stone et al 2000c]. The L444P mutation occurred alone (9 alleles), with the E326K polymorphism (1 allele), and as part of a recombinant allele (15 alleles). In another study, homozygosity for the L444P mutation was the most common genotype among individuals with type 3 GD (10/24 individuals, or 42%) [Koprivica et al 2000]. In individuals with GD and myoclonic epilepsy, Park et al [2003] identified 14 genotypes (including the mutations V394L, G377S, and N188S) previously associated with non-neuronopathic GD, and the mutations L444P and recombinant alleles that have been previously associated with neuropathic GD. Among Greek and Albanian individuals, a second mutation (H255Q) occurring in the compound heterozygous state with the D409H mutation has been associated with type 2 GD [Michelakakis et al 2006]. Perinatal-lethal form. Genotypic heterogeneity is significant in this rare subset of individuals. The following have been observed: Homozygosity for recombinant alleles [Stone et al 2000a] The mutant alleles S196P, R131L, R120W, and R257Q [Stone et al 2000a]Compound heterozygosity for an insertion-type mutation and the missense mutation R120Q, previously reported in an individual with type 1 GD [Felderhoff-Mueser et al 2004] Cardiovascular form. The basis for the unique clinical features associated with this clinical form is not fully delineated. 84GG and IVS2+1 Despite the observed allele frequencies for the mutations 84GG and IVS2+1, no live-born homozygous for either mutation has been identified. Thus, it is presumed that these genotypes are lethal. Children who are compound heterozygotes (i.e., 84GG/IVS2+1) have a subacute disease course with progressive pulmonary involvement and death in the first to second decade. Other. Although it is likely that other factors including modifier genes that influence phenotypic expression exist, none has been identified to date. In individuals homozygous for the N370S allele, no correlation with clinical variability was observed with polymorphisms in the gene encoding glucosylceramide (glucocerebroside) synthase (the enzyme involved in the anabolic pathway or substrate synthesis) [Beutler & West 2002]. Non-pathogenic sequence variants have been described, but none is over- or underrepresented in individuals with severe disease as compared to those with mild disease [Beutler et al 2004]. Certain missense mutations lead to misfolding of the enzyme protein within the endoplasmic reticulum (ER) and its degradation. Variability in the rate of retention and degradation of the defective enzyme within the ER has been shown to correlate with disease severity [Ron & Horowitz 2005]. The clinical usefulness of these observations remains to be determined.

Differential DiagnosisSaposin C deficiency or prosaposin deficiency. Saposin C is a cofactor for glucosylceramidase in the hydrolysis of GL1. Saposin C is derived from proteolytic cleavage of prosaposin, which is encoded by a gene on chromosome 10q21-q22. Individuals with saposin C deficiency or prosaposin deficiency may present with symptoms characteristic of severe neuropathic Gaucher disease (GD) (i.e., progressive horizontal ophthalmoplegia, pyramidal and cerebellar signs, myoclonic jerks, and generalized seizures) [Pampols et al 1999, Qi & Grabowski 2001] or non-neuronopathic disease [Tylki-Szymanska et al 2007]. These individuals demonstrate GL1 accumulation and visceromegaly but have normal glucosylceramidase enzyme activity measured in vitro. Lysosomal storage diseases (LSDs). Findings in GD may overlap with some lysosomal storage diseases; however, the distinctive clinical features associated with these lysosomal storage diseases, the availability of biochemical testing in clinical laboratories, and an understanding of their natural history should help distinguish between them. Hepatosplenomegaly is observed in Niemann-Pick disease types A and B (see Acid Sphingomyelinase Deficiency), Niemann-Pick disease type C, Wolman disease, the mucopolysaccharidoses (including mucopolysaccharidosis type I and mucopolysaccharidosis type II), and the oligosaccharidoses. The following features are not found in individuals with GD and should direct further investigations to these alternative diagnoses: Coarse facial features Dysostosis multiplex on skeletal radiographs Vacuolated lymphocytes on peripheral blood smear examination The presence of a cherry-red spot on fundoscopy White matter changes (leukodystrophy) on brain MRI Gaucher cells. The characteristic storage cells of GD should be distinguished from those found in other storage disorders such as Niemann-Pick disease type C. 