Gaucher Disease, Type I

A number sign (#) is used with this entry because Gaucher disease type I is caused by homozygous or compound heterozygous mutation in the gene encoding acid beta-glucosidase (GBA; 606463) on chromosome 1q22.

Description

Gaucher disease is an autosomal recessive lysosomal storage disorder due to deficient activity of beta-glucocerebrosidase. As a result of this deficiency, there is intracellular accumulation of glucosylceramide (GlcCer, glucosylcerebroside) primarily within cells of mononuclear phagocyte origin, which are the characteristic 'Gaucher cells' identified in most tissues (Jmoudiak and Futerman, 2005).

Gaucher disease is classically categorized phenotypically into 3 main subtypes: nonneuronopathic type I, acute neuronopathic type II (230900), and subacute neuronopathic type III (231000). Type I is the most common form of Gaucher disease and lacks primary central nervous system involvement. Types II and III have central nervous system involvement and neurologic manifestations (Knudson and Kaplan, 1962; Jmoudiak and Futerman, 2005).

All 3 forms of Gaucher disease are caused by mutation in the GBA gene. There are 2 additional phenotypes which may be distinguished: perinatal lethal Gaucher disease (608013), which is a severe form of type II, and Gaucher disease type IIIC (231005), which also has cardiovascular calcifications.

See also 610539 for a form of atypical Gaucher disease caused by mutation in the gene encoding saposin C (PSAP; 176801), which is an activator of beta-glucosidase.

Clinical Features

Type I Gaucher disease usually presents in childhood with hepatosplenomegaly, pancytopenia, and manifestations of bone marrow infiltration by characteristic 'Gaucher cells.' Other features include ocular pingueculae, or nodules, and dermal hyperpigmentation. There is a wide spectrum of clinical severity, ranging from affected infants to asymptomatic adults. There is no neurologic involvement in type I Gaucher disease (Goldblatt, 1988).

Choy (1988) reported a French Canadian family in which 5 sibs had type I Gaucher disease. Glucocerebrosidase activity in patients' fibroblasts was 7.5 to 15.5% of normal controls; obligate carriers had approximately 50% normal activity. The 5 affected sibs showed considerable phenotypic heterogeneity: age at diagnosis ranged from 16 to 41 years. The most severely affected patient was very anemic and thrombocytopenic, and had severe orthopedic complications, including vertebral compression, avascular necrosis of the femoral head, and pathologic fractures of long bones. The least affected male had no orthopedic complications at age 49 years and his hematologic complications had been reversed by splenectomy at age 25. There was no clear correlation between residual GBA enzyme activity in cultured fibroblasts and clinical severity.

In a retrospective study of 20 untreated Dutch patients with type I Gaucher disease, Maaswinkel-Mooij et al. (2000) found that the clinical manifestations were progressive in most patients, children as well as adults. This appeared to be in contrast with studies among Jewish patients. The results emphasized the need for regular follow-up to enable timely initiation of enzyme therapy.

Park et al. (2001) reported the clinical features and genotypes of 7 African American patients with type I Gaucher disease. Common features included hepatosplenomegaly, epistaxis, bone pain, anemia, and thrombocytopenia. All patients had moderate to severe manifestations, 4 presented before age 3 years, and all developed symptoms by adolescence. No probands shared the same genotype. The authors concluded that significant genotypic heterogeneity exists among African American patients with type I Gaucher disease, and that recombinations in the GBA gene may be common in this patient group.

Biochemical Features

Brady et al. (1965) demonstrated deficiency of the glucocerebrosidase enzyme in the spleen of patients with Gaucher disease. Wiedemann et al. (1965) found typical Gaucher cells in the bone marrow of unaffected obligate heterozygotes from 2 families with Gaucher disease. Danes and Bearn (1968) found giant fibroblasts containing metachromatic material in both affected persons and heterozygotes for the chronic noncerebral form of Gaucher disease. Beutler et al. (1971) demonstrated decreased beta-glucosidase activity in fibroblasts from homozygotes with the adult form of Gaucher disease. Heterozygotes showed intermediate levels of enzyme activity. Chiao et al. (1979) found deficiency of beta-xylosidase (see 278900) in different forms of Gaucher disease and suggested that clinical features such as severity may be related to this epiphenomenon.

