Clinical characteristics.

Gaucher disease (GD) encompasses a continuum of clinical findings from a perinatal lethal disorder to an asymptomatic type. The identification of three major clinical types (1, 2, and 3) and two other subtypes (perinatal-lethal and cardiovascular) is useful in determining prognosis and management.

GD type 1 is characterized by the presence of clinical or radiographic evidence of bone disease (osteopenia, focal lytic or sclerotic lesions, and osteonecrosis), hepatosplenomegaly, anemia and thrombocytopenia, lung disease, and the absence of primary central nervous system disease.

GD types 2 and 3 are characterized by the presence of primary neurologic disease; in the past, they were distinguished by age of onset and rate of disease progression, but these distinctions are not absolute.

• Disease with onset before age two years, limited psychomotor development, and a rapidly progressive course with death by age two to four years is classified as GD type 2.
• Individuals with GD type 3 may have onset before age two years, but often have a more slowly progressive course, with survival into the third or fourth decade.

The perinatal-lethal form is associated with ichthyosiform or collodion skin abnormalities or with nonimmune hydrops fetalis. The cardiovascular form is characterized by calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia. Cardiopulmonary complications have been described with all the clinical subtypes, although varying in frequency and severity.

Diagnosis/testing.

The diagnosis of GD relies on demonstration of deficient glucocerebrosidase (glucosylceramidase) enzyme activity in peripheral blood leukocytes or other nucleated cells or by the identification of biallelic pathogenic variants in GBA.

Note: The amino acid numbering for glucocerebrosidase used in this GeneReview follows the HGVS-recommended nomenclature, which includes the first 39 amino acids, and differs from the traditional numbering system, which does not include the first 39 amino acids. Using the HGVS-recommended nomenclature, the pathogenic variant p.Asn370Ser is named p.Asn409Ser and the pathogenic variant p.Leu444Pro is named p.Leu483Pro.

Management.

Treatment of manifestations: When possible, management by a multidisciplinary team at a Comprehensive Gaucher Center. For persons not receiving enzyme replacement therapy (ERT) or substrate reduction therapy (SRT), symptomatic treatment includes partial or total splenectomy for massive splenomegaly and thrombocytopenia. Supportive care for all affected individuals may include: transfusion of blood products for severe anemia and bleeding; analgesics for bone pain; joint replacement surgery for relief from chronic pain and restoration of function; and anti-bone resorptive agents, calcium, and vitamin D for osteoporosis.

Prevention of primary manifestations – targeted therapies: ERT is usually well tolerated and provides sufficient exogenous enzyme to overcome the block in the catabolic pathway, clearing the stored substrate, GL1, and thus reversing hematologic and liver/spleen involvement. Miglustat may be indicated in symptomatic individuals with GD type 1 who are not able to receive ERT. Eliglustat has been shown to improve or stabilize key disease features in those naïve to or switched from enzyme replacement therapy. Although bone marrow transplantation (BMT) had been undertaken in individuals with severe GD, primarily those with chronic neurologic involvement (GD type 3), this procedure has been largely superseded by ERT or SRT.

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: Recommendations for comprehensive serial monitoring have been published by the International Collaborative Gaucher Group Registry (ICGG) and other groups.

Agents/circumstances to avoid: Nonsteroidal anti-inflammatory drugs in individuals with moderate to severe thrombocytopenia.

Evaluation of relatives at risk: It is appropriate to offer testing to asymptomatic at-risk relatives so that those with glucocerebrosidase enzyme deficiency or biallelic pathogenic variants can benefit from early diagnosis and treatment if indicated.

Pregnancy management: Pregnancy can exacerbate preexisting symptoms and trigger new features in affected women. Those with severe thrombocytopenia and/or clotting abnormalities are at increased risk for bleeding around the time of delivery. Evaluation by a hematologist prior to delivery is recommended. The lack of studies on the safety of eliglustat use during pregnancy and lactation has led to the recommendation that this medication be avoided during pregnancy, if possible.

Genetic counseling.