'Pseudo Gaucher cells' which resemble Gaucher storage cells at the light microscopic but not ultrastructural level occur in a number of hematologic conditions including myeloproliferative and myelodysplastic disorders. Legg-Calve-Perthes disease. Osteonecrosis may be a presenting feature of GD, which should be considered in the differential diagnosis of children with suspected Legg-Calve-Perthes disease [Kenet et al 2003]. Congenital ichthyoses and collodion skin changes are observed in autosomal recessive congenital ichthyosis. Hydrops fetalis may be encountered in other LSDs, including GM1-gangliosidosis, sialidosis type 1, Wolman disease, mucopolysaccharidosis type VII (MPS VII), mucopolysaccharidosis type IV (MPS IV), galactosialidosis, Niemann-Pick disease type C, disseminated lipogranulomatosis (Farber disease), infantile free sialic acid storage disease (ISSD), and mucolipidosis II (I-cell disease) [Stone & Sidransky 1999]. Myoclonic seizures are also observed in GM2-gangliosidosis, sialidosis type 1, alpha-N-acetylgalactosaminidase deficiency, and fucosidosis. In addition to the LSDs, several genetic disorders are known to be associated with progressive myoclonic epilepsy [reviewed in de Siqueira 2010]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Type 1 GDType 2 GDType 3 GDGD, perinatal-lethal formGD, cardiovascular form

ManagementEvaluations Following Initial DiagnosisSee Surveillance for evaluations used to establish disease severity in an individual diagnosed with Gaucher disease (GD). Baseline (pre-treatment) assessments may be useful in selecting treatment modality and regimen (i.e., enzyme dose and frequency of infusion).Factors that may influence the extent of clinical testing at the time of diagnosis: Age Mode of ascertainment (e.g., family screening vs disease signs and symptoms) Presence/absence of primary neurologic involvement Treatment of ManifestationsManagement by a multidisciplinary team with expertise in treating GD is available at Comprehensive Gaucher Centers (see National Gaucher Foundation). Although enzyme replacement therapy (ERT) has changed the natural history of GD and eliminated the need for splenectomy in individuals with hypersplenism, persons not receiving ERT and certain other individuals may require symptomatic treatment, including the following: Miglustat, the first oral agent for the treatment of individuals with mild to moderate Gaucher disease for whom ERT is not a therapeutic option (e.g., because of constraints such as allergy, hypersensitivity, or poor venous access). Miglustat has been approved in Canada, countries of the European Union, Israel, Switzerland, and the US. In at least three studies, involving more than 30 individuals with GD type 1, miglustat treatment resulted in a significant decrease in liver and spleen volume after six to 18 months, with clinical improvement noted over 24 months. Bone involvement and platelet and hemoglobin values remained stable or were modestly improved [Cox et al 2000, Elstein et al 2004a, Pastores et al 2005]. An increase in bone density at the lumbar spine and femoral neck was reported to occur as early as six months after the initiation of miglustat monotherapy [Pastores et al 2007]. The most common adverse reactions noted in the clinical trials were weight loss (60% of individuals), and bloating, flatulence, and diarrhea (80%), which resolved or diminished with longer use of the product. Partial or total splenectomy for individuals with massive splenomegaly with significant areas of infarction and persistent severe thrombocytopenia with high risk of bleeding Transfusion of blood products for severe anemia and bleeding. Anemia and clotting problems unresponsive to ERT should prompt investigations for an intercurrent disease process. Evaluation by a hematologist is recommended prior to any major surgical or dental procedures or parturition [Hughes et al 2007]. Analgesics for bone pain. Persistent bone pain in individuals receiving ERT should prompt evaluations to exclude the possibility of a mechanical problem (e.g., pathologic