Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis

INTRODUCTION — Gaucher disease (GD) is an inborn error of metabolism that affects the recycling of cellular glycolipids. Glucocerebroside (also called glucosylceramide) and several related compounds that are ordinarily degraded to glucose and lipid components accumulate within the lysosomes of cells.

The epidemiology, pathogenesis, genetics, clinical manifestations, and diagnosis of GD are discussed here. The initial assessment, routine monitoring, and treatment are discussed separately. (See "Gaucher disease: Initial assessment, monitoring, and prognosis" and "Gaucher disease: Treatment".)

EPIDEMIOLOGY — GD is one of the most common lysosomal storage diseases. Type 1 GD (GD1) is the most prevalent type in the United States, Europe, and Israel and occurs with greater frequency in the Ashkenazi Jewish population. Type 2 GD (GD2) occurs in all ethnic types. There were approximately 20,000 individuals with GD in the United States in the mid-1990s based upon a gene frequency study, two-thirds of whom were Ashkenazi Jews [1], although fewer reached medical attention. A subsequent survey estimated the standardized birth incidence of GD in the general population to be between 0.4 and 5.8 per 100,000, with a prevalence of 0.7 to 1.8 per 100,000 [2].

In the United States, Europe, and Israel, approximately 90 percent of patients have GD1, which is the nonneuronopathic form. GD1 is the most common type seen in the Ashkenazi Jewish population, although most patients with GD1 are not Jewish. The carrier frequency in the Ashkenazi Jewish population is approximately 1 in 12 [3], and the frequency of disease-associated genotypes is calculated at 1 in 850 [4]. The incidence of GD1 is much lower in non-Jewish populations, occurring in approximately 1 in 40,000 [5] to 1 in 86,000 [6] livebirths.

GD2 (also called acute neuronopathic GD) has an estimated incidence of 1 in 150,000 [7].

The estimated incidence of type 3 GD (GD3, also called subacute or chronic neuronopathic GD) is 1 in 200,000, but the prevalence is considerably greater than GD2 because of the longer survival of these patients. GD3 is panethnic but with well-studied clusters in Northern Europe, Egypt, and East Asia [8].

The three types of GD are thought to represent a continuum from severely affected collodion babies through those with acute and chronic neuronopathic forms to patients with nonneuronopathic GD manifesting with skeletal and visceral involvement or Parkinson disease to older adults with mild or no clinical manifestations [9,10].

PATHOGENESIS — GD results from deficiency of a lysosomal enzyme, glucocerebrosidase (E.C.3.2.1.45, also known as glucosylceramidase or acid beta-glucosidase, GCase) [11,12]. GCase is a glycoprotein enzyme whose major substrate is glucocerebroside, a component of the cell membrane that is distributed widely in many organs. In the normal lysosome, the protein saposin C is thought to present glucocerebroside to GCase and thereby activate the enzyme [4]. Lysosomal integral membrane protein 2 (LIMP2) is another associated protein responsible for the transport of GCase to the lysosome [13]. There is also an association between progranulin (PGRN) insufficiency and GD since PGRN can be a co-chaperone for the lysosomal localization of GCase under pathologic conditions by linking GCase to heat shock protein 70 (HSP70) [14]. These associated proteins may provide new therapeutic targets for drug development [15,16].

In affected patients, the deficiency of GCase leads to accumulation of glucocerebroside and other glycolipids within the lysosomes of macrophages [11]. The tissue levels of these compounds may be increased 20 to 100 times [17]. In a murine model, there was also secondary accumulation of di- and trihexosyl ceramide in lipid rafts [18]. The deacylated form of glucosylceramide, glucosylsphingosine, is particularly elevated in the brain in patients with neuronopathic disease and may have a role in the pathogenesis of neurodegeneration [19]. It is highly elevated in plasma and visceral tissues from patients with all three types [19,20]. Data suggest it may also have an important role in aspects of the pathophysiology of the disease, including stimulation of gammopathy, inflammation, and neurotoxicity [21,22]. Its level correlates with severity, mutation, and treatment effect [23-25].

The clinical manifestations of GD result from the accumulation of the lipid-laden macrophages in the spleen, liver, bone marrow, bone, and other tissues/organs. However, pathologic lipid accumulation in macrophages accounts for less than 2 percent of the additional tissue mass in the liver and spleen [26]. The additional increase in organ weight and volume is attributed to an inflammatory and hyperplastic cellular response. Although the pathogenetic mechanisms are not understood, Gaucher cells and neighboring macrophages overexpress and secrete lysosomal proteases, such as cathepsins [27], and inflammatory mediators such as interleukin (IL) 6, IL-8, and IL-10; macrophage inflammatory proteins (MIP) 1-alpha and 1-beta [28-30]; and chemotactic factors cysteine-X-cysteine motif chemokine ligand (CXCL) 2, 9, 10, and 11 [13,31]. The Gaucher cells exhibit the secretory phenotype of the so-called "alternatively activated" macrophage. This phenotype is often associated in other conditions with chronic inflammation, healing, and fibrosis [32]. A mouse model of GD suggests that other cell types are affected, including thymic T cells, dendritic cells, and osteoblasts [33]. Activation of complement C5a and C5a receptor 1 (C5aR1) has been implicated in chemotaxis and Gaucher cell accumulation [34].

