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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Arch Intern Med. Author manuscript; available in PMC May 19, 2011.
Published in final edited form as:
PMCID: PMC3098047

Type 1 Gaucher Disease: Significant disease manifestations in “asymptomatic” homozygotes identified by prenatal carrier screening



Type 1 Gaucher Disease (GD), an autosomal recessive lysosomal storage disease, is most prevalent in the Ashkenazi Jewish (AJ) population. Experts have suggested that up to two-thirds of AJ homozygotes for the common mutation (N370S) are asymptomatic throughout life and never come to medical attention. However, there are no systematic studies of N370S homozygotes to support this presumption.


Prenatal carrier screening of 8069 AJ adults for six common GD mutations was performed. GD manifestations in 37 previously unrecognized homozygotes were assessed by clinical, laboratory and imaging studies.


Among the 8069 AJ screenees, 524 GD carriers (1:15.4) and nine previously unrecognized GD homozygotes (1:897) were identified, consistent with that expected (1:949, p=1.0). Six of these homozygotes, and 31 AJ GD homozygotes identified by other prenatal carrier screening programs in the New York metropolitan area were evaluated (aged 17-40 years). Of these, 84% were N370S homozygotes, others being heteroallelic for N370S and V394L, L444P or R496H. Notably, 65% reported no GD medical complaints. However, 49% had anemia and/or thrombocytopenia. Among the 29 who had imaging studies, 97% had mild to moderate splenomegaly and 55% had hepatomegaly; skeletal imaging revealed marrow infiltration (100%), Erlenmeyer flask deformities (43%), lucencies (22%) and bone infarcts (14%). DEXA studies of 25 homozygotes found 60% osteopenic or osteoporotic.


Contrary to previous discussions, almost all asymptomatic GD homozygotes serendipitously diagnosed by prenatal carrier screening had disease manifestations and should be followed for disease progression and institution of appropriate medical management.


Type 1 Gaucher disease (GD), is the most common lysosomal storage disease and is particularly prevalent in the Ashkenazi Jewish (AJ) population with an estimated frequency of ~1 in 1000.1 This autosomal recessive inborn error of metabolism results from the deficient activity of the degradative enzyme, acid β-glucosidase (β-Glu), and the lysosomal accumulation of its glycosphingolipid substrate, glucosylceramide (GL-1), primarily in the monocyte-macrophage cells of the liver, spleen, and bone marrow.1 Clinical manifestations include hepatosplenomegaly, anemia, thrombocytopenia, and significant bone disease.1 Enzyme replacement therapy (ERT) with a macrophage-targeted recombinant β-Glu has proven to be safe and effective in ameliorating, and even preventing, disease manifestations.2-5

The carrier frequency of GD in the AJ population has been estimated to be 1 in 14 to 18.6-8 Four Acid β-Glucosidase (GBA) gene mutations (N370S, 84GG, L444P and IVS2+1) account for ~95% of the disease-causing lesions in AJ patients.6,9 The most common mutation, N370S, a missense mutation that retains about 14% of wild-type expressed activity in vitro,10,11 is present in over 70% of the AJ Type 1 GD patients 12,13 who are either homoallelic or heteroallelic with another GD mutation.12,13 Based on data from the Gaucher Registry,14 it is estimated that ~56% of AJ GD patients are N370S homozygotes. The clinical spectrum of N370S homozygotes in the AJ population is highly variable, ranging from severely affected children with hepatosplenomegaly, pancytopenia and bone disease to adults who are asymptomatic until the 8th decade of life. 15-17Previous studies have characterized the age at diagnosis and severity of manifestations in diagnosed N370S homozygotes.12,16,17 Although some N370S homozygotes have early-onset disease, and are treated by ERT in childhood or adolescence, most are diagnosed later.17 About 32% of N370S homozygotes in the Gaucher Registry were diagnosed by age 20.17 However, the median age at diagnosis of over 1100 N370S homozygotes in the registry was 29 years,14 consistent with the slowly progressive course of the disease. In contrast, the median age at diagnosis for over 550 GD patients having the next most frequent N370S/L444P genotype was 16 years.14

