Gaucher Disease

[Glucocerebrosidase Deficiency, Glucosylceramidase Deficiency. Includes: Gaucher Disease Type 1; Gaucher Disease Type 2 (Acute); Gaucher Disease Type 3 (Subacute/Chronic); Gaucher Disease, Perinatal-Lethal Form; Gaucher Disease, Cardiovascular Form]

Clinical Diagnosis

Gaucher 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. Clinical findings alone are not diagnostic.

Testing

Assay 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 known to be associated with 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 for the four common mutations as well as seven rarer mutations is available on a clinical basis.

  • 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 and Table 2 summarize molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Gaucher Disease

Test Method	Mutations Detected	Mutation Detection Frequency by Test Method	Test Availability
Targeted mutation analysis	Four common GBA mutations  1	89%  2	Clinical
	11 GBA mutations  3	~98%
Sequence analysis	GBA mutations	~99%

1. N370S, L444P, 84GG, IVS2+1
2. See Table 2.
3. The four mutations in footnote 1 as well as the 'rare' mutations V394L, D409H, D409V, R463C, R463H, R496H, 55-bp deletion (exon 9)

Table 2. Proportion of Individuals with GBA Mutations Using the Panel of Four Common Mutations

Mutations  1	% of Affected Individuals  2,  3
N370S/N370S	29%
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 Program [www.gaucherregistry.com]
4. Recombinant (Rec) alleles 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, Stubblefield et al 2003].

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm the diagnosis in a proband

• Assay 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) Disorders

No 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].

• In another study examining the brains from individuals with GD and Parkinson disease, alpha-synuclein-reactive Lewy bodies were found. Family studies suggest that the incidence of parkinsonism may be higher in obligate heterozygotes for GD [Tayebi, Walker et al 2003; Halperin et al 2006].

Natural History

Genotype-Phenotype Correlations

The 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.

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].

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 GD type 2, L444P accounted for 25 alleles (40%) [Stone, Tayebi, Orvisky et al 2000]. 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 GD type 3 (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 has been observed:

• Homozygosity for recombinant alleles [Stone, Carey et al 2000]

• The mutant alleles S196P, R131L, R120W, and R257Q [Stone, Carey et al 2000]

• 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.

Prevalence

A study from Australia reported a disease frequency of 1:57,000 [Meikle et al 1999]; a similar study from the Netherlands reported 1.16:100,000 [Poorthuis et al 1999].

A founder effect for specific alleles underlies the observed occurrence of GD in specific populations:

• Ashkenazi Jewish, Spanish, and Portuguese (N370S)

• Swedish (L444P)

• Jenin Arab, Greek, and Albanian (D409H)

Non-neuropathic GD (type 1) is prevalent in the Ashkenazi Jewish population, with a disease prevalence of 1:855 and an estimated carrier frequency of 1:18.

The prevalence of neuropathic GD (types 2 and 3) varies across ethnic groups but appears to be higher among non-Caucasians.

Evaluations Following Initial Diagnosis

See 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 Manifestations

Management 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), has been approved in Canada, countries of the European Union, Israel, Switzerland, and the US. In at least three studies, involving over 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, Hollak et al 2004; Pastores, Barnett 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 Manifestations

Bone 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.

• Imiglucerase (Cerezyme ^®) is a recombinant glucosylceramidase enzyme preparation based on the human gene sequence and modified to expose the alpha-mannosyl (carbohydrate) residues for enhanced uptake by the macrophage. Regular intravenous infusions of imiglucerase have been demonstrated to be safe and effective in reversing those features resulting from hematologic and visceral (liver/spleen) involvement [Weinreb et al 2002]. It is likely that end-stage histologic changes (e.g., fibrosis, infarction) influence the response to ERT.

  ERT is well tolerated. Approximately 10%-15% of individuals develop antibodies to the infused enzyme, although 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 & Schiffman 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 2004, Grabowski et al 2004]. The optimal dose and frequency of imiglucerase 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, lungs). In the majority of individuals, treatment is initiated with a dose of 20-60 units of imiglucerase 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.

Prevention of Secondary Complications

The use of anticoagulants in individuals with severe thrombocytopenia and/or coagulopathy should be discussed with a hematologist to avoid the possibility of excessive bleeding.