Several pathologic processes occur within bone: decreased mineral density, marrow infiltration, and infarction of bone. The mechanisms leading to decreased bone mineral density are uncertain, but they may involve failure to achieve peak bone mass, abnormal osteoclast regulation, or overproduction of cytokines by activated macrophages [35]. Marrow fibrosis and osteosclerosis result in localized loss of hematopoiesis. In an in vitro model of GD, primitive hematopoiesis and proliferation of mesenchymal progenitors were impaired, suggesting that cytopenias are due an intrinsic defect in addition to hypersplenism and bone marrow infiltration with Gaucher cells [36]. In another in vitro study, mesenchymal stem cells from patients with GD had impaired capacity to develop into osteoblasts [37]. Thrombocytopenia results from splenic sequestration and occasionally marrow failure. The increased bleeding tendency in patients with GD1 is related to thrombocytopenia, coagulation abnormalities, and defective platelet function [38]. Several cases of acquired von Willebrand disease have been described [39].

GENETICS — GD is an autosomal recessively inherited disorder that is due to pathogenic variants in the gene glucocerebrosidase 1 (GBA1), located on chromosome 1q21 [40]. The gene is 7.6 kb in length and is composed of 11 exons. A highly homologous 5 kb unprocessed pseudogene is located 16 kb downstream and may be transcriptionally active [41]. Care must be taken in molecular diagnosis and research to avoid analysis of the pseudogene and its transcripts in place of the active GBA1 gene and to detect recombinant alleles, especially when performing next-generation sequencing [42].

More than 400 distinct GBA1 gene variants are listed in the Human Gene Mutation Database. Over 80 percent of these variants are single-nucleotide substitutions. Insertions, deletions, and other complex alleles account for approximately 20 percent of pathogenic variants [43]. Traditional nomenclature within the Gaucher field considers amino acid 1 the first amino acid after the signal peptide. However, Human Genome Variation Society (HGVS) recommended nomenclature, in which leader sequences are counted in codon numbering, results in the addition of 39 to the traditional residue number [44].

Three mutant alleles are particularly frequent in affected patients:

●The c.1226A>G allele (N370S or p.N409S) [45,46] is a missense variant that has some residual enzyme activity. There is a genotype-phenotype correlation in that the presence of the c.1226A>G variant in either a homozygous or compound heterozygous form leads to GD1 rather than a neurologic phenotype [3]. The c.1226A>G variant is encountered commonly in non-Jewish Europeans and Ashkenazi Jews (gene frequency 0.032) [47] but is rare in Asian populations.

●The c.1448T>C allele (L444P or p.L483P) [48], which accounts for 18 percent of mutant alleles in the Gaucher Registry [45], is common worldwide. Specifically, it has been described in northern Sweden and elsewhere in Northern Europe [49]. Patients homozygous for the c.1448T>C allele tend to have a severe phenotype, often with GD3, but the phenotype can be highly variable [50].

●The c.84dupG allele (c.84insG mutation), which represents approximately 7 percent of mutant alleles in the same registry [45], results from an insertion at position 84 that causes a frameshift. It is a null variant (ie, no protein is synthesized). It is primarily seen in Ashkenazi Jews with GD, where it is the second most common pathogenic variant. Affected patients are compound heterozygotes and can have any of the three types of GD. To date, homozygotes have not been described, presumably because of prenatal lethality.

The c.1226A>G, c.84dupG, IVS2+1G>A, and c.1448T>C pathogenic variants account for approximately 93 percent of alleles in Ashkenazi patients [3,47]. The c.1226A>G and c.1448T>C variants together account for approximately 70 percent of mutant alleles in non-Ashkenazi-European patients [51,52], but there is considerable variation among different ethnicities. The c.1448T variant is encountered worldwide. Among one series of patients being treated for GD, approximately 25 percent were c.1226A>G homozygotes, whereas c.1226A>G was paired with c.1448T>C, c.84dupG, or a less common variant in 59 percent [11]. Mutant allele frequencies are different in Asian populations. As an example, the c.1226A>G variant was not found in a series of 36 Korean patients [53].

