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Gaucher Disease

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

Summary

Disease characteristics.  Gaucher disease (GD) encompasses a continuum of clinical findings from a perinatal lethal disorder to an asymptomatic form. The identification of three major clinical subtypes (1, 2, and 3) and two other subtypes (perinatal lethal and cardiovascular) is useful in determining prognosis and management. 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 and thrombocytopenia, lung disease, and the absence of primary central nervous system disease. Types 2 and 3 GD 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 type 2 GD. Individuals with type 3 GD may have onset before age two years, but often have a more slowly progressive course and may live into the third or fourth decade. The perinatal-lethal form is associated with ichthyosiform or collodion skin abnormalities or with nonimmune hydrops fetalis. The cardiovascular form is characterized by calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia. Cardiopulmonary complications have been described with all the clinical subtypes, although varying in frequency and severity.

Diagnosis/testing.  The diagnosis of GD relies on demonstration of deficient glucosylceramidase enzyme activity in peripheral blood leukocytes or other nucleated cells. Carrier testing by assay of enzyme activity is unreliable because of overlap in enzyme activity between carriers and non-carriers. Identification of two disease-causing alleles in GBA, the only gene known to be associated with GD, provides additional confirmation of the diagnosis but should not be used for diagnosis in lieu of biochemical testing. Molecular genetic testing using sequence analysis identifies mutations in the majority of affected individuals.

Management.  Treatment of manifestations: When possible, management by a multidisciplinary team at a Comprehensive Gaucher Center. For persons not receiving enzyme replacement therapy (ERT) or substrate reduction therapy (SRT), symptomatic treatment includes partial or total splenectomy for massive splenomegaly and thrombocytopenia. Supportive care for all affected individuals may include: transfusion of blood products for severe anemia and bleeding, analgesics for bone pain, joint replacement surgery for relief from chronic pain and restoration of function, and oral bisphosphonates and calcium for osteopenia. Prevention of primary manifestations: ERT with imiglucerase 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. Individuals with severe GD, primarily those with chronic neurologic involvement (type 3 GD), can benefit from bone marrow transplantation (BMT). Miglustat may be indicated in symptomatic individuals with type 1 GD who are not able to receive imiglucerase. Surveillance: Recommendations for comprehensive serial monitoring have been published by the International Collaborative Gaucher Group Registry (ICGG) and other groups. Testing of relatives at risk: It is appropriate to offer testing to asymptomatic at-risk relatives so that those with acid β-glucosylceramidase enzyme deficiency, or two disease-causing alleles, can benefit from early diagnosis and treatment.

Genetic counseling.  Gaucher disease (GD) is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Targeted mutation analysis 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 N370S/N370S phenotype is variable, individuals who undergo carrier testing may be identified as being homozygous. Prenatal testing for pregnancies at increased risk is possible using assay of glucosylceramidase enzymatic activity and molecular genetic testing when two disease-causing  mutations in a family are known.

Diagnosis

Clinical Diagnosis

Gaucher disease (referred to as GD in this entry) is suspected in individuals with characteristic bone lesions, hepatosplenomegaly and hematologic changes, or signs of CNS involvement. Clinical findings alone are not diagnostic.

Testing

Assay of acid β-glucosylceramidase enzyme activity

• Affected individuals.   The most efficient and reliable method of establishing the diagnosis of GD is the assay of acid β-glucosylceramidase enzyme activity in peripheral blood leukocytes or other nucleated cells. The test is a fluorometric assay and uses the substrate 4-methylumbelliferyl-β-D-glucopyranoside. In affected individuals, glucosylceramidase enzyme activity in peripheral blood leukocytes is 0%-15% of normal activity.

  Note: The results of biochemical testing do not reliably enable prediction of disease severity or subtype.

• Carriers.   Glucosylceramidase enzyme activity is unreliable for carrier detection given the overlap in enzyme activity levels between carriers and non-carriers.

Bone marrow examination.  Affected individuals may first be suspected of having GD following bone marrow examination for GD-related manifestations (e.g., anemia, thrombocytopenia, and/or splenomegaly) [Beutler 2006]. Bone marrow examination reveals the presence of lipid-engorged macrophages ('Gaucher cells'), characterized by a fibrillary, 'crumpled silk' appearance to the cytoplasm and an eccentrically placed nucleus. This material stains positively with periodic acid-Schiff (PAS) reagent.

Note: The changes described are nonspecific, and bone marrow examination is not a reliable diagnostic test.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

Gene.   GBA is the only gene known to be associated with GD.