Pentchev et al. (1983) found the same glucocerebrosidase crossreacting material in the spleen in all 3 types of Gaucher disease. However, enzyme activity was about 15% of normal in the adult nonneurologic form (type I) and about 2.3% in the neurologic forms (types II and III). The authors concluded that all 3 forms of Gaucher disease result from a structurally mutated enzyme with altered catalytic efficiency. Gravel and Leung (1983) found no complementation from fusion of cultured fibroblasts from the infantile and adult forms of Gaucher disease, suggesting that the 2 forms are allelic.

Using various inhibitors, Grabowski et al. (1985) found 3 distinct groups of residual enzyme activity in patients with Gaucher disease. The groups were designated A, B, and C, but did not correspond to the phenotypic groups I, II, and III. The authors concluded that Gaucher disease type I is biochemically heterogeneous; that the nonneuronopathic and neuronopathic subtypes cannot be distinguished by such inhibitor studies; and that the Ashkenazi Jewish form of Gaucher disease type I results from a unique mutation in a specific active site domain of acid beta-glucosidase that leads to a defective enzyme. With monoclonal antibodies as well as polyclonal sera, Beutler et al. (1985) could demonstrate no differences of glucocerebrosidase in types I, II, and III Gaucher disease.

Based on enzymatic and phenotypic examination of 25 families with type I Gaucher disease, Zlotogora et al. (1986) concluded that the clinical variability results from different mutations at the same locus. The authors noted that Klibansky et al. (1973) had observed differences in heat activation profiles of glucocerebrosidase in type I patients with varying phenotypic severity.

Graves et al. (1986) found normal amounts of GBA mRNA in fibroblast extracts from patients with several types of Gaucher disease, suggesting single-base gene alterations leading to the synthesis of defective enzyme. Using immunoblotting techniques, Fabbro et al. (1987) found extensive heterogeneity in the nature of the biochemical defects in the various forms of Gaucher disease.

Bergmann and Grabowski (1989) found abnormalities in the posttranslational processing of GBA in patients with Gaucher disease, but the abnormalities could not be correlated firmly with phenotype.

Because glycosphingolipids may be involved in the induction of insulin resistance, and the primary genetic defect in Gaucher disease leads to increased levels of these molecules, Gaucher patients constitute a human model to study the relationship between glucose metabolism and glycosphingolipids. In a study of 6 patients with Gaucher disease and 6 controls, Langeveld et al. (2008) found that noninsulin-mediated glucose uptake during both euglycemia nad hyperglycemia did not differ between patients and controls, but insulin-mediated glucose uptake was lower in Gaucher patients. Suppression of lipolysis by insulin tended to be less effective in Gaucher disease patients. Langeveld et al. (2008) concluded that Gaucher disease is associated with peripheral insulin resistance, possibly through the influence of glycosphingolipids on insulin receptor functioning.

Other Features

Garfinkel et al. (1982) observed an association between Gaucher disease and monoclonal gammopathy or multiple myeloma and suggested that chronic glucocerebroside accumulation may provide a stimulus to the immune system. A possible experimental counterpart is myeloma in Balb/C mice, which develops several months after the intraperitoneal injection of mineral oil.

Calcific constrictive pericarditis was described by several authors in patients with type I Gaucher disease (Harvey et al., 1969; Tamari et al., 1983). The pericardial involvement in these cases was likely related to unrecognized hemorrhagic pericarditis (Chabas et al., 1995).

Choy (1985) found increased bone serum acid phosphatase only in patients with Gaucher disease who had bone involvement. Acid phosphatase was normal in lymphocytes and cultured fibroblasts from these patients, suggesting that it was a secondary feature of the disease in which there is bone involvement and is unreliable for diagnosis.

