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.
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.
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: 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. 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. 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.
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.
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.
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.
|1" colspan="1" style="text-align:left;vertical-align:middle;">Age||1" colspan="1" style="text-align:left;vertical-align:middle;">Subtype||1" colspan="1" style="text-align:left;vertical-align:middle;">Primary CNS Involvement||1" colspan="1" style="text-align:left;vertical-align:middle;">Bone Disease 1||1" colspan="1" style="text-align:left;vertical-align:middle;">Other|
|1" colspan="1" style="text-align:left;vertical-align:middle;">Adult||1" colspan="1" style="text-align:left;vertical-align:middle;">Type 1||1" colspan="1" style="text-align:left;vertical-align:middle;">No||1" colspan="1" style="text-align:left;vertical-align:middle;">Yes||1" colspan="1" style="text-align:left;vertical-align:middle;">|
|1" colspan="1" style="text-align:left;vertical-align:middle;">Infancy - early childhood||1" colspan="1" style="text-align:left;vertical-align:middle;">Type 2 (acute or infantile)||1" colspan="1" style="text-align:left;vertical-align:middle;">||1" colspan="1" style="text-align:left;vertical-align:middle;">No||1" colspan="1" style="text-align:left;vertical-align:middle;">|
|1" colspan="1" style="text-align:left;vertical-align:middle;">Childhood||1" colspan="1" style="text-align:left;vertical-align:middle;">Type 3 (subacute; juvenile)||1" colspan="1" style="text-align:left;vertical-align:middle;">||1" colspan="1" style="text-align:left;vertical-align:middle;">Yes||1" colspan="1" style="text-align:left;vertical-align:middle;">|
|1" colspan="1" style="text-align:left;vertical-align:middle;">Perinatal||1" colspan="1" style="text-align:left;vertical-align:middle;">Perinatal-lethal form||1" colspan="1" style="text-align:left;vertical-align:middle;">Pyramidal signs||1" colspan="1" style="text-align:left;vertical-align:middle;">No||1" colspan="1" style="text-align:left;vertical-align:middle;">|
|1" colspan="1" style="text-align:left;vertical-align:middle;">Cardiovascular-predominant variant||1" colspan="1" style="text-align:left;vertical-align:middle;">Cardiovascular form||1" colspan="1" style="text-align:left;vertical-align:middle;">Oculomotor apraxia||1" colspan="1" style="text-align:left;vertical-align:middle;">Yes||1" colspan="1" style="text-align:left;vertical-align:middle;">|
Osteopenia, focal lytic or sclerotic lesions, and/or osteonecrosis
Anemia, leukopenia, and/or thrombocytopenia
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 .
Molecular testing approaches can include single-gene testing or use of a multigene panel.
- 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 at the most reasonable cost 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.
|1" colspan="1" style="text-align:left;vertical-align:middle;">Gene 1||1" colspan="1" style="text-align:left;vertical-align:middle;">Method||1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with Pathogenic Variants 2 Detectable by Method|
|2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">GBA||1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis 3, 4||1" colspan="1" style="text-align:left;vertical-align:middle;">~99% 5|
|1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis 6||1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown; likely <1% 7|
See Table A. Genes and Databases for chromosome locus and protein.
See Molecular Genetics for information on allelic variants detected in this gene.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
Due to the presence of a highly homologous pseudogene (GBAP), PCR-based methods must be designed to differentiate GBA from the pseudogene.
Complex disease-causing alleles derived from GBA-GBAP recombinant events, such as the common RecNciI allele, may be detected by sequence analysis.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that rely on hybridization, such as multiplex ligation-dependent probe amplification (MLPA) or gene-targeted microarray designed to detect single-exon deletions or duplications, may not detect deletions or duplications in regions of high homology between GBA and GBAP. Methods such as quantitative PCR, long-range PCR, and Southern blotting may be used to detect deletion/duplication of GBA.