Based on heterozygote frequencies of 1 in 15 to 18 for GD reported by prenatal carrier screening programs for Jewish genetic diseases,7,18,19 it is estimated that 1 in 900 to 1300 AJ individuals is homozygous for GD. It has been suggested that only one-third of N370S homozygotes come to medical attention and that about two-thirds remain asymptomatic throughout life.6,20,21 That Type 1 GD is a “low penetrant” disorder, similar to hemochromatosis,22,23 has led to discussions on the value of including GD in the disease panel for prenatal carrier screening in the AJ population.24,25, 26

Is homozygosity for the N370S genotype truly “low penetrant”24 with the majority of patients remaining asymptomatic throughout life, or will these individuals eventually become symptomatic, and require therapeutic intervention, after significant, and possibly irreversible disease has occurred? Early recognition and characterization of the natural history of N370S homozygotes would provide data for improved genetic counseling, and informed medical care, including the rationale for early therapeutic intervention. To date however, there have been no systematic studies to determine the frequency of AJ N370S homozygotes or to evaluate their clinical manifestations and progression, particularly in those that report no symptoms. Since prenatal carrier screening programs for diseases prevalent in the AJ population serendipitously detect previously undiagnosed GD homozygotes, we analyzed our experience in screening over 8000 individuals who reported that both parents and all grandparents were of AJ descent.



The study population included 8069 unrelated AJ individuals who requested prenatal carrier testing for AJ genetic diseases at our Center from 1996 to 2008. All screenees reported that both their parents and grandparents were of AJ descent. Heterozygotes and homozygotes for GD were identified by molecular studies (see below) and informed of their genetic status by a geneticist and/or genetic counselor. Homozygous individuals were offered a GD-focused clinical, imaging, and laboratory evaluation at our Center. Six of these homozygotes, and 31 AJ GD homozygotes identified by other prenatal carrier screening programs in the New York metropolitan area were evaluated. Women who were pregnant at initial assessment had radiologic studies after delivery. Informed consent was obtained from all screenees, and subsequently identified GD homozygotes gave informed consent for evaluation by a GD physician expert following a protocol approved by the Mount Sinai Institutional Review Board.

Genotype Studies

Initially, screening was performed for the four most common AJ mutations causing GD, N370S, 84GG, L444P, IVS2+1, and after 2005, V394L and R496H were added to the screening panel. DNA extraction, PCR amplification, and mutation detection were performed by multiplex allele-specific primer extension using the Tag-It AJ panel kit (Luminex Molecular Diagnostics, Toronto).

Clinical, Imaging, and Laboratory Studies

Family and medical histories, review of systems, and physical examinations were performed on all 37 homozygotes by a GD expert physician. Routine laboratory studies on all 37 homozygotes included complete blood counts, liver function tests, electrolytes and iron studies. Chitotriosidase enzyme activities and chitotriosidase (CHIT 1) genotypes were performed as previously described.27 Hepatic and splenic volumes were measured using magnetic resonance imaging (MRI) or computed tomography (CT) and converted to multiples of normal based on body weight. Bone marrow infiltration was assessed by MRI or bone marrow scans, and bone infarctions by MRI. Erlenmeyer flask deformity, lucencies and osteopenia were detected on X-ray examination. Bone mineral density (BMD) was measured using dual energy X-ray absorptiometry (DEXA).

The severity of GD manifestations was assessed using the International Collaborative Gaucher Group guidelines.27, 29 Anemia was defined as a hemoglobin value <12.0 g/dL for adult men and <11.0 g/dL for adult women. Thrombocytopenia was classified as mild, moderate, or severe when the platelet counts were 120-150 × 103/mm3, 60-119 × 103/mm3, and <60 × 103/mm3, respectively. Splenomegaly was classified as mild (<5x normal), moderate (5-15x normal), and severe (>15x normal volume). Hepatomegaly was classified as mild (<1.25x normal volume for weight), moderate (1.25-2.5 x normal volume), and severe (>2.5x normal volume).


Identification of GD Heterozygotes and Homozygotes

Prenatal carrier screening of 8069 consecutive AJ individuals (60% female), identified 524 carriers of the six Type 1 GD mutations, an overall heterozygote frequency of 1 in 15.4 (Table 1), thus predicting the frequency of homozygotes to be 1 in ~950, and the frequency of AJ couples with a 1 in 4 risk for an affected pregnancy to be ~1 in 240. The frequency of heterozygotes for the common N370S mutation was 1 in 16.8, predicting ~1 in 1130 for N370S homozygotes, or seven N370S homozygotes among the screenees. In this cohort, nine homozygotes (66% female) for the GD mutations were identified, including eight homozygous for the N370S mutation, and one heteroallelic for N370S and V394L.