Ross et al. (1997) noted that aggregations of Gaucher cells within pulmonary alveolar spaces and interstitium in association with bilateral diffuse pulmonary reticulonodular infiltrates had been described in patients with type I Gaucher disease. In addition, there have been rare instances of Gaucher cells occluding pulmonary capillaries, with resulting pulmonary hypertension. The hepatopulmonary syndrome, as manifested by intrapulmonary shunting and hypoxemia, may also complicate type I Gaucher disease. Ross et al. (1997) described a patient with type I Gaucher disease and pulmonary hypertension in whom they identified Gaucher cells in pulmonary capillary blood drawn from a catheter in the wedged position.

Miller et al. (2003) evaluated pulmonary involvement in 150 consecutive patients with type I Gaucher disease. Clinical evidence of pulmonary involvement was noted in 5 patients, each of whom had dyspnea, diffuse infiltrates, restrictive impairment and low single breath carbon monoxide diffusing capacity. Two of these patients underwent exercise testing and showed abnormalities consistent with lung disease. In 13 patients randomly selected from the remaining 145, physical examination, chest radiographs, and pulmonary function were normal. However, responses on exercise testing in 6 patients were consistent with a circulatory impairment. Thus, the study found that less than 5% of patients with type I Gaucher disease have clinical interstitial lung disease. In addition, Miller et al. (2003) found that some patients, without evident lung involvement, experienced limitations in physical exertion and were easily fatigued; this was attributable to impaired pulmonary circulation.

Ocular manifestations in type I Gaucher disease include white deposits in the corneal epithelium, anterior chamber angle, ciliary body, and pupil margin (Petrohelos et al., 1975; Wang et al., 2005). Fundus abnormalities include perimacular grayness and scattered white spots (Cogan et al., 1980). In a 12-year follow-up of a patient with type I GD, Wang et al. (2005) demonstrated the presence of macular atrophy and increased retinal vascular permeability.

Pathogenesis

Pandey et al. (2017) showed that activation of complement C5a (120900) and C5a receptor-1 (C5AR1; 113995) controls glucosylceramide (GC) accumulation and the inflammatory response in experimental and clinical Gaucher disease. Marked local and systemic complement activation occurred in glucocerebrosidase (GCase)-deficient mice or after pharmacologic inhibition of GCase and was associated with GC storage, tissue inflammation, and proinflammatory cytokine production. Whereas all GCase-inhibited mice died within 4 to 5 weeks, mice deficient in both GCase and C5aR1, and wildtype mice in which GCase and C5aR were pharmacologically inhibited, were protected from these adverse effects and consequently survived. In mice and humans, GCase deficiency was associated with strong formation of complement-activating GC-specific IgG autoantibodies, leading to complement activation and C5a generation. Subsequent C5aR1 activation controlled UDP-glucose ceramide glucosyltransferase production, thereby tipping the balance between GC formation and degradation. Thus, extensive GC storage induces complement-activating IgG autoantibodies that drive a pathway of C5a generation and C5aR1 activation that fuels a cycle of cellular GC accumulation and innate and adaptive immune cell recruitment and activation in Gaucher disease. Pandey et al. (2017) suggested that targeting C5AR1 may serve as a treatment option for patients with Gaucher disease and possibly other lysosomal storage diseases.

Inheritance

Based on population studies among Ashkenazi Jewish populations in Israel, Fried (1973) concluded that Gaucher disease is an autosomal recessive disorder. Homozygotes were affected with the disease.

Diagnosis

Desnick et al. (1971) demonstrated that both homozygotes and heterozygotes for Gaucher disease could be identified by chemical analysis of the sediment from a 24-hour urine collection. Individual neutral glycosphingolipids were separated by thin-layer chromatography and quantitatively estimated by gas-liquid chromatography.

By an assay of leukocyte beta-glucosidase, Raghavan et al. (1980) devised a method for identifying both heterozygotes and homozygotes.

Magnetic resonance imaging is a sensitive method for detecting bone involvement in Gaucher disease, evaluating complications such as osteonecrosis (Lanir et al., 1986).