Deletions of 3,925 bp of exons 1-2 and 5'UTR (a region unique to GBA) and of the whole gene have been reported [Beutler & Gelbart 1994, Cozar et al 2011]
|1" colspan="1" style="text-align:left;vertical-align:middle;">Variants 1||1" colspan="1" style="text-align:left;vertical-align:middle;">% of Affected Individuals 2, 3|
|1" colspan="1" style="text-align:left;vertical-align:middle;">p.[Asn409Ser]+[Asn409Ser]||1" colspan="1" style="text-align:left;vertical-align:middle;">29%|
|1" colspan="1" style="text-align:left;vertical-align:middle;">p.[Asn409Ser]+[?]||1" colspan="1" style="text-align:left;vertical-align:middle;">20%|
|1" colspan="1" style="text-align:left;vertical-align:middle;">p.[Asn409Ser]+[Leu483Pro]||1" colspan="1" style="text-align:left;vertical-align:middle;">16%|
|1" colspan="1" style="text-align:left;vertical-align:middle;">p.Asn409Ser+c.84dupG||1" colspan="1" style="text-align:left;vertical-align:middle;">12%|
|1" colspan="1" style="text-align:left;vertical-align:middle;">p.[Leu483Pro]+[Leu483Pro] 4||1" colspan="1" style="text-align:left;vertical-align:middle;">6%|
|1" colspan="1" style="text-align:left;vertical-align:middle;">p.[Leu483Pro]+[?]||1" colspan="1" style="text-align:left;vertical-align:middle;">3%|
|1" colspan="1" style="text-align:left;vertical-align:middle;">p.Asn409Ser+c.115+1G>A||1" colspan="1" style="text-align:left;vertical-align:middle;">3%|
Table 5 provides the variant name and nucleotide changes according to current nomenclature guidelines.
Based on data from 1,097 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 (see Clinical Characteristics).
GD pathogenic variant detection rates based on sequence analysis available through the ICGG Registry Program (registration required)
Recombinant (Rec) alleles (i.e., the RecNciI allele; see Molecular Genetics) contain two to four single-nucleotide variants (including p.Leu483Pro ) that arise as a result of gene rearrangements between exons 9 and 10 of the functional gene and pseudogene. Thus, testing for the p.Leu483Pro variant alone does not allow distinction of the isolated p.Leu483Pro allele from Rec alleles, and may lead to an error in genotype designation [Tayebi et al 2003].
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).
Type 1 GD
Bone disease. Clinical or radiographic evidence of bone disease occurs in 70%-100% of individuals with type 1 GD. Bone disease ranges from asymptomatic osteopenia to focal lytic or sclerotic lesions and osteonecrosis [Wenstrup et al 2002]. Bone involvement, which may lead to acute or chronic bone pain, pathologic fractures, and subchondral joint collapse with secondary degenerative arthritis, is often the most debilitating aspect of type 1 GD [Pastores et al 2000].
Acute bone pain manifests as "bone crises" or episodes of deep bone pain that are usually confined to one extremity or joint [Cohen 2003] and are often accompanied by fever and leukocytosis but sterile blood culture. The affected region may be swollen and warm to touch; imaging studies may reveal signal abnormalities consistent with localized edema or hemorrhage; x-rays may show periosteal elevation ("pseudo-osteomyelitis") [Pastores & Meere 2005].
Conventional radiographs (x-rays) may reveal undertubulation (Erlenmeyer flask configuration) noted in the distal femur and endosteal scalloping as a sign of bone marrow infiltration. MRI reveals the extent of marrow involvement and the presence of fibrosis and/or infarction. In general, marrow infiltration extends from the axial to the appendicular skeleton, and greater involvement is often seen in the lower extremities and proximal sites of an affected bone. The epiphyses are usually spared, except in advanced cases. Bone densitometry studies enable quantitative assessment of the degree of osteopenia.
Bone disease in GD may not correlate with the severity of hematologic or visceral problems.
Secondary neurologic disease in type 1 GD. Although individuals with type 1 GD do not have primary CNS disease, neurologic complications (spinal cord or nerve root compression) may occur secondary to bone disease (e.g., severe osteoporosis with vertebral compression; emboli following long bone fracture), or coagulopathy (e.g., hematomyelia) [Pastores et al 2003].