Surveillance

The 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 2004, 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 Caucasians 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, Poll et al 2002]. 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, Hollak et al 2002].

Agents/Circumstances to Avoid

Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in individuals with moderate to severe thrombocytopenia.

Testing of Relatives at Risk

It 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 Investigation

Enzyme replacement therapy (ERT).  Alternative recombinant enzyme formulations, generated from either human cells through gene activation or transduced plant (carrot) cells, are currently in clinical trials [Shaaltiel et al 2007, Zimran et al 2007]. These other enzyme preparations also have mannosyl residues as the means for intracellular uptake, achieved by a process that differs from that used in the manufacture of imiglucerase.

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].

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 the GBA gene 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.

Other

The 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.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Gaucher disease (GD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• In most instances, the parents of a proband are heterozygotes and thus carry a single copy of a disease-causing mutation in the GBA gene.

• Heterozygotes are asymptomatic.

• Because the carrier frequency for GD in certain populations is high (e.g., 1:18 in individuals of Ashkenazi Jewish heritage) and the N370S/N370S phenotype is variable, it is possible that a parent may be found to be homozygous rather than heterozygous.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.

• Heterozygotes are asymptomatic.

Offspring of a proband

• The offspring of a proband are obligate heterozygotes.

• A high carrier rate for GD exists in certain populations, increasing the risk that an affected individual may have a reproductive partner who is heterozygous. In the Ashkenazi Jewish population, for example, one in 18 individuals is a carrier for GD; the offspring of such an individual and a proband are at 50% risk of being affected and 50% risk of being obligate heterozygotes.

Other family members.   Each sib of an obligate heterozygote is at a 50% risk of being a carrier.

Carrier Detection

Measurement of glucosylceramidase enzyme activity in peripheral blood leukocytes is unreliable for carrier determination because of significant overlap in residual enzyme activity levels between obligate carriers and the general (non-carrier) population.

Molecular genetic testing can be used to identify carriers among at-risk family members once the disease-causing mutations have been identified in the family.

Testing for the four common GBA alleles (N370S, L444P, 84GG, IVS2+1) has been included in panels specifically designed for carrier screening in the Ashkenazi Jewishf population [Zuckerman et al 2007].

Because the frequency for GD in certain populations is high (e.g., individuals of Ashkenazi Jewish heritage) and the N370S/N370S phenotype is variable, individuals who undergo carrier testing may be identified as being homozygous.

Pre-conception testing of the partner of a known carrier or affected individual may be requested, especially in ethnic groups of high prevalence. In this instance targeted mutation analysis is insufficient and full sequence analysis should be undertaken.

Related Genetic Counseling Issues

See Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Family planning.  The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being carriers.

DNA banking.   DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal testing is available for pregnancies at increased risk. Prenatal testing relies on analysis of glucosylceramidase enzymatic activity of fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15-18 weeks' gestation. If the disease-causing GBA mutations have been identified in both parents or in a previously affected sibling, prenatal testing results can be confirmed by mutation analysis of GBA performed on fetal DNA obtained by CVS or amniocentesis.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Except in cases in which a previously affected sibling had neurologic disease (i.e., types 2 or 3), it is not possible to be certain of the phenotypic severity in a pregnancy at risk. Individuals with GD with acute neurologic disease (i.e., type 2) tend to have a similar disease course. However, it should be noted that individuals with GD and chronic neurologic involvement (i.e., type 3) could show variable rates of disease progression, even when they are members of the same family.

Requests for prenatal testing for treatable conditions such as GD type 1 are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate [Beutler 2007, Zuckerman et al 2007].

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Molecular Genetic Pathogenesis

Gaucher 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: The GBA gene is 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, Stubblefield et al 2003; Montfort et al 2004]. The extent to which these variants may influence the phenotype or clinical disease expression remains to be established.

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].

Literature Cited

Published Statements and Policies Regarding Genetic Testing

Suggested Readings

Revision History

• 13 March 2008 (me) Comprehensive update posted to live Web site

• 23 November 2005 (gp) Revision: information on miglustat (Management)

• 2 June 2005 (me) Comprehensive update posted to live Web site

• 18 February 2004 (gp) Revision: Management

• 8 April 2003 (me) Comprehensive update posted to live Web site

• 27 July 2000 (me) Review posted to live Web site

• 23 March 2000 (gp) Original submission