Table 1
Frequency of GD heterozygotes and homozygotes among prenatally screened AJ individuals

Clinical, Imagining, and Laboratory Studies of GD Homozygotes Identified by Prenatal Carrier Screening Programs

A total of 37 previously undiagnosed Type 1 GD homozygotes were evaluated including 30 women (mean age 30.8 years, range 17 to 40 years) and seven men (mean age 28.6 years, range 21 to 36 years), reflecting the fact that in most centers women are screened first, and if heterozygous, their partners are then screened. Of these, 84% (31 of 37) were homozygous for the N370S mutation, while six were heteroallelic for N370S and either R496H (3), L444P (2) or V394L (1). Their baseline demographics, GD genotypes, clinical manifestations, and imaging and laboratory findings are summarized in Table 2.

Table 2
Clinical Manifestations of GD homozygotes at baseline evaluation

On review of systems, 24 patients (65%, mean age 31 years, range 17 to 40 years) reported no GD-related symptoms, while 13 patients (mean age 29 years, range 21 to 37 years) reported symptoms compatible with Type 1 GD. The most common symptom was easy bruisability (12 of 37; 32%); others included bone pain (3 of 37; 8%) and/or fatigue (2 of 37; 5%).

Of the 37 homozygotes, four (11%, 3 females, 1 male; mean age 30.8 years, range 21 to 36 years) were anemic on evaluation, including two women whose anemia was presumably due to their concurrent pregnancies. Sixteen homozygotes (43%) were thrombocytopenic, of which six (2 males, 4 females; mean age 29.0 years, range 21-35 years) had moderate thrombocytopenia (60,000-120,000 platelets/mm3) and one 30 year old woman had severe thrombocytopenia (<60,000 platelets/mm3).

Of the 37 homozygotes, 29 (78%) had an MRI or CT scan of the abdomen; of these, 97% (28 of 29) had splenomegaly, of which 86% (25 of 29) had mild splenomegaly (>1 to 5x normal for body weight) and 10% (3 of 29) had moderate splenomegaly (>5 to 15x normal for body weight), and 55% (16 of 29; 4 males, 12 females; mean age, 30 years, range 21-40 years) had hepatomegaly including seven (5 females, 2 males; mean age 29.7 years, range 21-35 years) who had moderately increased liver volumes (1.25-2.5x normal for body weight).

Twenty-nine homozygotes (78%, 22 females, 7 males; mean age, 30.0 years, range 17 to 40 years) had imaging studies to assess the skeletal involvement due to GD (28 had MRIs of the femur and one had a bone marrow scan). Of these, all had marrow infiltration of the spine and/or femur. Four homozygotes (4 of 29; 14%) had a bone infarction detected on MRI. Skeletal X-rays performed in 23 homozygotes revealed the Erlenmeyer flask deformity, due to failure of bone remodeling, in 43% (10 of 23) of homozygotes, lucencies in 22% (5 of 23), and osteopenia in 57% (13 of 23). Baseline bone mineral density in 25 homozygotes by dual energy X-ray absorptiometry (DEXA) (Table 2) showed low bone density at the hip, spine, and/or forearm in 60% (15 of 25); osteopenia in 52% and osteoporosis in 8% (11 females, 4 males; mean age 30 years, range 21-40 years). More patients (52%, 9 women, 4 men) had low bone density at the lumbo-sacral spine as compared to the hip (20%, 4 women, 1 man). Two women, a 31 year old with the N370S/R496H genotype and a 37 year old N370S homozygote, both had a significant fracture history including the 31 year old who had a non-traumatic fracture while pregnant. Subsequent evaluation of these two patients did not identify an endocrine cause for the bone disease. Of the seven males in our cohort, four (57%), aged 21-32 years were osteopenic indicating that early-onset osteopenia also occurs in Type 1 GD males.