Patients with GD can carry recombinant alleles that result from different recombinant events between the gene and pseudogene, and different recombinant alleles can have a variable amount of pseudogene sequence often including c.1448T>C [54]. Many of these recombinant alleles are null alleles, and homozygosity for such alleles leads to perinatal lethality [55]. Many infants with GD2 may carry a recombinant allele together with a c.1448T>C allele [56]. This is important because they can be mistakenly identified as c.1448T>C homozygotes.

CLINICAL MANIFESTATIONS — GD involves the visceral organs, bone marrow, and bone in almost all affected patients. Disease severity can range from perinatal lethal to asymptomatic. The presenting features are variable and may occur at any age. GD is categorized into three clinical types that are distinguished by their clinical features, course, and ethnic predilection (table 1) [57]. However, there is a broad spectrum of findings and overlap within and between types, and intermediate phenotypes are appreciated, suggesting that GD is a spectrum of disease manifestations rather than a disorder with three distinct subtypes [9,10].

GD1 (MIM #230800) is distinguished from GD2 (MIM #230900) and GD3 (MIM #231000) by the lack of characteristic involvement of the central nervous system (CNS), although studies have documented several neurologic features in GD1 patients that are totally distinct from those observed in GD2 and GD3 [58]. GD with neurologic involvement (neuronopathic GD) is designated as GD2 or GD3 based on the acute or chronic nature, respectively.

Presentation — GD has a variety of presenting features that may occur at any age with varying severity [45,51,53,59-62]. The common presenting features seen in all types of GD are listed in the table (table 2).

Features seen only in GD2 and/or GD3 include:

●Severe developmental delay or regression (GD2)

●Subtle cognitive problems on presentation that may later progress to developmental delay (GD3)

●Nonimmune hydrops (GD2)

●Congenital ichthyosis (GD2)

●Strabismus or supranuclear gaze palsy (GD2 and GD3)

●Progressive dementia, ataxia, and myoclonus (GD3, rare)

●Corneal opacity or hydrocephalus (GD3c, rare)

●Cardiovascular calcification (GD3c, rare)

Patients (usually GD1) may also present when a bone marrow biopsy or splenectomy is performed during investigation of suspected malignancy.

Type 1 (GD1) — GD1 is characterized by variability in signs, symptoms, severity, and progression [59,63], even among siblings with the same genotype and monozygotic twins [64,65]. Symptomatic patients have visceral involvement, bone disease, and bleeding (table 1). Fatigue is common, and pubertal delay with associated delay in growth may occur. Bone disease is common in all patients, especially those who have undergone splenectomy. Variability is described in individuals homozygous for the c.1226A>G allele (p.N409S or N370S variant), ranging from clinically significant anemia, thrombocytopenia, hepatosplenomegaly, marrow infiltration, bony abnormalities, and osteopenia/osteoporosis, to essentially asymptomatic with no or mild hematologic and skeletal findings on examination [66].

The age of diagnosis for GD1 is also variable. Some patients present between 12 and 24 months of age, whereas others have no clinical signs until late adulthood. Some individuals with this genotype remain asymptomatic throughout their life. Increasingly infants are diagnosed during prenatal or newborn screening (NBS) [62].

Visceral disease — Splenomegaly is the most common presenting sign [60,67]. The spleen can be enlarged as much as 5 to 75 times its normal size (median 15.2 times) [45]. Hepatomegaly is common, but the liver increases relatively less than the spleen. Liver volume can be increased to two to three times the normal size for age [45]. Hepatic fibrosis may occur, but hepatic failure, cirrhosis, and portal hypertension are uncommon [68]. Prior to the advent of treatment, these complications were seen, especially in splenectomized patients and those with coexisting viral hepatitis contracted through blood transfusion [69-72].

Hepatosplenomegaly may be asymptomatic or may be associated with early satiety, abdominal complaints (distension, discomfort, pain), and/or anemia and thrombocytopenia [59]. Thrombocytopenia may result in bleeding and easy bruising. Splenic infarction or even spontaneous rupture occurs rarely and can present as acute abdominal pain.

Bone marrow disease — Anemia, thrombocytopenia, or rarely leukopenia may be present simultaneously or independently. The degree of anemia and thrombocytopenia in patients with GD may be related to whether or not they have had a therapeutic splenectomy. Thrombocytopenia is common in nonsplenectomized patients and generally occurs prior to anemia and leukopenia, which are more indicative of bone marrow infiltration. Lymphopenia is detected more commonly than neutropenia at presentation and may help differentiate GD1 from hematologic malignancy [73].

Skeletal disease — Skeletal manifestations are associated with a high degree of morbidity and can have considerable impact on activities of daily living [74,75]. However, there is variability in the extent and severity of bone involvement, and some patient have radiographic evidence of bone disease without symptoms.

In some patients, skeletal disease is characterized by diffuse bone pain, punctuated by painful crises that may result in osteonecrosis (avascular necrosis) with subsequent joint collapse affecting the proximal and distal femur, proximal tibia, and proximal humerus. Osteolytic lesions, pathologic fractures, vertebral compression fractures, and other fragility fractures associated with low bone mineral density also occur [59,76].