Gaucher disease (GD) is inherited in an autosomal recessive manner. 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. Targeted analysis for pathogenic variants can be used to detect carriers in high-risk populations (e.g., Ashkenazi Jewish persons). Because the carrier frequency for GD in certain populations is high (e.g., 1:18 in individuals of Ashkenazi Jewish heritage) and the p.[Asn409Ser;Asn409Ser] phenotype is variable, individuals who undergo carrier testing may be identified as being homozygous. Prenatal testing for a pregnancy at increased risk is possible using molecular genetic testing when both pathogenic variants in a family are known – or assay of glucocerebrosidase enzymatic activity if only one or neither pathogenic variant in the family is known.

Suggestive Findings

Gaucher disease (GD) encompasses a continuum of clinical findings from a perinatal lethal disorder to an asymptomatic type. GD should be suspected in individuals (by age) with the following combinations of central nervous system, bony, hematologic, and other clinical findings.

Establishing the Diagnosis

The diagnosis of Gaucher disease (GD) is established in a proband by the finding of 0%-15% of normal glucocerebrosidase enzyme activity in peripheral blood leukocytes (or other nucleated cells) or by the identification of biallelic pathogenic variants in GBA on molecular genetic testing (see Table 2).

Note: (1) Molecular analysis of GBA is complicated by the presence of a highly homologous pseudogene, GBAP. (2) The amino acid numbering for glucocerebrosidase used in this GeneReview follows the HGVS-recommended nomenclature, which includes the first 39 amino acids, and differs from the traditional numbering system, which does not include the first 39 amino acids. Using the HGVS-recommended nomenclature, the pathogenic variant p.Asn370Ser is named p.Asn409Ser and the pathogenic variant p.Leu444Pro is named p.Leu483Pro. For a more complete list of pathogenic variants using traditional and standard nomenclature, see Montfort et al [2004].

Molecular testing approaches can include single-gene testing or use of a multigene panel.

Single-gene testing

• Sequence analysis of GBA is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
• Targeted analysis for pathogenic variants can be performed first, particularly in individuals of Ashkenazi Jewish ancestry.
  • The four most common variants account for approximately 90% of the pathogenic variants in this population:
    • c.84dupG (formerly known as 84GG)
    • c.115+1G>A (formerly known as IVS2+1)
    • p.Asn409Ser (formerly known as p.N370S)
    • p.Leu483Pro (formerly known as p.L444P)
  • In non-Jewish populations, the same four alleles account for approximately 50%-60% of pathogenic variants.
    Note: Non-Jewish individuals with GD tend to be compound heterozygotes with one common and one "rare" pathogenic variant (see Table 3) or a unique pathogenic variant.

A multigene panel that includes GBA and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) Special consideration for the presence of the highly homologous pseudogene, GBAP, must be taken into account. (2) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (3) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis (possibly excluding GBA), and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Gaucher 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 (see Table 1).

Genotype-Phenotype Correlations

The level of residual glucocerebrosidase 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 p.Asn409Ser allele do not develop primary neurologic disease [Koprivica et al 2000]. However, the presence of an p.Asn409Ser allele does not eliminate the risk for Parkinson disease among individuals with GD.
• In general, individuals who are homozygous for the p.Asn409Ser or p.Arg535His variant tend to have milder disease than those with other genotypes. 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 [Bronstein et al 2014]. However, surveillance is critical, as a proportion of these individuals do develop progressive disease [Taddei et al 2009].