The incidence of peripheral neuropathy may be higher than previously recognized [Halperin et al 2007, Capablo et al 2008]. In a two-year prospective study, which enrolled 103 affected individuals, 11 (10.7%) were diagnosed with sensory motor axonal polyneuropathy [Biegstraaten et al 2010].
Hepatosplenomegaly. The spleen is enlarged (i.e., 1,500-3,000 cc in size, compared to 50-200 cc in the average adult) with resultant hypersplenism associated with pancytopenia (i.e., anemia, leukopenia, and thrombocytopenia). Infarction of the spleen can result in acute abdominal pain. Rarely, acute surgical emergencies may arise because of splenic rupture [Stone et al 2000b].
Liver enlargement is common, although cirrhosis and hepatic failure are rare [Ayto et al 2010].
Cytopenias. Cytopenia is almost universal in untreated GD. Anemia, thrombocytopenia, and leukopenia may be present simultaneously or independently [Zimran et al 2005]. The pattern of cytopenia in GD is dependent on spleen status.
Low platelet count may result from hypersplenism, splenic pooling of platelets, or marrow infiltration or infarction. Immune thrombocytopenia has also been reported and should be excluded in individuals with persistent thrombocytopenia despite GD-specific therapy. Thrombocytopenia may be associated with easy bruising or overt bleeding, particularly with trauma, surgery, or pregnancy. The risk for bleeding may be increased in the presence of clotting abnormalities.
Anemia may result from hypersplenism, hemodilution (e.g., pregnancy), iron deficiency or B12 deficiency, and, in advanced disease, decreased erythropoiesis as a result of bone marrow failure from Gaucher cell infiltration or medullary infarction.
Leukopenia is rarely severe enough to require intervention. Deficient neutrophil function has been reported.
Coagulation abnormalities. Acquired coagulation factor deficiencies include low-grade disseminated intravascular coagulation and specific inherited coagulation factor deficiencies (e.g., factor XI deficiency among Ashkenazi Jews). An investigation of Egyptian individuals with type 1 GD revealed a wide variety of coagulation factor abnormalities (fibrinogen, factor II, VII, VIII, X, XII) [Deghady et al 2006]. Abnormal platelet aggregation may contribute to bleeding diathesis in the presence of normal platelet counts [Linari & Castaman 2016].
Pulmonary involvement. The following can be observed:
- Interstitial lung disease
- Alveolar/lobar consolidation
- Pulmonary arterial hypertension (PAH); well documented in individuals with liver disease and presumably the result of inability to detoxify gut-derived factors, which somehow adversely affect the pulmonary endothelium with resultant pulmonary hypertension. PAH can also occur in individuals with GD without liver disease [Mistry et al 2002]. In a study of 14 individuals with PAH, median age at GD diagnosis was 36 years (22-63). There was a female preponderance (ratio 5:2), and all individuals in this report had undergone splenectomy (median age 12 years) [Lo et al 2011].
Dyspnea and cyanosis with digital clubbing attributed to hepatopulmonary syndrome have been described in individuals with liver dysfunction, often caused by an intercurrent disease (e.g., viral hepatitis).
Those individuals with type 1 GD without evident lung involvement who limit physical exertion because of easy fatigability may have impaired circulation [Miller et al 2003].
Pregnancy and childbirth. Except in women with significant pulmonary arterial hypertension, pregnancy is not contraindicated in GD (see Pregnancy Management).
In some women the diagnosis of GD is first made in pregnancy because of exacerbation of hematologic features.
Malignancy. Epidemiologic studies have suggested elevated risk of certain malignancies in GD including the following:
- Multiple myeloma [Rosenbloom et al 2005]
- Hepatocellular carcinoma [de Fost et al 2006]
- Non-Hodgkins lymphoma, malignant melanoma, and pancreatic cancer [Landgren et al 2007]
Except in the case of multiple myeloma, other reports have failed to find these associations [Cox et al 2015b]. The basis for increased risk for multiple myeloma remains the subject of investigations [Nair et al 2018].