Data from 1698 patients in the Gaucher Registry, 94 percent with GD1, indicate that 63 percent had bone pain, 33 percent experienced bone crises, 8 percent required joint replacement, and 94 percent had radiologic evidence of skeletal disease [45]. Bone pain, bone crises, and severe radiologic bone disease were more common among asplenic patients. Bone crises were more common among patients diagnosed before age 10 years than after age 10 years (42 versus 24 percent). However, the registry data may not reflect the full spectrum of involvement, as milder patients are less likely to be included.

Growth/development — Many affected children grow poorly and have delayed puberty [60,77-80]. Approximately 50 percent of children diagnosed with GD have height ≤5^th percentile for age and sex at diagnosis [77,79], and 25 percent were found at presentation to be shorter than expected based upon midparental height [45,81]. However, in one series, all patients had spontaneous catch-up, and 83 percent achieved a final height within the range of what was expected based upon midparental height [77]. Most children with severe growth deficiency also have severe visceral involvement [77]. Thus, other causes of growth retardation should be evaluated in otherwise mildly affected children [82]. (See "Causes of short stature".)

In one series, puberty was delayed in 60 percent of 57 patients with GD in whom primary endocrine pathology was excluded [77]. Enzyme-replacement therapy started before puberty improved growth and appeared to normalize the onset of puberty. (See "Gaucher disease: Treatment", section on 'Enzyme replacement therapy'.)

Pulmonary disease — Interstitial lung disease is a less common manifestation of GD. It occurs when Gaucher cells infiltrate the alveolar spaces and interstitium [83]. The abnormal cells can also occlude pulmonary capillaries, perhaps contributing to pulmonary hypertension [84], but a role for soluble mediators in remodeling of pulmonary vasculature is also proposed [85]. Hepatopulmonary syndrome, with characteristic hypoxemia on standing resulting from abnormal vascular shunting within the lung, is a rare complication of GD that may occur in splenectomized patients with severe disease [68,86]. (See "Approach to the infant and child with diffuse lung disease (interstitial lung disease)" and "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)

Neurologic disease — Neurologic manifestations, such as peripheral polyneuropathy, are reported in GD1 even though it is "nonneuronopathic" [58,87,88]. GD is also associated with Parkinson disease. Both homozygous and heterozygous pathogenic variants in GBA1 are associated with a variety of Parkinsonian phenotypes including those that are earlier in onset and more progressive than non-Gaucher-associated Parkinson disease [89,90]. The mechanism underlying this association is unclear but may be related to either gain of function of improperly folded mutant enzyme or loss of enzyme function and substrate accumulation [91-94]. In addition, there is an increased frequency of heterozygosity for GBA1 variants in cohorts of patients with sporadic Parkinson disease [95-99]. Indeed, GBA1 variants are the most frequent genetic associations with Parkinson disease in the general population [100]. However, most patients with GD never develop Parkinson disease [45]. This suggests that GBA1 variants may only increase the risk in individuals who are otherwise prone to developing Parkinson disease [101,102]. (See "Clinical manifestations of Parkinson disease" and "Epidemiology, pathogenesis, and genetics of Parkinson disease".)

Malignancy — Increased rates of malignancies, particularly hematologic (lymphoma, leukemia, multiple myeloma), have been reported in patients with GD [69]. Some patients have had multiple malignancies. Pathogenic variants in modifier genes may underlie the increased susceptibility to cancer in these patients. A homozygous variant in the mutS homolog 6 (MSH6) gene that results in defective mismatch repair, for example, was identified in two siblings with GD1 and T cell acute lymphoblastic lymphoma [103]. B cell lymphoma and myeloma were seen in a murine model of GD with visceral storage of glucosylceramide and elevated plasma glucosylsphingosine, and a proportion of paraproteins in mice and humans with GD have been found to recognize glucosylsphingosine [104]. Malignancy in GD is discussed in greater detail separately. (See "Gaucher disease: Initial assessment, monitoring, and prognosis", section on 'Prognosis'.)

Other manifestations — Additional metabolic abnormalities described include elevated basal metabolic rate, insulin resistance, and lipid abnormalities [105-107]. "Gaucheromas," a rare situation in which clusters of Gaucher cells form a "pseudotumor," can be observed in liver, spleen, bone, lymph nodes, or soft tissue. They tend to be slow growing but can pose a management challenge [83].

Type 2 (GD2) — GD2 is the acute, neuronopathic form of GD. It is characterized by early onset, typically in the first year after birth (table 1) [108]. Visceral involvement is extensive and severe. Infants may present clinically with congenital ichthyosis, also known as collodion baby [109,110]. (See 'Visceral disease' above and "Overview and classification of the inherited ichthyoses", section on 'Gaucher disease type 2'.)