Primary neurologic disease (type 2 and type 3 GD)

• Individuals who are homozygous for the p.Leu483Pro variant 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 variant results in an unstable enzyme with little or no residual activity.
  • In a study of 31 individuals with type 2 GD, p.Leu483Pro accounted for 25 alleles (40%) [Stone et al 2000c]. The p.Leu483Pro variant occurred alone (9 alleles), with the p.Glu365Lys polymorphism (1 allele), and as part of a recombinant allele (15 alleles).
  • In another study, homozygosity for the p.Leu483Pro variant was the most common genotype among individuals with type 3 GD (10/24 individuals, or 42%) [Koprivica et al 2000].
  • In a study of affected individuals of Japanese and Korean ancestry with GD including type 1 disease, p.Leu483Pro accounted for 41% and 20.8% of alleles, respectively. The second most common allele among Japanese was p.Phe252Ile (14%); among Koreans, p.Gly85Glu (13.9%). The absence of p.Asn409Ser among those examined accounted for the higher frequency of the neuropathic subtype when compared to that seen in Western countries [Eto & Ida 1999, Jeong et al 2011].
• In individuals with GD and myoclonic epilepsy, Park et al [2003] identified 14 genotypes (including the variants p.Val433Leu [commonly known as V394L], p.Gly416Ser [commonly known as G377S], and p.Asn227Ser [commonly known as N188S]) previously associated with non-neuronopathic GD, in combination with the variant p.Leu483Pro and recombinant alleles that have been previously associated with neuropathic GD.
• A second variant, p.His294Gln (commonly known as H255Q) occurring in cis with the p.Asp448His variant has been identified among Greek and Albanian individuals. Homozygosity for the p.[Asp448His;His255Gln] allele 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 mutated alleles p.Ser235Pro (S196P), p.Arg170Leu (R131L), p.Arg159Trp (R120W), and p.Arg296Gln (R257Q) [Stone et al 2000a]
• Compound heterozygosity for an insertion-type pathogenic variant and the pathogenic missense variant p.Arg159Gln (R120Q), previously reported in an individual with type 1 GD [Felderhoff-Mueser et al 2004]

Cardiovascular form. This phenotype has been described only in individuals who are homozygous for the p.Asp448His (commonly known as D409H) allele. The biochemical basis for the unique clinical features associated with this form is not fully delineated. It should be noted that homozygosity for the p.[Asp448His;p.His294Gln] allele is associated with neuropathic type 2 GD and not the cardiovascular form (see Primary neurologic disease above).

c.84dupG and c.115+1G>A

• Despite the observed allele frequencies for the pathogenic variants c.84dupG and c.115+1G>A, no live-born homozygote for either variant has been identified. Thus, it is presumed that these genotypes are lethal.
• Children who are compound heterozygotes (i.e., c.[84dupG]+[115+1G>A]) have a subacute disease course with progressive pulmonary involvement and death in the first to second decade.

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]. In the Czech Republic, the birth prevalence was reported as 1.13 per 100,000 [Poupetová et al 2010].

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

• Ashkenazi Jewish, Spanish, and Portuguese (p.Asn409Ser)
• Swedish (p.Leu483Pro)
• Jenin Arab, Greek, and Albanian (p.Asp448His). Among Greeks and Albanians, p.Asp448His has been found in cis with p.His294Gln.

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 those who are not of European origin.

Genetically Related (Allelic) Disorders

Parkinsonian features have been reported in a few individuals with type 1 GD; studies suggest a possible cause-and-effect relationship rather than mere coincidence, although the underlying basis remains incompletely understood [Blanz & Saftig 2016, Lopez et al 2016, Aflaki et al 2017]. The following findings suggest that pathogenic variants in GBA and/or alterations in glucosylceramide metabolism may be a risk factor for parkinsonism [Sidransky 2005].

• The precise risk to individuals with Gaucher disease of developing Parkinson disease (PD) is not known, but has been variously estimated at 20- to 30-fold the risk to an individual in the general population [Bultron et al 2010, McNeill et al 2012].
• GBA pathogenic variants have been identified in 5%-10% of individuals with PD [Sidransky et al 2009]. PD associated with pathogenic variants in GBA (GBA-PD) is clinically, pathologically, and pharmacologically indistinguishable from idiopathic "sporadic" PD, although GBA-PD is associated with slightly earlier onset (~5 years earlier) and more frequent cognitive dysfunction [Neumann et al 2009].
• Family studies suggest that the incidence of parkinsonism may be higher in obligate heterozygotes for GD. Among Ashkenazi Jewish individuals who developed PD, those with GD experienced a younger age at onset than those who were obligate heterozygotes (mean, 54.2 vs 65.2 years, respectively; P = .003). Estimated age-specific risk for PD at 60 and 80 years of age was 4.7% and 9.1% among those with GD, 1.5% and 7.7% among heterozygotes, and 0.7% and 2.1% among non-carriers, respectively [Alcalay et al 2014].