Zuckerman et al. (2007) reviewed the outcome of screening for Gaucher disease among Ashkenazi Jewish individuals in Israel between 1995 and 2003. The carrier frequency was 5.7% in testing for 4 or 6 main GBA mutations. N370S (606463.0003) was by far the most common variant identified. Importantly, most individuals homozygous for the mild N370S mutation are mildly symptomatic or even asymptomatic (Beutler et al., 1993). Of 82 couples at risk for offspring with type 1 GD, 70 (85%) were at risk for asymptomatic or mildly affected offspring, and 12 (15%) were at risk for moderately affected offspring. Prenatal diagnosis performed in 68 pregnancies detected 16 fetuses with GD. Pregnancies were terminated in 2 (15%) of 13 fetuses predicted to be asymptomatic or mildly affected and in 2 (67%) of 3 fetuses with predicted moderate disease. There were significantly fewer pregnancy terminations (1 of 13) in couples who consulted with a GD expert in addition to genetic counseling compared to those who had not consulted with a GD expert (3 of 3). Two of the 3 terminations performed in the group without medical consult were homozygous for N370S. In an accompanying editorial, Beutler (2007) commented that carrier screening for Gaucher disease may do more harm than good given the extreme phenotypic variability and the inability to predict disease severity, especially in those with the common N370S mutation who may remain asymptomatic. Beutler (2007) recalled a 72-year-old patient with Gaucher disease who had low levels of enzyme activity but remained asymptomatic (Beutler, 1977).

In a review of the molecular genetics of Gaucher disease, Hruska et al. (2008) noted that most GBA mutations can be found in patients with various forms of the disorder. The phenotype is mainly determined by the combination of mutations on both alleles; thus the prediction of phenotype from genotypic data has limited utility. In addition, it has become increasingly difficult to categorize patients into 1 of the 3 classic types of Gaucher disease, indicating that the phenotypes fall into a continuum, with the major distinction being the presence and degree of neurologic function.

Clinical Management

Most patients with type I Gaucher disease require splenectomy for management of thrombocytopenia and anemia; however, splenectomy is often followed by an increase in bone involvement, with osteolytic lesions within a few months of surgery (Ashkenazi et al., 1986). Partial splenectomy has been advocated with the dual goals of minimizing the deleterious effect on bone and avoiding postsplenectomy sepsis (Rubin et al., 1986).

Goldblatt et al. (1988) reported that of 8 patients with Gaucher disease treated with 15 total hip arthroplasties, 11 (73%) remained fully mobile and asymptomatic with a follow-up time of up to 14 years after surgery.

Wang et al. (2011) described the ACMG standards and guidelines for the diagnostic confirmation and management of presymptomatic individuals with lysosomal storage diseases.

Gene Therapy

In vitro, Sorge et al. (1987) reported complete correction of the enzyme defect in fibroblasts from patients with type I Gaucher disease after retroviral-mediated GBA gene transfer. Fink et al. (1990) demonstrated that retroviral gene transfer could be used to correct the GBA deficiency in primary hematopoietic cells from patients with Gaucher disease. Correction was achieved in the progeny of transduced hematopoietic progenitor cells. Nolta et al. (1992) demonstrated that retroviral vectors can efficiently transfer the GBA gene into long-lived hematopoietic progenitor cells from the bone marrow of patients with Gaucher disease and express physiologically relevant levels of enzyme activity.

Starzl et al. (1993) reported that liver transplantation in a patient with type I Gaucher disease resulted in dramatic reduction in the lymph node deposits of glucocerebroside. They concluded that microchimerism corrected the metabolic abnormality.

See also ANIMAL MODEL section below.

Enzyme Replacement Therapy

Barton et al. (1990) found that weekly intravenous infusions of macrophage-targeted human placental glucocerebrosidase resulted in clinical improvement in a patient with type I Gaucher disease. Sequential deglycosylation of the oligosaccharide chains of the native enzyme were used to yield a mannose-terminated preparation that is specifically bound by lectin on the membrane of macrophages. Twenty-week treatment resulted in increased hemoglobin, increased platelet count, and radiographic evidence of skeletal improvement. Barton et al. (1991) reported clinical improvement with intravenous infusion of macrophage-targeted enzyme therapy in 12 patients with type I disease. Serum hemoglobin concentration increased in all 12 patients, platelet count increased in 7, serum acid phosphatase decreased in 10, and plasma glucocerebroside level decreased in 9. After 6 months of treatment, splenic volume decreased in all patients, and hepatic volume in 5. Early signs of skeletal improvement were seen in 3 patients. The enzyme infusions were well tolerated, and no antibody to the exogenous enzyme developed.