The first sign of CNS disease typically is oculomotor dysfunction, which may include strabismus, saccade (fast eye movement) initiation abnormalities, and bulbar palsy or paresis [56,111-113]. Children with saccadic initiation abnormalities may compensate for lack of saccades by moving their head to shift their gaze [112]. Neurologic progression is marked by severe hypertonia, rigidity, arching (opisthotonus), swallowing impairment, and seizures. Most affected infants demonstrate an impaired swallow, often necessitating a feeding tube and/or tracheostomy, and a swallow study is recommended [114]. A study reporting the natural history of GD in the 21^st century documented that longevity can be prolonged with intensive intervention, but the neurologic outcome remains quite dismal [115].

A perinatal-lethal form (lethal in utero or in the newborn period) can present as nonimmune hydrops [116,117]. Thus, GD should be considered in the differential diagnosis of pregnancy loss accompanied by severe hydrops. (See "Nonimmune hydrops fetalis".)

Type 3 (GD3) — GD3 is the subacute or chronic neuronopathic form of GD (table 1). Often, it has a later onset than GD2. However, some persons with GD3 may have onset before age two years with very slow disease progression. The distinction between GD2 and GD3 is therefore often difficult [62]. Three forms of GD3 are recognized, although there is marked overlap supporting that this is a spectrum of disease manifestations, and some authors have recommended eliminating the subclassification of GD3.

●Type 3a is characterized by progressive dementia, ataxia, and myoclonus [118]. Patients with GD3a have mild hepatosplenomegaly and earlier development of neurologic symptoms including myoclonic seizures, strabismus, and supranuclear gaze palsy. Bone involvement is variable. (See "Symptomatic (secondary) myoclonus".)

●Type 3b has extensive visceral and bone involvement with massive hepatosplenomegaly and progressive skeletal abnormalities including kyphoscoliosis and barreled chest. CNS involvement is often limited to supranuclear gaze palsy (saccade initiation failure, with compensatory head thrusting), either alone or with learning disabilities. Longitudinal neurocognitive evaluations have shown wide variability in intellectual performance, but most patients do not have a degenerative course [119]. Electroencephalograms (EEGs) often demonstrate background slowing [120]. Rarely, it is associated with a more slowly progressive neurodegenerative syndrome that can include later onset of myoclonic seizures, scanning (explosive) speech, and intellectual impairment [112,121-125]. Many of the Norrbottnian patient variant from northern Sweden, who are homozygous for the c.1448T>C allele (p.L483P variant), share this phenotype. Ophthalmologic findings in these patients include abnormalities of the vitreous, retina, cornea, uvea, conjunctiva, and eye movements. These can be varied and are challenging to diagnose and manage [126,127]. (See "Ocular gaze disorders".)

●Type 3c (cardiovascular form) is rare and characterized by supranuclear gaze palsy, cardiovascular calcification, and, in some cases, corneal opacity and/or noncommunicating hydrocephalus with little visceral and bone disease [128-131]. It is a unique phenotype associated with homozygosity for the p.D448H variant (c.1342G>C allele), usually found in populations originating from the Mediterranean basin, Jordan, or Japan [128,132,133]. Neurologic involvement can begin late, and progression is variable. (See "Ocular gaze disorders".)

PATHOLOGY FINDINGS — Macrophages filled with lipid material are known as Gaucher cells and are a cardinal feature of the disease (picture 1). Gaucher cells have a characteristic histologic appearance of wrinkled tissue paper. Membrane-bound inclusions filled with glucocerebroside are seen with electron microscopy. Gaucher cells have the protein expression profile of the so-called alternatively activated macrophage, a phenotype associated with chronic inflammation and fibrosis [134].

Neuropathologic examination of patients with GD2 reveals extensive central nervous system (CNS) abnormalities, including neuronal loss, gliosis, periadventitial Gaucher cells, free Gaucher cells, and neuronophagia [109,135]. Involvement is widespread and includes the frontal cortex, thalamus, caudate, globus pallidus, pons, and cerebellum. The finding of neuronal loss suggests that the accumulated glycolipid, glucosylsphingosine in particular, is neurotoxic [19].

LABORATORY FINDINGS — Thrombocytopenia and anemia typically are found on blood counts. Liver enzymes may be mildly elevated, and serum angiotensin-converting enzyme (ACE) is often increased [136,137]. Acid phosphatase activity, particularly the tartrate-resistant isoenzyme, is elevated. Chitotriosidase, an enzyme of unknown natural function, is secreted from lipid-laden macrophages and is elevated in the serum of patients with GD commensurate with their disease burden [138]. However, some patients have an inherited deficiency of chitotriosidase, and, in these patients, measuring CCL18/PARC may have utility in therapeutic monitoring [139]. Hyperferritinemia is common and is associated with increased liver volume and prior splenectomy [140]. The incidence of polyclonal gammopathy and monoclonal gammopathy, including plasma cell myeloma, is increased [141]. These are detected on serum protein electrophoresis and quantification of serum free light chains. Blood count abnormalities should be interpreted with caution in the presence of a paraprotein and should prompt a bone marrow examination and skeletal imaging to differentiate anemia due to GD with coexisting symptomatic myeloma.