Plasma Chitotriosidase Activity

This biomarker of macrophage activation30 serves as an indicator of GD severity and response to treatment.31 The plasma chitotriosidase enzymatic activity31 (normal <180 nmol/hr/ml) and CHIT 1 genotype32,33 were determined in these patients at initial evaluation, and the patients were stratified by their number of functional wild-type CHIT 1 genes as ~6% of Caucasians are homozygous and 30-40% are heterozygous for a non-functional 24 bp duplication allele.34,35 As expected, the two patients with the more severe N370S/L444P genotype had markedly elevated chitotriosidase activities (3390 and 3500 nmol/hr/ml). The plasma chitotriosidase activities in the 31 N370S homozygotes ranged from 0 (two null alleles) to 6400 nmol/hr/ml (Table 3). When stratified by the CHIT 1 genotype, 19 of the 20 N370S homozygotes with at least one wild-type allele had elevated plasma chitotriosidase activities (250 to 6400 nmol/hr/ml). Of the 12 who had significant disease manifestations and were recommended enzyme replacement therapy, the mean plasma chitotriosidase activities were 910 and 4081 nmol/hr/ml for those with one or two wild-type CHIT 1 alleles, respectively. In contrast, the mean plasma chitotriosidase activities for the 17 N370S homozygotes with milder manifestations were 599 and 1760 nmol/hr/ml for those with one or two wild-type CHIT 1 alleles, respectively. Thus, the mean baseline plasma chitotriosidase levels, classified by CHIT 1 genotypes, were higher in the group of N370S homozygotes who were subsequently recommended ERT suggesting a correlation with disease severity.

Table 3
Biomarkers of GD homozygotes at baseline evaluation


For over two decades, physician experts have suggested that up to two-thirds of AJ N370S homozygous Type 1 GD patients were asymptomatic throughout life and eluded medical attention.6,20 This presumption was based on studies that estimated the heterozygote frequency of the common N370S mutation in the AJ population to be ~1 in 14.5 to 17.5 which predicted that ~1 in 840 to 1225 AJ individuals were N370S homozygotes.12,13 However, experts in North America and Israel noted that the frequency of N370S homozygotes in their clinics was less than expected.6,12,20 Is homozygosity for N370S “benign’” or “low penetrant”?24 Are “asymptomatic” GD homozygotes essentially “normal” throughout life21 or do they have clinical manifestations that progress? Here, we addressed these issues by identifying asymptomatic N370S homozygotes diagnosed by prenatal carrier screening programs and evaluating their GD manifestations.

First, the heterozygote and homozygote frequencies were determined by testing for six common AJ Type 1 GD mutations in over 8000 AJ individuals who sought prenatal genetic carrier screening. The overall heterozygote frequency in this population was 1 in 15.4; the heterozygote frequency for the most common mutation, N370S, was 1 in 16.8, representing 92% of the GD alleles detected. Notably, the predicted homozygote frequency for the common mutations of 1 in 949 was, in fact, essentially that observed, nine previously undiagnosed GD homozygotes were detected or 1 in 897. Of these, eight were N370S homozygotes, an observed frequency (1 in 1009) which also was close to that expected (1 in 1129), based on the carrier frequency (p = 0.94). Thus, our ascertainment of AJ GD homozygotes in this population was complete.

Second, what proportion of GD homozygotes detected by prenatal carrier screening were “symptomatic or asymptomatic”? Of the 37 GD homozygotes detected by our or other prenatal carrier screening programs, 35% (13 of 37 reported symptoms consistent with Type 1 GD, including bruising, bone pain, and fatigue. As might be expected, the two previously undiagnosed N370S/L444P patients, whose genotype typically manifests in childhood,36 were both symptomatic reporting easy bruisability, had significant disease manifestations (Table 2) and were referred for enzyme replacement therapy. Notably, 65% (24 of 37) were asymptomatic for GD on review of systems, consistent with previous expert predictions of the proportion of asymptomatic patients.6,20,21 However, clinical, laboratory, and/or imaging studies of all 37 patients revealed GD manifestations ranging from mild to relatively severe at a mean age of 30 years, with the youngest, and mildest, a 17 year old N370S/N370S female who had only marrow infiltration (Table 2). Even the three patients identified with the mildest N370S/R496H genotype had disease manifestations.

Third, what are the manifestations in these previously undiagnosed homozygotes? All 37 patients had bone marrow infiltration which is evidence of GD and is the precursor of future irreversible bone involvement. Notably, of the 29 patients who had imaging studies, 43% (10 of 23) had the Erlenmeyer flask deformity, 14% (4 of 28) had a bone infarction, and 22% (5 of 23) had bone lucencies on imaging. Among the others, the manifestations ranged from splenomegaly, thrombocytopenia, anemia, marrow infiltration, bone infarctions, osteoporosis and pathologic fractures.

