Clinical characteristics.

Gaucher disease (GD) encompasses a continuum of clinical findings from a perinatal-lethal disorder to an asymptomatic type. The characterization of three major clinical types (1, 2, and 3) and two clinical forms (perinatal-lethal and cardiovascular) is useful in determining prognosis and management. Cardiopulmonary complications have been described with all the clinical phenotypes, although varying in frequency and severity.

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

Type 2 GD is characterized by primary central nervous system disease with onset before age two years, limited psychomotor development, and a rapidly progressive course with death by age two to four years.

Type 3 GD is characterized by primary central nervous system disease with childhood onset, a more slowly progressive course, and 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.

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 GBA1 on molecular genetic testing.

Management.

Targeted therapy: Options include enzyme replacement therapy (ERT) or substrate reduction therapy (SRT; e.g., miglustat, eliglustat). Hematopoietic stem cell transplantation may be an option in individuals with severe GD, primarily those with chronic neurologic involvement (type 3 GD).

Supportive care: When possible, management by a multidisciplinary team at a GD Comprehensive Treatment Center. Symptomatic treatment includes partial or total splenectomy for those with massive splenomegaly, significant areas of splenic fibrosis, and persistent significant thrombocytopenia (platelets <30,000/mm³) with a risk of bleeding; splenectomy may be needed even in those on targeted therapy. Supportive care for all affected individuals may include: orthopedic management of bone disease; analgesics for bone pain; joint replacement surgery for relief from chronic pain and restoration of function; anti-bone resorptive agents, calcium, and vitamin D for osteoporosis; transfusion of blood products for severe anemia and bleeding; 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; treatment of cholelithiasis, pulmonary disease, pulmonary hypertension, multiple myeloma, psychological manifestations, parkinsonism, and seizures according to the relevant specialist; social work support and care coordination as needed.

Surveillance: Clinical assessment of disease progression at least every six months to include hematologic, orthopedic, pulmonary, cardiac, psychiatric, and neurologic assessment; clinical assessment for abdominal pain, early satiety, evidence of bleeding diathesis, growth and weight gain, clinical disease markers, and liver enzymes; imaging for spleen and liver volumes at least every one to two years. Additional evaluations to be done as needed include radiographs, MRI, and dual-energy x-ray absorptiometry (DXA) scan; bone age in children with growth and pubertal delay; ultrasound for gallstones; serum iron, ferritin, and vitamin B₁₂ in those with anemia; and EKG and echocardiography with Doppler in individuals after splenectomy and those with elevated pulmonary artery pressure.

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.

GD is inherited in an autosomal recessive manner. The parents of an affected individual are typically heterozygous for a GBA1 pathogenic variant; in some families, an asymptomatic parent may be found to be homozygous rather than heterozygous. If both parents are known to be heterozygous for a GBA1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a heterozygote, and a 25% chance of inheriting neither of the familial GBA1 pathogenic variants. Once the GBA1 pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk family members, preimplantation genetic testing, and prenatal testing for GD are possible. The identification of 0%-15% of normal glucocerebrosidase enzyme activity in fetal samples obtained by chorionic villus sampling (CVS) or amniocentesis – ideally complemented by molecular genetic testing – can also be used to establish affected status in a fetus.

Suggestive Findings

Establishing the Diagnosis

The diagnosis of 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 (or likely pathogenic) variants in GBA1 on molecular genetic testing (see Table 2). Note: Identification of deficient glucocerebrosidase enzyme activity is recommended in individuals with biallelic GBA1 variants to confirm the diagnosis.

Note: (1) Molecular analysis of GBA1 is complicated by the presence of a highly homologous pseudogene, GBAP1. (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]. (3) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (4) Identification of biallelic GBA1 variants of uncertain significance (or of one known GBA1 pathogenic variant and one GBA1 variant of uncertain significance) does not establish or rule out the diagnosis.