Clinical testing

• Targeted mutation analysis

  • Four mutations account for approximately 90% of the disease-causing alleles in the Ashkenazi Jewish population (Table 1).

  • In non-Jewish populations, the same four alleles account for approximately 50%-60% of disease-causing alleles. Non-Jewish individuals with GD tend to be compound heterozygotes with one common and one 'rare' mutation (Table 1) or a unique mutation.

  • Targeted mutation analysis for the four common mutations as well as seven rarer mutations is available on a clinical basis.

  • Note: The 55-bp deletion (exon 9) overlaps with the N370S mutation. Thus, individuals who are compound heterozygotes with N370S and the 55-bp deletion may appear to be homozygous for the N370S mutation. In practice, these individuals are recognized when parents are tested simultaneously and the N370S allele is confirmed in only one parent (except for cases of alternate paternity), and/or by specifically testing for the 55-bp deletion in all individuals homozygous for N370S.

• Sequence analysis.  Sequence analysis of the GBA coding region may be used to detect mutations in affected individuals in whom mutation analysis has identified only a single mutation.

Table 1 and Table 2 summarize molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Gaucher Disease Test Method Mutations Detected Mutation Detection Frequency by Test Method Test Availability Targeted mutation analysis Four common GBA mutations  1 89%  2 Clinical 11 GBA mutations  3 ~98% Sequence analysis GBA mutations ~99%

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

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

Testing Strategy

To confirm the diagnosis in a proband

• Assay of glucosylceramidase enzyme activity in leukocytes or other nucleated cells is the confirmatory diagnostic test.

• Molecular genetic testing and the identification of two disease-causing alleles provides additional confirmation of the diagnosis but should not be used in place of biochemical testing.

• As the diagnosis of GD can be confirmed through biochemical testing performed on peripheral blood leukocytes, it is not necessary to perform a bone marrow examination.

• Molecular genetic testing of a proband originally diagnosed by biochemical testing may be considered for genetic counseling purposes, primarily to identify the disease-causing mutations to permit carrier detection among at-risk relatives.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Genetically Related (Allelic) Disorders

No other phenotypes have been associated with GBA mutations.

Parkinsonian features have been reported in a few individuals with type 1 GD; although studies suggest a possible cause-and-effect relationship rather than mere coincidence, the underlying basis remains to be established [Tayebi et al 2001 , Bembi et al 2003]. The following findings suggest that GBA mutations and/or alterations in glucosylceramide metabolism may be a risk factor for parkinsonism [Sidransky 2005]; however, only a few cases have been identified and other factors may predispose to parkinsonian features in these individuals with type 1 GD.

• Brain pathology in a few individuals with type 1 GD (with and without parkinsonism and dementia) revealed astrogliosis as well as changes in the hippocampal regions. Brain pathology in individuals with type 2 and type 3 GD additionally revealed neuronal loss [Wong et al 2004].

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

Clinical Description

Natural History

Gaucher disease (GD), previously described as having discrete phenotypes, is now recognized as encompassing a continuum 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 spectrum 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 (Table 3).

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 (Erhlenmeyer 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 osteopenia 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 [Capablo et al 2007 , Halperin et al 2007].

Hepatosplenomegaly.   The spleen is enlarged (i.e., 1500-3000 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, Ginns et al 2000].

Liver enlargement is common, although cirrhosis and hepatic failure are rare.

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, II, VII, VIII, X, XII) [Deghady et al 2006]. Abnormal platelet aggregation may contribute to bleeding diathesis in the presence of normal platelet counts.

Pulmonary involvement.   The following can be observed:

• Interstitial lung disease

• Alveolar/lobar consolidation

• Pulmonary hypertension; 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. Pulmonary hypertension can also occur in individuals with GD without liver disease [Mistry et al 2002].

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 hypertension, pregnancy is not contraindicated in GD.

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 have an increased risk of bleeding around the time of delivery [Elstein, Eisenberg et al 2004].

In some women the diagnosis of GD is first made in pregnancy because of exacerbation of hematologic features.

Other.  Cholelithiasis occurs in a significant proportion of adults with GD (21/66 cases) [Rosenbaum & Sidrandsky 2002].

Cardiac and renal complications are rare.

Malignancy.  Epidemiologic studies have suggested elevated risk of certain malignancies in GD including the following:

• Multiple myeloma [Rosenbloom 2005]

• Hepatocellular carcinoma [de Fost et al 2006]

• Non-Hodgkins lymphoma, malignant melanoma, and pancreatic cancer [Landgren et al 2007]

Other reports have failed to find these associations.