Economic and other societal aspects of the use of modified glucocerebrosidase, alglucerase ('Ceredase'), in the treatment of Gaucher disease were discussed by Beutler et al. (1991) and Zimran et al. (1991). Theoretical considerations suggested to Figueroa et al. (1992) that more frequent administration might be more efficient. A series of 7 letters beginning with one by Moscicki and Taunton-Rigby (1993) discussed the economics and related aspects of alglucerase therapy. Ceredase, derived from human placental tissues and produced by Genzyme Corporation of Cambridge, Massachusetts, was approved by the Food and Drug Administration in 1991. In mid-1994, the FDA approved a recombinant alternative to Ceredase, Cerezyme, which is also produced by Genzyme (Fox, 1995). From a retrospective analysis, Kaplan et al. (1996) noted that in most children with type I Gaucher disease with subnormal growth velocity, adequate alglucerase (Ceredase) treatment resulted in growth velocity improvement.

In a review of 1,028 Gaucher patients treated with macrophage-targeted enzyme replacement therapy for 2 to 5 years, Weinreb et al. (2002) found improvement in anemia, thrombocytopenia, organomegaly, bone pain, and bone crises.

Hollak et al. (1994) observed a very marked increase (more than 600-fold) of chitotriosidase (CHIT1; 600031) activity in the plasma of 30 of 32 symptomatic patients with type I Gaucher disease. Chitotriosidase activity declined dramatically during enzyme supplementation therapy, suggesting that it could be used as a biomarker of therapeutic efficacy. In contrast, 3 GBA-deficient individuals without clinical symptoms had only slight increases in chitotriosidase. The authors considered it unlikely that chitotriosidase itself contributes to the clinical presentation of Gaucher disease. Hollak et al. (1994) suggested that the macrophages loaded with glucosylceramide in Gaucher disease are the main source of the plasma CHIT1 enzyme activity.

Approximately 6% of Caucasians have chitotriosidase deficiency (614122) without clinical symptoms. Grace et al. (2007) noted that the identification of CHIT1 gene mutations that alter plasma chitotriosidase activity is important for the use of this biomarker to monitor disease activity and therapeutic response in Gaucher disease. The authors thus genotyped the CHIT1 gene in 320 unrelated patients with Gaucher disease, including 272 of Ashkenazi Jewish descent. Among all patients, 4% and 37.2% were homozygous and heterozygous, respectively, for a common 24-bp duplication in the CHIT1 gene (600031.0001) that results in decreased enzyme activity. In addition, Grace et al. (2007) identified 3 novel mutations in the CHIT1 gene (600031.0002-600031.0005) in individuals with Gaucher disease and chitotriosidase deficiency. The findings were important for use and interpretation of plasma chitotriosidase activity in patients with Gaucher disease.

Chemical Chaperone Therapy

Some lysosomal storage diseases appear to be caused by lysosomal enzyme variants that retain catalytic activity but are predisposed to misfolding or mistrafficking in the cell (Berg-Fussman et al., 1993). The use of chemical chaperones to template proper folding within the secretory pathway, prevent postsecretory misfolding, or stabilize proteins with a predilection to misfold is well documented (Morello et al., 2000). Pursuant to experience in Fabry disease (301500), Sawkar et al. (2002) found that addition of subinhibitory concentrations of the GBA inhibitor deoxynojirimycin (NN-DNJ) to fibroblasts in vitro resulted in a 2-fold increase in the activity of the N370S mutant (606463.0003) GBA enzyme. The increased activity persisted for at least 6 days after withdrawal of the putative chaperone. The same chaperone increased wildtype beta-glucosidase activity, but not that of the L444P mutation (606463.0001). Beta-glucosidase was stabilized against heat denaturation in a dose-dependent fashion. Sawkar et al. (2002) proposed that NN-DNJ chaperones beta-glucosidase folding at neutral pH, thus allowing the stabilized enzyme to transit from the endoplasmic reticulum to the Golgi, enabling proper trafficking to the lysosome. Importantly, a modest increase in beta-glucosidase activity seemed to be sufficient to achieve a therapeutic effect.