fracture or joint collapse secondary to osteonecrosis, degenerative arthritis). Joint replacement surgery for relief from chronic pain and restoration of function (i.e., improved joint range of motion). Bone pain in individuals who have undergone joint replacement may indicate a problem with the prosthesis and the need for surgical revision. Supplemental treatment. Oral bisphosphonates and calcium/vitamin D may benefit individuals with GD and low bone density [Wenstrup et al 2004]. Persons with GD with findings suggestive of multiple myeloma and parkinsonism should be referred to the appropriate specialists.Prevention of Primary ManifestationsBone marrow transplantation (BMT) Individuals with severe GD, primarily those with chronic neurologic involvement (type 3 GD), can benefit from BMT. Successful engraftment can correct the metabolic defect, improve blood counts, and reduce increased liver volume. In a few individuals, stabilization of neurologic and bone disease has occurred; however, the morbidity and mortality associated with BMT limit its use in individuals with type 1 and type 3 GD. Individuals with chronic neurologic GD and progressive disease despite ERT may be candidates for BMT or a multi-modal approach (i.e., combined ERT and BMT). Enzyme replacement therapy (ERT). ERT is based on the provision of sufficient exogenous enzyme to overcome the block in the catabolic pathway and effect the clearance of the stored substrate, GL1. The two recombinant glucosylceramidase enzyme preparations currently available commercially are based on the human gene sequence and are distinguished according to the cell type involved in their production: imiglucerase (Cerezyme®) generated in Chinese hamster ovary cells; velalglucerase alfa (VPRIV®) from human cell line. Each formulation is modified to expose the alpha-mannosyl (carbohydrate) residues for enhanced uptake by the macrophage.Regular intravenous infusions of the recombinant enzyme have been demonstrated to be safe and effective in reversing those features resulting from hematologic and visceral (liver/spleen) involvement [Weinreb et al 2002, Zimran et al 2010]. It is likely that end-stage histologic changes (e.g., fibrosis, infarction) influence the response to ERT. Thrombocytopenia may persist in individuals with residual spleneomegaly and\or the presence of splenic nodules [Stein et al 2010].
ERT is well tolerated. Approximately 10%-15% of individuals develop antibodies to infused imiglucerase; whereas antibody formation has been reported in 1% of persons receiving velaglucerase. In most cases these individuals remain asymptomatic [Rosenberg et al 1999, Starzyk et al 2007]. Adverse effects (e.g., pruritus, hives) are relatively well controlled with premedication using antihistamines. Individuals with type 1 GD report improved health-related quality of life after 24-48 months of ERT [Damiano et al 1998, Masek et al 1999, Weinreb et al 2007].
After prolonged treatment, ERT reduces the rate of bone loss in a dose-dependent manner [Wenstrup et al 2007], improves bone pain, and reduces bone crises [Charrow et al 2007].
The effectiveness of ERT for the treatment of neurologic disease remains to be established, although a few reports have suggested some benefit [Poll et al 2002].Individuals with type 2 GD and pyramidal tract signs are not likely to respond to ERT, perhaps because the underlying neuropathology is cell death rather than lysosomal storage of GL1 [Takahashi et al 1998]. These individuals and those with hydrops fetalis are not appropriate candidates for BMT, ERT, or substrate reduction therapy (SRT) [Campbell et al 2003, Migita et al 2003]. Individuals with type 3 GD appear to derive some benefit from ERT, although long-term prognosis remains to be defined for this heterogeneous group [Vellodi et al 2001]. Onset of progressive myoclonic seizures while on ERT appears to indicate a poor prognosis [Frei & Schiffmann 2002]. Brain stem auditory evoked responses have deteriorated in individuals with type 3 GD on ERT [Campbell et al 2003]. SRT used in combination with ERT for type 3 GD with progressive neurologic disease does not appear to alter ultimate prognosis. Consensus recommendations exist for ERT and monitoring of children with type 1 GD [Baldellou et al 2004, Charrow et al 2004b, Grabowski et al 2004] (see Published