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

• Single-gene testing. Sequence analysis of GBA1 is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
• A multigene panel that includes GBA1 and other genes of interest (see Differential Diagnosis) may also be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) Special consideration for the presence of the highly homologous pseudogene, GBAP1, 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. (4) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (5) Methods used in a panel may include sequence analysis, deletion/duplication analysis, 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 type 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 (CNS) 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 [Lepe-Balsalobre et al 2020]. 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].

Type 1 GD

• Individuals with at least one p.Asn409Ser variant do not develop primary neurologic disease [Koprivica et al 2000]. However, the presence of a p.Asn409Ser allele does not eliminate the risk for PD 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 develop progressive disease [Taddei et al 2009].

Primary neurologic disease (type 2 and type 3 GD)

• Individuals who are homozygous for GBA1 pathogenic variant p.Leu483Pro tend to have severe disease, often with neurologic complications (i.e., types 2 and 3 GD), 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 (nine alleles), with the p.Glu365Lys polymorphism (one allele), and as part of a recombinant allele (15 alleles).
  • In another study, homozygosity for p.Leu483Pro 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, p.Leu483Pro accounted for 41% and 20.8% of alleles, respectively. The second most common allele among Japanese individuals was p.Phe252Ile (14%); among Korean individuals, 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, p.Gly416Ser, and p.Asn227Ser) 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, occurring in cis with the p.Asp448His variant has been identified among Greek and Albanian individuals. Homozygosity for the p.[Asp448His;His294Gln] 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]
• GBA1 pathogenic variants p.Ser235Pro, p.Arg170Leu, p.Arg159Trp, and p.Arg296Gln [Stone et al 2000a]
• Compound heterozygosity for an insertion-type pathogenic variant and the pathogenic missense variant p.Arg159Gln, 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 GBA1 pathogenic variant p.Asp448His. 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;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.

Prevalence

Incidence and prevalence estimates for GD are scarce, except for reports regarding specific populations. Prevalence estimates are also variable, with higher prevalence in populations or regions with known founder variants (e.g., Ashkenazi Jews). A recent review, based on a targeted literature search conducted from January 2011 to September 2020, revealed incidence estimates including all GD subtypes ranging from 0.45-25.0:100,000 live births (16 studies); incidence was lowest for Asia-Pacific populations. The incidence of type 1 GD was estimated at 0.45-22.9:100,000 live births (Europe and North America) and type 3 GD at 1.36:100,000 live births (Asia-Pacific only). GD type-specific prevalence estimates per 100,000 population were type 1 GD: 0.26-0.63; type 2 GD and type 3 GD: 0.02-0.08 (Europe only). Estimates for GD type unspecified or overall ranged from 0.11-139.0:100,000 inhabitants (17 studies); the highest prevalence was in North America [Castillon et al 2022].

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.

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

As noted, the prevalence of types 2 and 3 GD (neuropathic) varies across ethnic groups but appears to be higher among those who are not of European origin.

Lysosomal Storage Disorders

Findings in Gaucher disease (GD) may overlap with some lysosomal storage diseases (see Table 3); however, the distinctive clinical features associated with these lysosomal storage disorders, biochemical testing, and an understanding of their natural history should help distinguish between them.

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.

Other Disorders

Osteonecrosis may be a presenting feature of GD, which should be considered in the differential diagnosis of children with suspected Legg-Calvé-Perthes disease [Kenet et al 2003]. A heterozygous pathogenic variant in COL2A1 causes a subset of cases of Legg-Calvé-Perthes disease inherited in an autosomal dominant manner (OMIM 150600).

Congenital ichthyoses and collodion skin changes are observed in autosomal recessive congenital ichthyosis.

Myoclonic seizures. In addition to the lysosomal storage disorders noted in Table 3, several genetic disorders are known to be associated with progressive myoclonic epilepsy (see SCARB2-Related Action Myoclonus – Renal Failure Syndrome and OMIM Phenotypic Series: Progressive myoclonic epilepsy).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GD, the evaluations summarized in Table 4a or Table 4b (if not performed as part of the evaluation that led to the diagnosis) are recommended. Recommended evaluations following initial diagnosis can vary based on age at diagnosis, mode of ascertainment (e.g., asymptomatic vs symptomatic individual), and presence or absence of primary neurologic involvement. Baseline (pre-treatment) assessments may be useful in selecting treatment modality and regimen (e.g., enzyme dose, frequency of infusion).