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, Endert et al 2007 ; Langeveld, Fost et al 2007 ; Langeveld, Scheij et al 2007].

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 utility of these findings in clinical practice is undetermined [Drugan et al 2002 , Ciana et al 2003 , van Breeman et al 2007].

Psychological complications.  Persons with GD exhibit moderate to severe psychological complications including somatic concerns and depressed mood [Packman et al 2006].

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 two years of age, 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 [Harris et al 1999]. 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 [Verghese et al 2000 , Frei & Schiffmann 2002].

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). 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, Tayebi, Coble et al 2000 ; Inui et al 2001].

Cardiovascular Form

Individuals homozygous for the D409H allele present with an atypical phenotype dominated by cardiovascular disease with calcification of the mitral and aortic valves [Bohlega et al 2000]. Additional findings include mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia [George et al 2001].

Genotype-Phenotype Correlations

The amount of residual glucosylceramidase enzyme activity as measured in vitro from extracts of nucleated cells does not correlate with disease type or severity.

Genotype-phenotype correlations in GD are imperfect. Significant overlap in the clinical manifestations found between individuals with the various genotypes precludes specific counseling about prognosis in individual cases.

The following observations apply:

Type 1 GD

• Individuals with at least one N370S allele do not develop primary neurologic disease [Koprivica et al 2000].

• In general, individuals who are homozygous for the N370S mutation tend to have milder disease than those who are compound heterozygous. It is suspected that a significant proportion of Ashkenazi Jewish individuals with this genotype may be asymptomatic and thus do not come to the attention of medical professionals [Azuri et al 1998].

Primary neurologic disease

• Individuals who are homozygous for the L444P mutation tend to have severe disease, often with neurologic complications (i.e., types 2 and 3), although several individuals (including adults) with this genotype have had no overt neurologic problems. This mutation results in an unstable enzyme with little or no residual activity. In a study of 31 individuals with GD type 2, L444P accounted for 25 alleles (40%) [Stone, Tayebi, Orvisky et al 2000]. The L444P mutation occurred alone (9 alleles), with the E326K polymorphism (1 allele), and as part of a recombinant allele (15 alleles). In another study, homozygosity for the L444P mutation was the most common genotype among individuals with GD type 3 (10/24 individuals, or 42%) [Koprivica et al 2000].

• In individuals with GD and myoclonic epilepsy, Park et al (2003) identified 14 genotypes (including the mutations V394L, G377S, and N188S) previously associated with non-neuronopathic GD, and the mutations L444P and recombinant alleles that have been previously associated with neuropathic GD.

• Among Greek and Albanian individuals, a second mutation (H255Q) occurring in the compound heterozygous state with the D409H mutation has been associated with type 2 GD [Michelakakis et al 2006].

Perinatal-lethal form.  Genotypic heterogeneity is significant in this rare subset of individuals. The following has been observed:

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

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

• Compound heterozygosity for an insertion-type mutation and the missense mutation R120Q, previously reported in an individual with type 1 GD [Felderhoff-Mueser et al 2004]

Cardiovascular form.   The basis for the unique clinical features associated with this clinical form is not fully delineated.

84GG and IVS2+1

• Despite the observed allele frequencies for the mutations 84GG and IVS2+1, no live-born homozygous for either mutation has been identified. Thus, it is presumed that these genotypes are lethal.

• Children who are compound heterozygotes (i.e., 84GG/IVS2+1) have a subacute disease course with progressive pulmonary involvement and death in the first to second decade.

Other.  Although it is likely that other factors including modifier genes that influence phenotypic expression exist, none has been identified to date.

• In individuals homozygous for the N370S allele, no correlation with clinical variability was observed with polymorphisms in the gene encoding glucosylceramide (glucocerebroside) synthase (the enzyme involved in the anabolic pathway or substrate synthesis) [Beutler & West 2002].

• Non-pathogenic sequence variants have been described, but none is over- or underrepresented in individuals with severe disease as compared to those with mild disease [Beutler et al 2004].

• Certain missense mutations lead to misfolding of the enzyme protein within the endoplasmic reticulum (ER) and its degradation. Variability in the rate of retention and degradation of the defective enzyme within the ER has been shown to correlate with disease severity [Ron & Horowitz 2005]. The clinical usefulness of these observations remains to be determined.