Guidelines/Consensus Statements). The optimal dose and frequency of recombinant enzyme administration is not certain, mostly because of limited information regarding tissue half-life and distribution and the limitations associated with the modalities used for assessing clinical disease course. Intravenously infused enzyme may not reach adequate concentrations in certain body sites (e.g., brain, bones, and lungs). In the majority of individuals, treatment is initiated with a dose of 15-60 units of enzyme per kg of body weight administered intravenously every two weeks. The enzyme dose may be increased or decreased after initiation of treatment and during the maintenance phase, based on response – i.e., hematopoietic reconstitution, reduction of liver and spleen volumes, and stabilization or improvement in skeletal findings [Pastores et al 2004]. Affected individuals may require assistance with insurance-related issues and reimbursement because of the high cost of ERT. Substrate reduction therapy (SRT). SRT aims to restore metabolic homeostasis by limiting the amount of substrate precursor synthesized (and eventually subject to catabolism) to a level that can be effectively cleared by the mutant enzyme with residual hydrolytic activity [Dwek et al 2002]. A potential concern regarding the use of SRT is its nonspecificity; i.e., the substrate whose production is blocked or limited is a precursor in the formation of other glycosphingolipids (ganglio- and lacto- series). An alternative inhibitor of glucosylceramide synthetase (Genz-112638), currently under clinical evaluation, was shown to be effective in reducing substrate storage in a murine model of GD (D409V/null) [McEachern et al 2007]. Prevention of Secondary ComplicationsThe use of anticoagulants in individuals with severe thrombocytopenia and/or coagulopathy should be discussed with a hematologist to avoid the possibility of excessive bleeding. SurveillanceThe physicians who are the US regional coordinators for the International Collaborative Gaucher Group Registry (ICGG) and other groups have published recommendations for comprehensive serial monitoring of the severity and rate of disease progression [Baldellou et al 2004, Charrow et al 2004b, Grabowski et al 2004, Vom Dahl et al 2006]:Medical history (at least every 6-12 months) including weight loss, fatigue, depression, change in social, domestic, or school- or work-related activities, bleeding from the nose or gums, menorrhagia, shortness of breath, abdominal pain, early satiety as a result of abdominal pressure, joint aches or reduced range of movement, and bone pain Physical examination (at least every 6-12 months) including: heart and lungs, joint range of motion, gait, neurologic status, evidence of bleeding (bruises, petechiae). In children, attention should be given to growth (height, weight, and head circumference using standardized growth charts) and pubertal changes (using the Tanner staging system). Neurologic evaluation is particularly important in the early detection of type 2 and type 3 disease in children. A severity scoring tool has been developed to evaluate neurologic features of neuronopathic GD [Davies et al 2007]. Assessment of hemoglobin concentration and platelet count (with frequency based on symptoms and treatment status). Hemoglobin, platelet count, and coagulation indices should also be assessed prior to surgical or dental procedures. Other blood tests at the physician's discretion may include measurement of the following: Serum concentrations of tartrate-resistant acid phosphatase, liver enzymes (aspartate aminotransferanse or alanine amino transferase), iron, ferritin, and vitamin B₁₂ Plasma activity of chitotriosidase, a macrophage-derived chitin-fragmenting hydrolase, and plasma concentration of PARC/CCL18. Levels are typically elevated, and are felt to correlate with body-wide burden of disease. An enzyme dose-dependent decrease in plasma chitotriosidase activity has been observed in affected individuals on ERT; however, up to 40% of affected individuals of European origin are homozygous or heterozygous for a common null mutation, complicating interpretation of test results [Grace et al 2007]. Assessment of spleen and liver volumes by MRI or volumetric computed tomography (CT). Parenchymal abnormalities can be identified as well. In situations in which