Evaluations Following Initial Diagnosis

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

Baseline (pre-treatment) assessments may be useful in selecting treatment modality and regimen (i.e., enzyme dose and frequency of infusion).

The following evaluations may be considered, if they were not performed as part of the diagnostic assessment:

• Hemoglobin concentration and platelet count
• Baseline spleen and liver volumes by MRI
• EKG and echocardiography to identify elevated pulmonary artery pressure
• Plain radiographs of the femur (anterior-posterior view), spine (lateral view), and any symptomatic sites
• Bone age in individuals with growth and pubertal delay
• Consultation with a clinical geneticist

Treatment of Manifestations

Management by a multidisciplinary team with expertise in treating GD is available at Comprehensive Gaucher Centers (see National Gaucher Foundation). Enzyme replacement therapy and substrate reduction therapy are available options for this condition (see Prevention of Primary Manifestations). Clinical management guidelines have been published [Biegstraaten et al 2018].

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:

• 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 on treatment 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. Calcium and vitamin D may benefit individuals with GD and low bone density. Anti-bone-resorbing agents may also be indicated; ideally, evaluations and management should be undertaken in consultation with metabolic bone specialists [Wenstrup et al 2004, Masi & Brandi 2015].

Persons with GD with findings suggestive of multiple myeloma and parkinsonism should be referred to the appropriate specialists.

Prevention of Primary Manifestations

There is no cure for GD. However, enzyme replacement therapy and substrate reduction therapy are available to mitigate manifestations.

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

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]. A European working group has also published a consensus document relating to management goals for individuals with GD1 [Biegstraaten et al 2018]:

• 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, and 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 vitamins B₁₂ and D.
  • 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 variant, confounding interpretation of test results [Grace et al 2007].
• Assessment of spleen and liver volumes by MRI. Parenchymal abnormalities can be identified as well. In situations in which access to an MRI 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 (DXA) to identify osteoporosis and 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 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]. A new framework, based on the disease severity scoring system (DS3), has been used to project the long-term health outcomes of individuals with GD1 who are starting treatment [Ganz et al 2017].

Agents/Circumstances to Avoid

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

Evaluation of Relatives at Risk

It is appropriate to evaluate asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early diagnosis and treatment to reduce morbidity. Evaluations can include:

• Assay of glucocerebrosidase enzyme activity in peripheral blood leukocytes or other nucleated cells;
• Molecular genetic testing if the pathogenic variants in the family are known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

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 be at an increased risk for bleeding around the time of delivery [Elstein et al 2004b]; therefore, evaluation by a hematologist prior to delivery is recommended [Hughes et al 2007]. In symptomatic women, treatment should ideally be started prior to conception [Granovsky-Grisaru et al 2011].

Although eliglustat use is not contraindicated during pregnancy and breastfeeding, the lack of controlled studies demonstrating the safety of eliglustat during human pregnancy and lactation has led to a recommendation to avoid this treatment during pregnancy, if possible [Balwani et al 2016, Belmatoug et al 2017].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Substrate reduction therapy. Preclinical studies involving analogs that may be efficacious for primary CNS involvement are ongoing [Larsen et al 2012, Marshall et al 2016].

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 endoplasmic reticulum. 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, Mena-Barragán et al 2018].

Ambroxol, a mucolytic agent, is also a potential pharmacologic glucocerebrosidase chaperone [Zimran et al 2013]. An open-label pilot study of high-dose oral ambroxol in combination with ERT in five Japanese affected individuals found that ambroxol had a good safety and tolerability profile. Significantly increased lymphocyte glucocerebrosidase activity and decreased glucosylsphingosine levels in the cerebrospinal fluid were also noted. Myoclonus, seizures, and pupillary light reflex dysfunction markedly improved in all affected individuals. Relief from myoclonus led to impressive recovery of gross motor function in two patients, allowing them to walk again [Narita et al 2016].