The laboratory evaluation of GD is discussed separately. (See "Gaucher disease: Initial assessment, monitoring, and prognosis", section on 'Laboratory evaluation'.)

RADIOLOGIC FINDINGS — Imaging studies can suggest the diagnosis of GD and/or its complications [142]. Radiologic findings were found with the following frequencies among the patients that were included in the Gaucher Registry:

●The characteristic Erlenmeyer flask deformity of the distal femur caused by abnormal modeling of the metaphysis (image 1) was present in 46 percent of the registry patients [45]. Although this finding is not specific for GD, it has a limited differential diagnosis (fibrous dysplasia, Niemann-Pick disease, osteopetrosis, heavy metal poisoning).

●Fractures and lytic lesions were present on plain radiographs in 15 and 8 percent, respectively [45]. Among patients with GD1, irreversible skeletal lesions were present in 17 percent of c.1226A>G homozygotes and 26 percent of c.1226A>G compound heterozygotes [63]. These numbers may be changing with the advent of improved therapies for GD.

●Marrow infiltration was present on magnetic resonance imaging (MRI) in 40 percent of the patients who had this assessment performed [45], and bone infarction and osteonecrosis were each present on MRI in 25 percent [45].

●Osteopenia was present on dual-energy x-ray absorptiometry (DXA) in 42 percent [82].

The radiologic evaluation of GD is discussed separately. (See "Gaucher disease: Initial assessment, monitoring, and prognosis", section on 'Radiology evaluation'.)

DIAGNOSIS — The diagnosis of GD is confirmed by the finding of reduced glucocerebrosidase activity, usually in peripheral leukocytes, in a patient with clinical features consistent with GD (table 2). Mutation analysis provides additional confirmation of the diagnosis, can help with genetic counseling, and can identify undiagnosed affected family members and heterozygote carriers. Determining the genotype may also help to determine prognosis [59]. Diagnosis can be delayed in patients with nonspecific symptoms and due to lack of awareness of the disease. Scoring systems to help determine which patients to test have been designed and validated [143,144]. In addition, several diagnostic algorithms designed to evaluate persons with particular features of the disease have been tested and may result in earlier diagnosis. As an example, a diagnosis of GD1 was made in 15 out of 455 (3.3 percent) adults with splenomegaly and/or thrombocytopenia referred to Italian hematology outpatient units [145]. Laboratory findings associated with diagnosis of GD1 in this population included a lower platelet count and a higher serum ferritin level with a lower transferrin saturation.

Evaluation is directed toward assessment of disease severity and detection of concomitant conditions that can be aggravated by GD once the diagnosis is confirmed. (See "Gaucher disease: Initial assessment, monitoring, and prognosis".)

Enzyme analysis — The diagnosis of GD is usually confirmed by identifying reduced glucocerebrosidase activity in peripheral leukocytes [146]. The enzyme activity varies in each white cell type, decreasing from monocytes to lymphocytes to granulocytes. The diagnosis can also be made by measuring glucocerebrosidase activity in cultured skin fibroblasts or other nucleated cells [59,147-150] or dried blood spots [151,152].

The peripheral leukocyte assay uses an artificial substrate, 4-methylumbilliferyl-beta-glucoside. With this assay, GD1 patients generally demonstrate residual enzymatic activity (10 to 15 percent of the control enzyme activity) [146]. GD2 and GD3 patients generally have much lower activity but cannot reliably be distinguished from each other. Activity in heterozygote carriers and normal individuals shows considerable overlap. Thus, enzyme analysis cannot be used alone to distinguish carriers from noncarriers.

An ultramicro-fluorometric assay for diagnosis of GD from dried blood spots on filter paper has been developed and may facilitate diagnostic efforts in newborns and adults [153].

Mutation analysis — Targeted DNA analysis to detect the most common pathogenic variants is an effective method for confirming the diagnosis and has been used as the first-line option for carrier identification among family members. However, the failure to find a mutation in a limited panel does not exclude the diagnosis because of the heterogeneity of affected alleles. Uncommon alleles occur more often in the non-Ashkenazi than in Ashkenazi ethnic groups. DNA sequencing of the entire glucocerebrosidase (GBA1) coding region is clinically available and more reliable in patients who do not have identified family members with GD. Care must be taken to accurately characterize recombinant alleles arising from recombinant events occurring between the gene and pseudogene and to make certain that there is not an allele with more than one mutation in cis [154]. It is often recommended to genotype parents, as patients have been identified with uniparental disomy [155] and germline mosaicism [156].