In post-menopausal women, osteopenia is a well-established risk factor for fracture, particularly of the hip.37 However, the relationship between osteopenia and fracture risk in young premenopausal women and in men has not been defined. The guidelines for treatment of osteopenia/osteoporosis in post-menopausal women with low BMD values are not applicable to pre-menopausal osteopenic women.38 Moreover, there are limited data on the use of standard pharmacologic therapy (e.g., bisphosphonates) in women who are planning a pregnancy. These findings highlight the need to recognize and closely monitor young GD patients with low bone mass. Bone density should be monitored annually and supplementation with calcium and Vitamin D for GD patients who are osteopenic is recommended. Early detection of disease manifestations in these patients will facilitate monitoring and therapeutic intervention prior to the development of irreversible complications.

Of the 29 GD homozygotes who had complete GD evaluations, imaging studies revealed that 97% (28 of 29) had splenomegaly and 49% (18 of 37) had abnormal hematologic values. Two women needed treatment during pregnancy due to progressive thrombocytopenia. There was no correlation between the hematologic and/or visceral involvement and the presence or severity of bone manifestations among AJ Type 1 GD patients, as previously noted.39 In fact, of our 19 patients with normal blood counts, 79% (15 of19) had imaging studies which showed varying degrees of bone involvement including two (13%) patients with bone infarcts and five (42%) with osteopenia/osteoporosis based on DEXA.

Finally, do they remain mostly “asymptomatic” throughout life or do they become the patients who are diagnosed and treated later in life as the disease progresses? Of this cohort, 21 patients continue to be followed by our center and have been evaluated annually or biannually. The oldest patient in our group was 50 years old at her last evaluation, which showed no evidence of disease progression since her initial evaluation 10 years earlier revealed mild splenomegaly and minimal bone involvement. Her plasma chitotriosidase activity was low at 564 nmol/hr/ml. Contrary to the variable progression observed over years in the other N370S/N370S homozygotes, this patient’s experience suggests that a small subset of N370S homozygotes may remain stable for years with minimal disease progression. In contrast, enzyme replacement therapy has been recommended for 13 (42%) of the N370S homozygotes who had significant disease at diagnosis or evidence of disease progression over a 9 year observation period. These results indicate that this disease genotype is not low penetrant, but manifests in adulthood and is often progressive. In fact, the later-onset of manifestations in N370S homozygotes may contribute to its diagnostic delay which may be associated with irreversible complications.40

Our findings are in contrast to those reported by Azuri et al. who suggested asymptomatic/mild patients do not require frequent monitoring.41 The fact that all 31 N370S homozygotes detected by carrier screening had GD manifestations at mid-life solves the perception about the genotype being benign. Clearly, these patients should be identified as early as possible, a likelihood if future genome (exome) sequencing becomes commonplace. A comprehensive baseline evaluation based on GD consensus recommendations should be performed to assess disease involvement for these homozygotes on an annual or biannual basis.27 Based on our experience; at least 40% will become candidates for enzyme replacement or future therapies.42,43

In summary, the evaluation of AJ GD homozygotes identified serendipitously by prenatal carrier screening revealed that these young to middle aged homozygotes actually had disease manifestations, particularly bone involvement that progressed with age in many homozygotes, often requiring therapeutic intervention. Our findings indicate that homozygosity for the common N370S mutation does not result in a benign or low penetrant disease, and emphasizes the importance of early recognition and appropriate management to minimize or prevent future irreversible disease complications.


Funding/Support: Dr. Balwani is the recipient of the NORD/Roscoe Brady Lysosomal Storage Disease Fellowship (2006-2008). This study was supported in part by a grant (M01 RR00071) for the Mount Sinai General Clinical Research Center from the National Center for Research Resources, National Institutes of Health.


Disclosures: Drs. Kornreich and Edelmann and Ms. Fuerstman report no conflicts. Dr. Balwani is a member of the International Collaborative Gaucher Group (ICGG) North American Scientific Advisory Board. Dr. Desnick is a consultant and receives a research grant and royalties for Fabrazyme for the treatment of Fabry disease from the Genzyme Corporation. He is a consultant and owns stock as a scientific founder of Amicus Therapeutics. Mount Sinai School of Medicine and the Department of Genetics and Genomic Sciences receive a grant from the Genzyme Corporation for participation in the Lysosomal Storage Disease Registry and royalties from the sale of Fabrazyme manufactured by Genzyme Corporation.


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