access to an MRI or CT is problematic, abdominal ultrasonography (US) may be performed. Abdominal US may provide information on organ volume and parenchymal abnormalities and also call attention to the presence of gallstones [Patlas et al 2002]. MRI or US are the preferred modalities in the pediatric population. Screening for pulmonary hypertension. EKG and echocardiography with Doppler studies to identify elevated pulmonary artery pressure Skeletal assessment Plain radiographs of the femur (anterior-posterior view), spine (lateral view), and any symptomatic sites. Radiographs can reflect the status of both the compact/mineralized compartment and medullary compartment. In children, particularly those with signs of growth and pubertal delay, x-ray of the left hand and wrist to determine bone age is appropriate. Coronal T1- and T2-weighted MR images of the hips to the distal femur. T₁-weighted MRI is the most sensitive method for following bone marrow infiltration. T₂-weighted MRI is the most sensitive method for detecting active bone infarcts, osteonecrosis, and osteomyelitis [Maas et al 2002b]. The developmental transition from cellular (red) to fatty (yellow) bone marrow, which normally occurs from childhood to early adulthood, may confound interpretation of the extent of long bone infiltration by Gaucher cells (lipid-engorged macrophages) in affected children younger than age 15 years [McHugh et al 2004]. Semiquantitative methods (BMB score and S-MRI score) have been developed to facilitate serial assessments [Robertson et al 2007, Roca et al 2007]. Other methods include dual-energy x-ray absorptiometry (DEXA) to identify risk for pathologic fractures, technetium Tc-99 sulfur colloid nuclear scanning to assess location and extent of infiltration [Mariani et al 2003], and quantitative chemical-shift MRI or spectroscopy to quantify decrease in bone marrow fat content as a marker of bone marrow infiltration [Maas et al 2002a]. Assessment of disease severity. Two recent reports have delineated a means for scoring disease severity, incorporating standard assessments of disease severity [Di Rocco et al 2008, Weinreb et al 2010]. With increasing therapeutic options, the ability to benchmark response may inform the modality of choice and selected regimen [Weinreb et al 2008].Agents/Circumstances to AvoidNonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in individuals with moderate to severe thrombocytopenia.Evaluation of Relatives at RiskIt is appropriate to offer testing to asymptomatic at-risk relatives so that those with glucosylceramidase enzyme deficiency or two disease-causing alleles can benefit from early diagnosis and treatment to reduce morbidity.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationEnzyme replacement therapy (ERT). An alternative recombinant enzyme formulation generated from transduced plant (carrot) cells (taliglucerase alfa), is currently in clinical trials [Shaaltiel et al 2007, Zimran et al 2007]. This enzyme preparation also has exposed mannose residues involved in intracellular uptake. Substrate reduction therapy (SRT). Eliglustat, an alternative inhibitor of glucosylceramide synthetase currently under clinical evaluation, has shown in a phase I/II study to be effective in reversing the hematologic, visceral, and skeletal manifestations of GD [Lukina et al 2010]. Eliglustat is metabolized by CYP345, which implies potential for drug interactions and thus requires monitoring not currently undertaken with ERT.It is possible that a switch from ERT to SRT, or combination therapy, based on reduced substrate load (using SRT) and the provision of exogenous enzyme may permit enzyme dose/frequency manipulation for cost-effective treatment [Elstein et al 2007]. However, the long-term safety of these agents needs to be carefully evaluated. Chaperone-mediated enzyme enhancement therapy. Pharmacologic chaperones, competitive reversible active site inhibitors, serve as a folding template for the defective enzyme during its transit to the ER. Such agents may restore enzyme activity within the lysosome and clear stored substrate. The drug isofagamine, which has been shown to exhibit these properties in studies of cultured fibroblasts in vitro, is currently in clinical trials to establish its safety and efficacy when given to adults with type 1 GD [Steet et al 