Immunologic abnormalities. Children or adults may have polyclonal gammopathy [Wine et al 2007]. An increased incidence of monoclonal gammopathy has been reported in adults [Brautbar et al 2004]. Affected individuals also exhibit altered cellular immune profiles with increased peripheral blood NKT lymphocytes and reduced numbers of functionally normal dendritic cells [Lalazar et al 2006, Micheva et al 2006].
Metabolic abnormalities. GD is associated with metabolic abnormalities including high resting energy expenditures (possibly the result of elevated cytokine levels) and low circulating adiponectin and peripheral insulin. The hypermetabolic state is not associated with altered thyroid hormone resistance [Langeveld et al 2007a, Langeveld et al 2007b, Langeveld et al 2008].
Serum concentrations of angiotensin-converting enzyme, tartrate-resistant acid phosphatase, ferritin, chitotriosidase, and PARC/CCL18 are usually elevated. Serum concentrations of total and HDL cholesterol are often low.
Abnormalities in the concentration of certain bone markers have been found in some individuals with GD in serum (e.g., osteocalcin, bone-specific alkaline phosphatase, macrophage inhibitory protein-1 alpha and beta) and urine (e.g., urinary hydroxyproline, free deoxypyridinoline, calcium); however, the routine utility of these findings in clinical practice is not established [Giuffrida et al 2012, Masi & Brandi 2015].
Psychological complications. Persons with GD exhibit moderate to severe psychological complications including somatic concerns and depressed mood [Packman et al 2006].
- Cholelithiasis occurs in a significant proportion of adults with GD:
- In a cohort of 417 affected individuals, the prevalence of gallstones (GS) was 32%, and found to be higher in women.
- Those with GS were more likely to be asplenic (p<0.0001) and older (p<0.0001); and have higher low-density lipoprotein (LDL) cholesterol concentrations (p=0.002) and more severe GD1 disease than those without GS [Taddei et al 2010].
- Additional risk factors include age, family history of GS, higher body mass index values, disease severity, and splenectomy [Zimmermann et al 2016].
- Cardiac and renal complications are rare.
Type 2 GD / Type 3 GD (Primary Neurologic Disease)
Neurologic disease. Previously, affected individuals were classified into type 2 or type 3 GD based on the age of onset of neurologic signs and symptoms and the rate of disease progression. Children with onset before age two years with a rapidly progressive course, limited psychomotor development, and death by age two to four years were classified as having type 2 GD. Individuals with type 3 GD may have onset before age two years but often have a more slowly progressive course, with life span extending into the third or fourth decade in some cases. However, these distinctions are not absolute and it is increasingly recognized that neuropathic GD represents a phenotypic continuum, ranging from abnormalities of horizontal ocular saccades at the mild end to hydrops fetalis at the severe end [Goker-Alpan et al 2003].
Bulbar signs include stridor, squint, and swallowing difficulty.
Pyramidal signs include opisthotonus, head retroflexion, spasticity, and trismus.
Oculomotor apraxia, saccadic initiation failure, and opticokinetic nystagmus are common [Nagappa et al 2015]. Oculomotor involvement may be found as an isolated sign of neurologic disease in individuals with a chronic progressive course and severe systemic involvement (e.g., massive hepatosplenomegaly).
Generalized tonic-clonic seizures and progressive myoclonic epilepsy have been observed in some individuals [Roshan Lal & Sidransky 2017]. In a study of 122 affected individuals, seizures and myoclonic seizures were reported in 19 (16%) and three (2%) persons, respectively [Tylki-Szymańska et al 2010].
Dementia and ataxia have been observed in the later stages of chronic neurologic disease.
Brain stem auditory evoked response (BAER) testing may reveal abnormal wave forms (III and IV) [Okubo et al 2014]. MRI of the brain may show mild cerebral atrophy. (A normal EEG, BAER, or brain MRI does not exclude neurologic involvement.)
Perinatal-lethal form. The perinatal-lethal form is associated with hepatosplenomegaly, pancytopenia, and microscopic skin changes (i.e., abnormalities in the stratum corneum attributed to altered glucosylceramide-to-ceramide ratio) and may present clinically with ichthyosiform or collodion skin abnormalities or as nonimmune hydrops fetalis [Orvisky et al 2002]. Arthrogryposis and distinctive facial features are seen in 35%-43% [Mignot et al 2003].