Histone deacetylase inhibitors increase the quantity and activity of glucocerebrosidase by limiting the deacetylation of heat shock protein 90. As a consequence, there was less enzyme degradation [Yang et al 2013].

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 (p.Asp448Val/null) intravenous administration of a recombinant AAV8 serotype vector bearing human glucocerebrosidase 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]. AVROBIO, a clinical-stage biotechnology company, has announced a planned lentiviral-based gene therapy trial in Gaucher disease, to commence in late 2018 / early 2019.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for 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 individuals 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, Møller et al 2004, Smid et al 2016]. However, the prognostic value of these markers, their role in patient stratification according to clinical disease severity, and determination of the optimum time to initiate therapy are unknown.

Glucosylsphingosine (Lyso-GL1), a deacylated lysolipid, has been found to be massively elevated in the plasma of individuals with GD1 (n-169), with marked reduction observed following treatment with ERT or SRT [Murugesan et al 2016]. Lyso-GL1 levels correlated significantly with plasma chitotriosidase levels, hepatomegaly, splenomegaly, splenectomy, and treatment mode.

Elevation of the protein glycoprotein non-metastatic B, found in brain samples from individuals with type 2 and 3 GD, may be used as a marker to quantify neuropathology in those with GD and as a marker of treatment efficacy once suitable treatments are initiated [Zigdon et al 2015].

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 (i.e., carriers of one GBA pathogenic variant).
• Heterozygotes are asymptomatic and are not at risk of developing the disorder.
• Because the carrier frequency for GD in certain populations is high (e.g., 1:18 in individuals of Ashkenazi Jewish heritage) and the p.[Asn409Ser]+[Asn409Ser] phenotype is variable, 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.
• Heterozygotes are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• The offspring of an individual with GD are obligate heterozygotes (carriers) for a pathogenic variant in GBA.
• 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 of a GBA pathogenic variant.

Carrier Detection

Biochemical genetic testing. Measurement of glucocerebrosidase 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 pathogenic variants have been identified in the family.

Testing for the four common GBA alleles (p.Asn409Ser, p.Leu483Pro , c.84dupG, c.115+1G>A) has been included in panels specifically designed for carrier screening in the Ashkenazi Jewish population [Zuckerman et al 2007].

Because the frequency for GD in certain populations is high (e.g., individuals of Ashkenazi Jewish heritage) and the p.[Asn409Ser]+[Asn409Ser] 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 analysis for pathogenic variants is insufficient and full sequence analysis should be undertaken.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating 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/preimplantation genetic 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, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the GBA pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for GD are possible.

Except in families in which a previously affected sib 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.

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. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful [Beutler 2007, Zuckerman et al 2007].

Molecular Pathogenesis

Gaucher disease (GD) is caused by deficient activity of the lysosomal enzyme glucocerebrosidase 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].

Gene structure. GBA ("glucosidase, beta, acid") 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, GBAP, (5 kb) is located 16 kb downstream. For a detailed summary of gene and protein information, see Table A, Gene.

Note: A related gene, GBA2 (glucosidase beta (bile acid) 2), encodes a microsomal nonlysosomal glucosylceramidase that catalyzes the conversion of glucosylceramide to free glucose and ceramide and the hydrolysis of bile acid 3-O-glucosides. Pathogenic variants of GBA2 have been shown to cause an autosomal recessive (AR) form of cerebellar ataxia with spasticity [Hammer et al 2013] and AR hereditary spastic paraplegia 46 (HSP46) [Martin et al 2013].