2007]. Gene therapy. Gene therapy involves the introduction of GBA into hematopoietic stem cells [Enquist et al 2006]. In limited trials, some enzyme has been produced by transduced cells, but enzyme production does not appear to be sustained and therefore does not result in a permanent cure. It is anticipated that transduced cells would not have a proliferative advantage over uncorrected cells. Furthermore, it is unlikely that significant metabolic cross-correction would occur as only small amounts of enzyme are secreted into the circulation. In a murine model of GD (D409V/null) intravenous administration of a recombinant AAV8 serotype vector bearing human glucosylceramidase resulted in sustained hepatic enzyme secretion, preventing GL-1 accumulation in presymptomatic mice and normalizing GL-1 levels in older mice [McEachern et al 2006]. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherThe elevation of the serum concentration of several serologic markers (e.g., D-dimer, CCL18/PARC, CD163) in persons with GD is considered a possible surrogate indicator of disease burden that could be used in monitoring treatment response [Shitrit et al 2003, Boot et al 2004, Moller et al 2004]. However, the prognostic value of these markers, their role in patient stratification according to clinical disease severity, and/or determination of the optimum time to initiate therapy are unknown.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Gaucher Disease: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGBA1q22GlucosylceramidasePD mutation database
CCHMC - Human Genetics Mutation DatabaseGBAData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Gaucher Disease (View All in OMIM) View in own window 230800GAUCHER DISEASE, TYPE I 230900GAUCHER DISEASE, TYPE II 231000GAUCHER DISEASE, TYPE III 231005GAUCHER DISEASE, TYPE IIIC 606463GLUCOSIDASE, BETA, ACID; GBA 608013GAUCHER DISEASE, PERINATAL LETHALMolecular Genetic PathogenesisGaucher disease (GD) is caused by deficient activity of the lysosomal enzyme glucosylceramidase and the resultant accumulation of its undegraded substrate, glucosylceramide (GL1) and other glycolipids. The major peripheral substrate source is the breakdown of senescent blood cells and tissue debris; the incompletely metabolized GL1 substrate is stored in cells of monocyte/macrophage lineage of the reticuloendothelial system. In the CNS, GL1 is believed to originate from the turnover of membrane gangliosides, although neuronal cell death may be the basis of neuropathic involvement [Aerts et al 2003].Normal allelic variants. GBA comprises 7 kb with 11 exons; the cDNA is approximately 2.5 kb. Two different upstream ATG codons are utilized as translation initiation sites. A highly homologous (96% identity) pseudogene (5 kb) is located 16 kb downstream. Several sequence alterations that are not believed to have a primary role in disease causation have been found [Diaz-Font et al 2003, Tayebi et al 2003a, Montfort et al 2004]. The extent to which these variants may influence the phenotype or clinical disease expression remains to be established. Pathologic allelic variants. The abnormal alleles include missense and nonsense mutations, splice junction mutations, deletions and insertions of one or more nucleotides, and complex alleles resulting from gene conversion or recombination with the downstream pseudogene (see Table A) [Rozenberg et al 2006, Alfonso et al 2007]. At least 200 GBA mutations have been identified. Historically, GBA mutations were numbered based on the position in the nucleotide sequence that encodes the mature glucosylceramidase protein, wherein the first nucleotide of the alanine codon (GCC) was designated as 1. This naming convention continues to be used (see Table A), although it does not comply with current standards of nomenclature (Table 5). The variants N370S, 84GG, IVS2+1G>A, and L444P account for 90% of the mutant alleles in Ashkenazi Jewish individuals with type 1 GD and for 50%-60% of mutant alleles in non-Jewish individuals with type 1 GD. The frequencies of the most common genotypes associated with the N370S allele are listed in Table 4. The frequency of the N370S allele is higher among Iberians (Portuguese: 63%; Spanish: 46%) than among other non-Jewish population groups from Western, Central, and Eastern Europe [Giraldo et al 2000, Alfonso et al 