Steet et al. (2006) found that the iminosugar isofagomine (IFG), an active-site inhibitor of beta-glucosidase, facilitated the folding and transport of newly synthesized mutant N370S GBA from the endoplasmic reticulum to lysosomes. IFG increased beta-glucosidase activity approximately 3-fold in N370S fibroblasts and the enzyme showed some altered kinetic properties. Although IFG inhibited the enzyme in situ, washout of the drug resulted in full recovery of enzyme activity by 24 hours.

Substrate Reduction Therapy

Pastores et al. (2005) reported results from treatment with N-butyldeoxynojirimycin (NB-DNJ; Miglustat), an inhibitor of glucosylceramide synthase (UGCG; 602874), in 10 adult patients with type I Gaucher disease. Treatment over 24 months resulted in decreased liver and spleen volumes and clinical improvement. Bone involvement and platelet and hemoglobin levels remained stable and the treatment was well tolerated.

Bone Marrow Transplantation

Ringden et al. (1995) reported experience with allogenic bone marrow transplantation (BMT) in 6 patients, ranging from 2 to 9 years, with severe Gaucher disease in Sweden. The donors were HLA-identical sibs in 4 cases, the father with 1 incompatible HLA antigen in one case, and an HLA-A, -B, and -DR-identical unrelated donor in the sixth case. Among the donors, 3 were heterozygous for glucocerebrosidase and 3 were healthy homozygotes. Before transplantation, 4 patients underwent total splenectomy and 2 had partial splenectomy. In the former, 1 of the 4 patients developed pneumococcal meningitis. In the group with partial splenectomy, transfusion requirements were increased. The parental graft was rejected, but 4 of 5 other patients had donor enzyme levels from 2 to 11 years after BMT. Two patients became mixed chimeras with approximately 40% of donor erythrocyte markers for 1 and 80% for the other. One of these had low enzyme activity in his lymphocytes, but the clinical outcome was excellent. Gaucher cells disappeared from the bone marrow and liver size normalized or decreased within 2 to 3 years after BMT. All patients with engraftment had a growth spurt. Ringden et al. (1995) suggested that if an HLA-compatible donor is available, BMT is the treatment of choice in advanced Gaucher disease.

Molecular Genetics

Tsuji et al. (1987) identified an L444P substitution in the GBA gene (606463.0001) in patients with Gaucher disease types I, II, and III. All 4 patients with type I disease had the mutation as a single allele and were presumably compound heterozygous with another unidentified pathogenic GBA mutation.

In 3 unrelated Ashkenazi Jewish patients with type I Gaucher disease, Tsuji et al. (1988) identified a homozygous mutation in the GBA gene (N370S; 606463.0003). Further studies showed that 15 of 21 additional type I patients had 1 allele with this mutation. The N370S mutation was not identified in patients with the type II or type III phenotype. One patient with type I disease was compound heterozygous for N370S and L444P.

Among 62 Ashkenazi Jewish patients with Gaucher disease, Zimran et al. (1991) found that N370S represented 73% of the 124 mutant alleles, making N370S the most common mutant GBA allele among Ashkenazi Jewish patients with type I disease.

Population Genetics

Choy et al. (1987) described a method for identification of the carrier state in French Canadians.

In 1982, approximately 20,000 cases of Gaucher disease were reported in the United States. Over two-thirds of these persons were of Ashkenazi extraction (Brady, 1982).

By examination of glucocerebrosidase activity in leukocytes of a series of blood donors, Matoth et al. (1987) estimated the frequency of carriers among Ashkenazi Jews in Israel as 4.6%. This figure was in close agreement with the carrier rate of 4% estimated from the number of known cases of Gaucher disease in Israel.

Zimran et al. (1991) estimated the total gene frequency for Gaucher disease among Ashkenazi Jews to be 0.047, which is equivalent to a carrier frequency of 8.9% and a birth incidence of 1 in 450.