Another rare severe variant of GD is associated with hydrocephalus, corneal opacities, deformed toes, gastroesophageal reflux, and fibrous thickening of splenic and hepatic capsules [Stone et al 2000b, Inui et al 2001].
Cardiovascular form. Individuals homozygous for the p.Asp448His allele present with an atypical phenotype dominated by cardiovascular disease with calcification of the mitral and aortic valves [Altunbas et al 2015]. Additional findings include mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia [George et al 2001].
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  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.
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].
Saposin C deficiency or prosaposin deficiency (OMIM 610539). Saposin C is a cofactor for glucocerebrosidase in the hydrolysis of GL1. Individuals with saposin C deficiency or prosaposin deficiency may present with symptoms characteristic of severe neuropathic Gaucher disease (GD) (i.e., progressive horizontal ophthalmoplegia, pyramidal and cerebellar signs, myoclonic jerks, and generalized seizures) [Pàmpols et al 1999, Qi & Grabowski 2001] or non-neuronopathic disease [Tylki-Szymańska et al 2007]. These individuals demonstrate GL1 accumulation and visceromegaly but have normal glucocerebrosidase enzyme activity measured in vitro. Saposin C deficiency is caused by biallelic pathogenic variants in PSAP and inherited in an autosomal recessive manner.
Lysosomal storage diseases (LSDs). Findings in GD may overlap with some lysosomal storage diseases; however, the distinctive clinical features associated with these lysosomal storage diseases, the availability of biochemical testing in clinical laboratories, and an understanding of their natural history should help distinguish between them.
Hepatosplenomegaly is observed in Niemann-Pick disease types A and B (see Acid Sphingomyelinase Deficiency), Niemann-Pick disease type C, Wolman disease (lysosomal lipase deficiency), the mucopolysaccharidoses (including mucopolysaccharidosis type I and mucopolysaccharidosis type II), and the oligosaccharidoses. The following features are not found in individuals with GD and should direct further investigations to these alternative diagnoses:
- Coarse facial features
- Dysostosis multiplex on skeletal radiographs
- Vacuolated lymphocytes on peripheral blood smear examination
- The presence of a cherry-red spot on fundoscopy
- White matter changes (leukodystrophy) on brain MRI
Gaucher cells. The characteristic storage cells of GD should be distinguished from those found in other storage disorders such as Niemann-Pick disease type C. "Pseudo Gaucher cells," which resemble Gaucher storage cells at the light microscopic but not ultrastructural level, occur in a number of hematologic conditions including myeloproliferative and myelodysplastic disorders.
Legg-Calvé-Perthes disease (OMIM 150600). 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.
Congenital ichthyoses and collodion skin changes are observed in autosomal recessive congenital ichthyosis.
Hydrops fetalis may be encountered in other LSDs, including GM1 gangliosidosis, sialidosis type 1 (OMIM 256550), Wolman disease, mucopolysaccharidosis type VII (MPS VII; OMIM 253220), mucopolysaccharidosis type IV (MPS IV; see MPS IVA), galactosialidosis (OMIM 256540), Niemann-Pick disease type C, disseminated lipogranulomatosis (Farber disease), infantile free sialic acid storage disease (ISSD), and mucolipidosis II (I-cell disease) [Stone & Sidransky 1999, Kooper et al 2006].
Myoclonic seizures are also observed in hexosaminidase A deficiency, sialidosis type 1, alpha-N-acetylgalactosaminidase deficiency (OMIM 609241), and fucosidosis (OMIM 230000). In addition to the LSDs, several genetic disorders are known to be associated with progressive myoclonic epilepsy (reviewed in de Siqueira ). Lysosome membrane protein 2 (encoded by SCARB2) has been shown to facilitate lysosomal targeting for the nascent glucocerebrosidase [Reczek et al 2007]. Biallelic pathogenic variants in SCARB2 have been associated with action myoclonus-renal failure (OMIM 254900).