Treatment of Manifestations

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 type 1 GD [Biegstraaten et al 2018]. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

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

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 targeted therapy 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; therefore, evaluation by a hematologist prior to delivery is recommended [Hughes et al 2007, Rosenbaum 2015]. 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. Venglustat, an investigational, brain-penetrant glucosylceramide synthase inhibitor, has been administered to adults with type 3 GD receiving imiglucerase. In an early phase clinical trial, addition of once-daily venglustat showed acceptable safety and tolerability and preliminary evidence of clinical stability but inconsistent changes in selected biomarkers [Schiffmann et al 2023]. These findings need to be validated and confirmed in future research.

Chaperone-mediated enzyme enhancement therapy. Pharmacologic chaperones (PCs), 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 exhibited these properties in studies of cultured fibroblasts in vitro, was evaluated in clinical trials to establish its safety and efficacy in adults with type 1 GD [Steet et al 2007, Mena-Barragán et al 2018]. To date, no PCs have been approved for treatment of GD.

Ambroxol, a mucolytic agent, is also a potential pharmacologic glucocerebrosidase chaperone. An open-label pilot study of high-dose oral ambroxol in combination with ERT in five 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 individuals, allowing them to walk again [Narita et al 2016]. The beneficial effects of treatment with high-dose ambroxol has also been described in a more recent report [Istaiti et al 2023].

Gene therapy. Ex vivo gene therapy involves the introduction of GBA1 into hematopoietic stem cells. 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. In vivo gene therapy involves a GBA1 transgene delivered using an adeno-associated virus vector resulting in liver expression of glucocerebrosidase and release of the enzyme into the circulation.

AVROBIO, a clinical-stage biotechnology company, initiated a lentiviral-based gene therapy trial in GD, but this study has been discontinued. A new in vivo gene therapy trial (GALILEO-1) is recruiting adults with type 1 GD (NCT05324943).

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., CCL18/PARC, chitotriosidase) in individuals with GD is considered a possible surrogate indicator of disease burden that could be used in monitoring treatment response [Smid et al 2016]. However, the prognostic value of these markers, their role in stratification according to clinical disease severity, and determination of the optimum time to initiate therapy are unknown.

Glucosylsphingosine (lyso-Gb1), a deacylated lysolipid, has been found to be massively elevated in the plasma of individuals with type 1 GD (n=169), with marked reduction observed following treatment with ERT or SRT [Murugesan et al 2016]. Lyso-Gb1 levels correlated significantly with plasma chitotriosidase and CCL18/PARC levels, hepatomegaly, splenomegaly, splenectomy, and treatment mode [Giuffrida et al 2023].

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

• The parents of an affected individual are typically heterozygous for a GBA1 pathogenic variant. In some families, an asymptomatic parent may be found to be homozygous rather than heterozygous (it is suspected that a significant proportion of Ashkenazi Jewish individuals who are homozygous for the p.Asn409Ser or p.Arg535His variant may be asymptomatic [see Genotype-Phenotype Correlations]).
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a GBA1 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes are not at risk of developing GD. However, family studies suggest that the incidence of parkinsonism may be higher in obligate heterozygotes for GD (see Clinical Description, Heterozygotes).

Sibs of a proband

• If both parents are known to be heterozygous for a GBA1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a heterozygote, and a 25% chance of inheriting neither of the familial GBA1 pathogenic variants.
• If one parent has biallelic GBA1 pathogenic variants (e.g., p.[Asn409Ser];[Asn409Ser]) and the other parent is heterozygous for a GBA1 pathogenic variant, each sib of an individual with GD has a 50% chance of inheriting biallelic GBA1 pathogenic variants and being affected and a 50% chance of inheriting one GBA1 pathogenic variant and being heterozygous.
• Heterozygotes are not at risk of developing GD. However, family studies suggest that the incidence of parkinsonism may be higher in obligate heterozygotes for GD (see Clinical Description, Heterozygotes).