Prevalence

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

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

• Ashkenazi Jewish, Spanish, and Portuguese (N370S)
• Swedish (L444P)
• Jenin Arab, Greek, and Albanian (D409H)

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

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

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

Saposin C deficiency or prosaposin deficiency.   Saposin C is a cofactor for glucosylceramidase in the hydrolysis of GL1. Saposin C is derived from proteolytic cleavage of prosaposin, which is encoded by a gene on chromosome 10q21-q22. 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) [Pampols et al 1999 , Qi & Grabowski 2001] or non-neuronopathic disease [Tylki-Szymanska et al 2007]. These individuals demonstrate GL1 accumulation and visceromegaly but have normal glucosylceramidase enzyme activity measured in vitro.

Lysosomal storage diseases (LSD).   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, 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 funduscopy
• 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-Calve-Perthes disease.  Osteonecrosis may be a presenting feature of GD, which should be considered in the differential diagnosis of children with suspected Legg-Calve-Perthes disease [Kenet et al 2003].

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

Hydrops fetalis may be encountered in other lysosomal storage diseases, including GM1-gangliosidosis, sialidosis type 1 (see Free Sialic Acid Storage Disorders), Wolman disease, mucopolysaccharidosis type VII (MPS VII), mucopolysaccharidosis type IV (MPS IV), galactosialidosis, Niemann-Pick disease type C , disseminated lipogranulomatosis (Farber disease), infantile free sialic acid storage disease (ISSD) (see Free Sialic Acid Storage Disorders), and mucolipidosis II (I-cell disease) [Stone & Sidransky 1999].

Myoclonic seizures are also observed in GM2-gangliosidosis , sialidosis type 1, alpha-N-acetylgalactosaminidase deficiency, and fucosidosis. In addition to the LSDs, several genetic disorders are known to be associated with progressive myoclonic epilepsy [reviewed in Delgado-Escueta et al 2001].

Management

Evaluations Following Initial Diagnosis

See Surveillance for evaluations used to establish disease severity in an individual diagnosed with Gaucher disease (GD).

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

Factors that may influence the extent of clinical testing at the time of diagnosis:

• Age
• Mode of ascertainment (e.g., family screening vs disease signs and symptoms)
• Presence/absence of primary neurologic involvement

Treatment of Manifestations

Management by a multidisciplinary team with expertise in treating GD is available at Comprehensive Gaucher Centers (see National Gaucher Foundation).

Although enzyme replacement therapy (ERT) has changed the natural history of GD and eliminated the need for splenectomy in individuals with hypersplenism, persons not receiving ERT and certain other individuals may require symptomatic treatment, including the following:

• Miglustat, the first oral agent for the treatment of individuals with mild to moderate Gaucher disease for whom ERT is not a therapeutic option (e.g., because of constraints such as allergy, hypersensitivity, or poor venous access), has been approved in Canada, countries of the European Union, Israel, Switzerland, and the US. In at least three studies, involving over 30 individuals with GD type 1, miglustat treatment resulted in a significant decrease in liver and spleen volume after six to 18 months, with clinical improvement noted over 24 months. Bone involvement and platelet and hemoglobin values remained stable or were modestly improved [Cox et al 2000 ; Elstein, Hollak et al 2004 ; Pastores, Barnett et al 2005]. An increase in bone density at the lumbar spine and femoral neck was reported to occur as early as six months after the initiation of miglustat monotherapy [Pastores et al 2007]. The most common adverse reactions noted in the clinical trials were weight loss (60% of individuals), and bloating, flatulence, and diarrhea (80%), which resolved or diminished with longer use of the product.

• Partial or total splenectomy for individuals with massive splenomegaly with significant areas of infarction and persistent severe thrombocytopenia with high risk of bleeding

• Transfusion of blood products for severe anemia and bleeding. Anemia and clotting problems unresponsive to ERT should prompt investigations for an intercurrent disease process. Evaluation by a hematologist is recommended prior to any major surgical or dental procedures or parturition [Hughes et al 2007].

• Analgesics for bone pain.  Persistent bone pain in individuals receiving ERT should prompt evaluations to exclude the possibility of a mechanical problem (e.g., pathologic fracture or joint collapse secondary to osteonecrosis, degenerative arthritis).

• Joint replacement surgery for relief from chronic pain and restoration of function (i.e., improved joint range of motion). Bone pain in individuals who have undergone joint replacement may indicate a problem with the prosthesis and the need for surgical revision.

• Supplemental treatment.  Oral bisphosphonates and calcium/vitamin D may benefit individuals with GD and low bone density [Wenstrup et al 2004].

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

Prevention of Primary Manifestations