Among 593 unrelated normal Ashkenazi Jewish individuals, Zimran et al. (1991) identified 37 heterozygotes and 2 homozygotes for the N370S mutation, yielding an allele frequency of 0.035. Among 1,528 Ashkenazi Jewish individuals, Beutler et al. (1993) identified 87 heterozygotes and 4 homozygotes for N370S, yielding a frequency of 0.0311; pooling with data reported by Zimran et al. (1991) yielded a frequency of 0.032 for the N370S allele. Beutler et al. (1993) found that 10 of 2,305 normal Ashkenazi Jewish individuals were heterozygous for the 84GG insertion mutation (606463.0014), yielding an allele frequency of 0.00217. The authors found that the ratio of N370S to 84GG was higher in the general Jewish population than in the patient population, which was presumably due to the fact that N370S homozygotes may have late-onset disease or no significant clinical manifestations at all. To bring the gene frequency in the patient population into conformity with the gene frequency in the general population, nearly two-thirds of persons with a Gaucher disease genotype would be missing from the patient population, presumably because their clinical manifestations were very mild.

Both Tay-Sachs disease (TSD; 272800) and Gaucher disease have a high frequency in the Ashkenazi Jewish population, reaching a frequency of about 1:29 for TSD carriers and 1:16 for Gaucher disease carriers. By comparing the frequencies of the common GBA N370S mutation among carriers of the common TSD mutation, 1277TATC (606869.0001), and in the general Ashkenazi population, Peleg et al. (1998) determined that carriers of both diseases do not possess additional evolutionary advantage over single mutation carriers. The frequency of GD carriers among 308 TSD heterozygotes was 1:28, which is about half that expected (p = 0.03). The authors concluded that one or both mutations arose relatively recently in different regions of Europe and had not yet reached genetic equilibrium.

Rockah et al. (1998) found linkage disequilibrium between the 2 common Ashkenazi Gaucher disease mutations N370S and 84GG and polymorphic sites in the PKLR gene (609712). One hundred of 104 (96%) alleles carrying N370S also carried the A1 allele of the PKLR gene, which was present in only 6.7% of the control population, yielding a calculated linkage disequilibrium of 0.957. The mutation 84GG was found to be associated uniquely with the PKLR A6 allele, with a linkage disequilibrium of 1.00. These results suggested that the N3670S and 84GG mutations each originated in a single founder in the Ashkenazi Jewish population. Thus, founder effect followed by genetic drift rather than an evolutionary advantage for heterozygotes best explains the high frequency of these mutations in Ashkenazi Jews.

Despite considerable uncertainty about the demographic history of Ashkenazi Jews and their ancestors, Slatkin (2004) considered available genetic data to be consistent with a founder effect resulting from a severe bottleneck in population size between 1100 A.D. and 1400 A.D. and an earlier bottleneck in 75 A.D., at the beginning of the Jewish Diaspora. Slatkin (2004) concluded that a founder effect could account for the relatively high frequency of alleles causing 4 different lysosomal storage disorders, including Tay-Sachs disease and Gaucher disease, if the disease-associated alleles are recessive in their effects on reproductive fitness.

History

Type I Gaucher disease was first described in a doctoral thesis by Gaucher (1882) as a nonleukemic splenic epithelioma (Goldblatt, 1988). Brill et al. (1905) first used the eponym 'Gaucher disease.'

Although Gaucher disease is clearly autosomal recessive, a dominant form was suggested by Hsia et al. (1959) on the basis of affected father and son. The father was German-Jewish and the mother Swedish-English. The mother may have been a carrier; this quasi-dominant mechanism is even more likely in reports of presumed dominant inheritance in Jewish groups where the frequency of the Gaucher disease is relatively high.

Animal Model

Enquist et al. (2006) used the Cre/loxP system to conditionally delete exons 9-11 of the Gba gene in mice after birth. The mice were viable, demonstrated deficiency of glucocerebrosidase, and developed splenomegaly and microcytic anemia similar to type I Gaucher disease, including infiltration of Gaucher cells in the bone marrow, spleen, and liver. Both bone marrow transplantation and gene therapy with a retroviral vector prevented the disease and corrected an already established Gaucher phenotype. Both therapies resulted in increased Gba activity and decreased numbers of Gaucher cells 5 to 6 months after treatment.