2007]. On the other hand, the N370S and 84GG alleles have not been identified among Japanese and Chinese individuals with GD. The occurrence of deleterious alleles among the Japanese (e.g., L444P: 41% allele frequency; F213I: 14%) and Chinese (L444P: 54%; RecNciI: 25%) may explain the higher incidence of neuropathic disease in these populations [Wan et al 2006]. Thus, screening restricted to the four 'common' mutations (N370S, 84GG, IVS2+1G>A, and L444P) does not lead to 100% detection.Table 4. Frequency of Genotypes Involving at Least One Copy of N370SView in own windowGenotype ¹ % of Ashkenazi Jewish Individuals ² % of Non-Jewish Individuals ³ N370S/N370S41%9%N370S/L444P3%19%N370S/c84-85insG23%0%N370S/IVS2+1G>A6%2%N370S/V394L8%0%N370S/RecNciI ^{40%4%Table does not include all possible genotype permutations and thus frequency figures do not account for 100% of individuals. 1. Table 5 provides the mutation name and nucleotide changes according to current nomenclature guidelines.2. Data derived from Koprivica et al [2000]. In this paper, the R463C mutation was identified in nine (14%) of the non-Jewish individuals with type 1 GD, but in only one Ashkenazi Jewish individual with type 1 GD (L444P/R463C). The 55-bp deletion was found in two non-Jewish individuals with type 1 GD (both N370S/del 55bp) and one non-Jewish individual with type 3 GD in whom the second allele remains to be identified.3. Data derived from Filocamo et al [2002], a study involving 144 unrelated Italian individuals with GD. This study represents the largest single group of non-Jewish individuals examined, with information on genotype rather than individual disease allele frequency.4. Recombinant allele; see Table 5.Table 5. Selected GBA Pathologic Allelic Variants View in own windowCommon Variant Name 1DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences IVS2+1G>Ac.115+1G>A 2 --NM_000157​.3
NP_000148​.284GGc.84dupG 2 p.Leu29Alafs*18R120Qc.476G>Ap.Arg159GlnR120Wc.475C>Tp.Arg159TrpR131Lc.509G>Tp.Arg170LeuN188Sc.680A>Gp.Asn227SerS196Pc.703T>Cp.Ser235ProF213Ic.754T>Ap.Phe252Ile R257Qc.887G>Ap.Arg296GlnG377Sc.1246G>A p.Gly416SerN370Sc.1226A>Gp.Asn409SerL444Pc.1448T>Cp.Leu483Pro55bp del exon 9c.1263del55--V394Lc.1297G>Tp.Val433LeuD409Hc.1342G>Cp.Asp448HisD409Vc.1343A>Tp.Asp448ValR463Cc.1504C>Tp.Arg502CysR463Hc.1505G>Ap.Arg502HisR496Hc.1604G>Ap.Arg535HisRecNciI 3(complex allele involving several changes at a specific location) 3See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. The common variant names are used in this GeneReview. In these instances, amino acid number 1 is the first residue (Ala) of the mature protein. In contrast, the standard naming convention designates amino acid number 1 as the first residue (Met) of the signal sequence.2. Variants in the signal sequence3. Recombinant allele derived from a recombination between functional GBA and pseudogene GBAP1; see also Table 2 [Eyal et al 1990].Normal gene product. Glucosylceramidase is a lysosomal membrane-associated glycoprotein. The mature protein is composed of 497 amino acids, with four oligosaccharide chains coupled to specific asparagine residues [van Weely & Aerts 2000]. The three-dimensional conformation of the enzyme is stabilized by the formation of three disulfide bonds. The enzyme is responsible for hydrolyzing glucosylceramide into glucose and ceramide. Glucosylceramidase enzyme activity is stimulated by interaction with the lipid phospatidylserine and the protein saposin C. Structural predictions (based on hydrophobic cluster analysis) indicate that the glutamine residues 235 and 340 play key roles in the active site of human glucocerebrosidase [Fabrega et al 2002]. The nascent glucosylceramidase polypeptide is composed of 536 amino acids, including 39 that encode a signal sequence that is later cleaved after it directs the polypeptide to transit the endoplasmic reticulum. Two different upstream ATG codons are utilized as translation initiation sites; use of the second ATG translation start leaves a functional signal sequence of 19 amino acid residues. The 497-amino acid sequence of the mature protein is the same regardless of the translation start codon.Abnormal gene product. GBA mutations result in mRNA instability, and/or a severely truncated protein, or an enzyme with altered activity and/or conformation [Grabowski & Horowitz 1997].}