Mutation analysis may help to classify patients and predict clinical findings. As an example, individuals who are homozygous for the c.1226A.G allele (p.N409S variant) may have symptoms of GD but do not have primary neurologic involvement [157]. The c.1342G>C allele (p.D443H variant) is uniquely associated with the cardiovascular and corneal involvement in GD3c [128-131].

Mutation analysis can definitively identify carriers of specific variant segregating within a family but cannot exclude carrier status among unrelated individuals, except through complete sequencing of the GBA gene.

There are several variants that can complicate genotype-phenotype studies. A 55-bp deletion in exon 9 can result in false genotype as polymerase chain reaction (PCR) primers are directed to that region [158]. Recombinant (Rec) alleles resulting from gene rearrangement between exon 9 and 10 of the functional gene and pseudogene, respectively, contain two to four point variants, including c.1448T>C. Testing for c.1448T>C variant alone does not allow detection of the Rec allele. This requires a specifically designed test that selectively amplifies the gene and not the pseudogene introns [54].

Bone marrow — The diagnosis is often made when Gaucher cells (picture 1) are detected in the bone marrow of patients who are being evaluated for splenomegaly, anemia, or thrombocytopenia, although further enzymatic evaluation is required to exclude other disorder including Niemann-Pick disease [159]. However, bone marrow studies are not necessary to make the diagnosis and are only specifically indicated for the investigation of coexisting hematologic malignancy.

Prenatal diagnosis — Prenatal diagnosis is performed by enzyme analysis of fetal cells obtained by chorionic villus sampling or amniocentesis [160]. Obtaining a skin biopsy from the proband and assaying cultured skin fibroblasts simultaneously with the prenatal sample is helpful in cases where there may be significant residual enzymatic activity. Knowledge of the DNA mutations in the proband or in the heterozygous parents allows the use of DNA mutation analysis together with enzyme analysis for prenatal diagnosis. Mutation analysis is recommended as a confirmatory assay. Preimplantation genetic diagnosis is also possible [161,162]. (See 'Genetic counseling' below and "Diagnostic amniocentesis" and "Chorionic villus sampling".)

Issues related to prenatal screening in Ashkenazi Jews are discussed separately. (See "Preconception and prenatal carrier screening for genetic disease more common in people of Ashkenazi Jewish descent and others with a family history of these disorders", section on 'Gaucher disease'.)

Newborn screening — The value of newborn screening (NBS) for GD by measuring beta-glucosidase activity on dried blood spots is a controversial topic and is under investigation, most often in multiplex assays with other lysosomal storage disease, due to the availability of enzyme therapy for these disorders. In a statewide pilot study in Illinois in the United States from November 2014 through August 2016, there were 117 positive or borderline tests for GD with 5 cases confirmed out of 219,793 infants screened [163]. The confirmed cases were asymptomatic at the time of diagnosis and are being monitored for clinical manifestations of the disease (none are on therapy). Of the remainder of the initial positive tests, 91 were determined to be normal with further testing (nearly three-quarters were born at <37 weeks gestation), 2 were undetermined, and 19 were unresolved. The last two groups of patients will also require ongoing monitoring for disease manifestations. No false-negative tests have been identified. Additional states and countries have also instituted pilot NBS studies [164].

Genetic counseling — The recurrence risk for a couple who has a child with GD is 1:4 if both parents are heterozygotes and 1:2 if one of the parents is affected and the other is a heterozygous carrier.

Prediction of disease severity based on genotype is only approximate because of the wide range of phenotypic variability. Patients sharing the same genotype, even siblings, can have vastly different symptoms and response to therapy. Thus, genetic modifiers or environmental factors probably impact the patient phenotype [50]. There are some recognized associations between disease severity and genotype [11], although this is not always the case [64]. Thus, the use of genotype-phenotype correlations in counseling should be approached with care.

When the parents are heterozygous carriers of one of the common alleles, parental genotype can provide some guidance for prenatal counseling, as indicated below [11]:

●If both parents are heterozygotes for c.1226A>G (p.N409S or N370S variant), affected children will have GD1 and will not have central nervous system (CNS) disease [165]. It is probable that the child will have a milder disease course or possibly be asymptomatic well into adulthood, but severe disease with early onset has been observed.

●If the fetus is at risk for the c.1226A>G/c.84dupG or c.1226A>G /c.1448T>C genotype, neurologic disease is not expected, but the disease course is often more severe than observed in c.1226A>G homozygotes. The median age of onset of symptoms for children with these compound heterozygote genotypes was reported as six years [166].