Offspring of a proband

• Unless an affected individual's reproductive partner also has GD or is a carrier (see Family planning), offspring will be obligate heterozygotes (carriers) for a pathogenic variant in GBA1.
• A higher carrier rate for GD exists in populations or regions with known founder variants (see Prevalence), 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 heterozygous.

Other family members. Each sib of an obligate heterozygote is at a 50% risk of being a carrier of a GBA1 pathogenic variant.

Carrier Detection

Molecular genetic carrier testing for at-risk relatives requires prior identification of the GBA1 pathogenic variants in the family.

Note: 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.

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 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.
• The American Academy of Medical Genetics includes GD among those disorders for which expanded carrier screening should be offered to all pregnant individuals and individuals planning a pregnancy [Gregg et al 2021]. Of note, because of the inherent detection limitations of ancestry-based targeted variant testing, sequence analysis (rather than targeted variant analysis) is recommended in the National Society of Genetic Counselors practice guidelines for expanded carrier screening [Sagaser et al 2023].

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). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the GBA1 pathogenic variants have been identified in an affected family member, molecular genetic prenatal and preimplantation genetic testing for GD are possible.

Biochemical testing. The identification of 0%-15% of normal glucocerebrosidase enzyme activity in fetal samples obtained by chorionic villus sampling (CVS) or amniocentesis – ideally complemented by molecular genetic testing – establishes affected status in a fetus. Enzyme activity testing does not reliably detect fetal carrier status.

With the exception of 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. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

GBA1 encodes glucocerebrosidase (also known as glucosylceramidase), 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 (GL1) into glucose and ceramide.

Glucocerebrosidase enzyme activity is stimulated by interaction with the lipid phosphatidylserine 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.

Gaucher disease (GD) is caused by deficient glucocerebrosidase activity and the resultant accumulation of its undegraded substrate, 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 central nervous system, 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].

Mechanism of disease causation. GBA1 pathogenic variants result in mRNA instability and/or loss of protein, or in an enzyme with altered activity and/or conformation [Grabowski & Horowitz 1997].

GBA-specific laboratory technical considerations

• Two different upstream ATG codons are utilized as translation initiation sites.
• A highly homologous (96% identity) pseudogene, GBAP1, is located 16 kb downstream. Approximately 12% of disease-causing alleles are formed by recombination between GBA1 and GBAP1 [Tayebi et al 2003]. The most common recombinant allele, termed RecNciI, is defined by the creation of an NciI restriction site [Zimran et al 1990, Tayebi et al 2003].

Revision History

• 7 December 2023 (sw) Comprehensive update posted live
• 21 June 2018 (ma) Comprehensive update posted live
• 19 September 2013 (me) Comprehensive update posted live
• 1 February 2011 (me) Comprehensive update posted live
• 13 March 2008 (me) Comprehensive update posted live
• 2 June 2005 (me) Comprehensive update posted live
• 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

• Belmatoug N, Di Rocco M, Fraga C, Giraldo P, Hughes D, Lukina E, Maison-Blanche P, Merkel M, Niederau C, Plӧckinger U, Richter J, Stulnig TM, Vom Dahl S, Cox TM. Management and monitoring recommendations for the use of eliglustat in adults with type 1 Gaucher disease in Europe. Eur J Intern Med. 2017;37:25-32. [PubMed]
• Dardis A, Michelakakis H, Rozenfeld P, Fumic K, Wagner J, Pavan E, Fuller M, Revel-Vilk S, Hughes D, Cox T, Aerts J; International Working Group of Gaucher Disease (IWGGD). Patient centered guidelines for the laboratory diagnosis of Gaucher diseasetype 1. Orphanet J Rare Dis. 2022;17:442. [PubMed]
• Kishnani PS, Al-Hertani W, Balwani M, Göker-Alpan Ö, Lau HA, Wasserstein M, Weinreb NJ, Grabowski G. Screening, patient identification, evaluation, and treatment in patients with Gaucher disease: Results from a Delphi consensus. Mol Genet Metab. 2022;135:154-162. [PubMed]

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