Pathogenic variants. At least 200 pathogenic variants in GBA have been identified; they include missense and nonsense variants, splice junction variants, deletions and insertions of one or more nucleotides, and complex alleles resulting from gene conversion or gene fusion with the downstream pseudogene (see Table A) [Tayebi et al 2003, Rozenberg et al 2006, Alfonso et al 2007].

Approximately 12% of disease-causing alleles are formed by recombination between GBA and GBAP [Tayebi et al 2003]; the most common recombinant allele, termed RecNciI, is defined by the creation of a NciI restriction site [Zimran et al 1990, Tayebi et al 2003].

Historically, GBA variants were numbered based on the position in the nucleotide sequence that encodes the mature glucocerebrosidase protein, wherein the first nucleotide of the alanine codon (GCC) was designated as 1. This naming convention is still often used, although it does not comply with current standards of nomenclature (see Table 5).

The variants p.Asn409Ser, c.84dupG, c.115+1G>A, and p.Leu483Pro account for 90% of the mutated alleles in Ashkenazi Jewish individuals with type 1 GD and for 50%-60% of mutated alleles in non-Jewish individuals with type 1 GD. The frequencies of the most common genotypes associated with the p.Asn409Ser allele are listed in Table 4. The frequency of the p.Asn409Ser 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]. In contrast, the p.Asn409Ser and c.84dupG alleles have not been identified among Japanese and Chinese individuals with GD. The occurrence of deleterious alleles among the Japanese (e.g., p.Leu483Pro: 41% allele frequency; p.Phe252Ile: 14%) and Chinese (p.Leu483Pro: 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" pathogenic variants (p.Asn409Ser, c.84dupG, c.115+1G>A, and p.Leu483Pro) does not lead to 100% detection.

Normal gene product. Glucocerebrosidase (also known as 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.

Glucocerebrosidase 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 glucocerebrosidase 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 pathogenic variants result in mRNA instability and/or loss of protein, or in an enzyme with altered activity and/or conformation [Grabowski & Horowitz 1997].

Revision History

• 9 March 2023 (aa) Revision: targeted therapies ERT and SRT to prevent primary manifestations linked as Key Sections
• 21 June 2018 (ma) Comprehensive update posted live
• 26 February 2015 (gp) Revision: eliglustat FDA approved for use in the US
• 19 September 2013 (me) Comprehensive update posted live
• 21 July 2011 (cd) Revision: corrections to mutation nomenclature
• 1 February 2011 (me) Comprehensive update posted live
• 13 March 2008 (me) Comprehensive update posted live
• 23 November 2005 (gp) Revision: information on miglustat (Management)
• 2 June 2005 (me) Comprehensive update posted live
• 18 February 2004 (gp) Revision: Management
• 8 April 2003 (me) Comprehensive update posted live
• 27 July 2000 (me) Review posted live
• 23 March 2000 (gp) Original submission

Published Guidelines / Consensus Statements

• Baldellou A, Andria G, Campbell PE, Charrow J, Cohen IJ, Grabowski GA, Harris CM, Kaplan P, McHugh K, Mengel E, Vellodi A. Paediatric non-neuronopathic Gaucher disease: recommendations for treatment and monitoring. Eur J Pediatr. 2004;163:67-75. [PubMed]
• Charrow J, Andersson HC, Kaplan P, Kolodny EH, Mistry P, Pastores G, Prakash-Cheng A, Rosenbloom BE, Scott CR, Wappner RS, Weinreb NJ. Enzyme replacement therapy and monitoring for children with type 1 Gaucher disease: consensus recommendations. J Pediatr. 2004;144:112-20. [PubMed]
• Grabowski GA, Andria G, Baldellou A, Campbell PE, Charrow J, Cohen IJ, Harris CM, Kaplan P, Mengel E, Pocovi M, Vellodi A. Pediatric non-neuronopathic Gaucher disease: presentation, diagnosis and assessment. Consensus statements. Eur J Pediatr. 2004;163:58-66. [PubMed]
• NIH Technology Assessment Panel on Gaucher Disease. Gaucher disease. Current issues in diagnosis and treatment. JAMA. 1996;275:548-53. [PubMed]

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