●If the fetus is at risk for the c.1448T>C homozygous genotype, children usually reach medical attention in the first years of life with visceral and skeletal disease and impaired oculomotor involvement, although the disease severity can be variable [10,48,50,167].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of GD depends upon the presenting symptoms and signs. Splenomegaly, anemia, and thrombocytopenia can be observed in many disorders. The chronicity of the timeframe; elevation of lysoGb1, ferritin, and chitotriosidase; and hepatosplenomegaly with concomitant bone disease are all suggestive of GD over another disorder. The evaluation of each of these findings is discussed in greater detail separately. (See "Approach to the child with an enlarged spleen" and "Approach to the child with anemia" and "Approach to the child with unexplained thrombocytopenia".)

Conditions including leukemia; lymphoma; inflammatory diseases, such as rheumatoid arthritis; or other storage diseases, such as Niemann-Pick types A, B, or C [168], often are considered in the differential. Patients with Niemann-Pick disease typically have more severe/extensive liver disease and neurologic findings. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Clinical presentation' and "Overview of Niemann-Pick disease", section on 'Classification and clinical features' and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)

Osteopenia, pathologic fractures, and bone pain are features of metabolic bone disease from a variety of causes, including rickets, vitamin C deficiency, copper deficiency, sickle cell disease, Paget disease, and a number of inherited disorders associated with kidney disease or skeletal abnormalities. Most of these disorders have characteristic clinical, radiographic, or laboratory features that distinguish them from GD. (See "Overview of rickets in children", section on 'Clinical manifestations' and "Overview of water-soluble vitamins", section on 'Deficiency' and "Overview of dietary trace elements", section on 'Deficiency' and "Overview of the clinical manifestations of sickle cell disease" and "Clinical manifestations and diagnosis of Paget disease of bone".)

Deficiency of saposin C (MIM #610539, also called atypical GD) results in a severe disorder similar to GD [169,170]. Saposin C is derived from prosaposin, which is encoded on 10q21-q22. Patients present with severe disease with or without neuronopathic manifestations, but glucocerebrosidase activity is normal in vitro. (See 'Pathogenesis' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gaucher disease".)

SUMMARY AND RECOMMENDATIONS

●Overview – Gaucher disease (GD) is the most common lysosomal storage disease. It is caused by deficiency of glucocerebrosidase (also called acid beta-glucosidase, GCase), which results in abnormal accumulation of glycolipids within cellular lysosomes. (See 'Introduction' above and 'Pathogenesis' above.)

●Genetics – GD is an autosomal-recessive disorder caused by pathogenic variants in glucocerebrosidase 1 (GBA1), located on chromosome 1q21. More than 400 distinct variants are reported. However, among Ashkenazi Jewish patients, four mutant alleles account for most cases: c.1226A>G (p.N409S), c.1448T>C (p.L483P), IVS2+1G>A, and c.84dupG. The prevalence of these alleles varies with ethnicity. The c.1226A>G variant is encountered commonly in non-Jewish Europeans and Ashkenazi Jews, whereas c.1448T>C is relatively common worldwide. Disease onset, severity, and clinical manifestations vary with the genotype, although the genotype-phenotype correlation is not entirely consistent. (See 'Genetics' above and 'Genetic counseling' above.)

●Clinical features – The presenting features of GD are variable and may occur at any age (table 2). Macrophages filled with lipid material are known as Gaucher cells and are a cardinal feature of the disease (picture 1). Thrombocytopenia, anemia, and hyperferritinemia are common. The characteristic Erlenmeyer flask deformity of the distal femur caused by abnormal modeling of the metaphysis (image 1) is seen in half of patients with GD. Although this finding is not specific for GD, it has a limited differential diagnosis. (See 'Clinical manifestations' above and 'Pathology findings' above and 'Laboratory findings' above and 'Radiologic findings' above.)

●Types of GD – GD is classified into three clinical types (table 1). The visceral organs, bone marrow, and bone are affected in all types (table 2). Type 1 (GD1) is distinguished from types 2 and 3 (GD2 and GD3) by the lack of characteristic involvement of the central nervous system (CNS). GD with neurologic involvement (neuronopathic GD) is designated as GD2 or GD3 based on the acute or chronic nature, respectively. (See 'Type 1 (GD1)' above and 'Type 2 (GD2)' above and 'Type 3 (GD3)' above.)

●Diagnosis – The diagnosis of GD is confirmed by the finding of reduced glucocerebrosidase activity in peripheral leukocytes. Diagnosis can also be confirmed by mutation analysis. Early identification leading to prompt treatment can prevent development of irreversible complications. (See 'Diagnosis' above and "Gaucher disease: Initial assessment, monitoring, and prognosis" and "Gaucher disease: Treatment".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Patrick Deegan, MD, MRCPI, FRCP, who contributed to an earlier version of this topic review.