We aimed to estimate the natural history of N370S GD in a large, predominantly Caucasian, Ashkenazi Jewish patient population. We found that the phenotype resulting from homozygosity for N370S mutation in the GBA
gene is distinct from commonly depicted features of GD in which visceral and hematologic disease predominates with variable bone involvement. N370S/N370S GD results predominantly in an adult-onset disease with a disproportionate burden of progressive skeletal disease in the absence of major visceral or hematologic involvement; a minority of patients present with the classic form manifesting as early onset-childhood disease with prominent visceral/hematologic disease and variable skeletal disease. These patients are at a striking 25–37.5-fold increased lifetime risk of developing multiple myeloma and are also at increased risk of developing other cancers. The predilection of N370S homozygous GD patients to develop progressive skeletal disease with only mild visceral and hematologic disease may contribute to diagnostic delays [21
]. Furthermore, our findings suggest that in adults with N370S/N370S GD, the risk from occult skeletal disease, multiple myeloma, and other cancers should be addressed when evaluating patients who may appear to have insignificant visceral and hematologic disease.
Two studies are frequently cited as depicting a benign course of GD. One study [20
] reported that there was no change in the severity score index (SSI) of 29 patients after 2–13 years of follow-up; 13 patients in this series were N370S homozygous and the remainder had severe genotypes, including homozygous L444P, known to result invariably in progressive and frequently, neuronopathic disease. A later study [19
] concluded that there was no progression of disease in 68 N370S homozygous GD patients followed for a mean of 2.6 years. However, this conclusion is surprisingly at variance with the finding in that study of a statistically significant increase in the SSI and significant decreases in hemoglobin and platelet counts. Despite these observations indicating progressive disease in N370S homozygous GD, the prevailing view is that it is a benign disorder of extremely low penetrance, and regular comprehensive monitoring or consideration of ERT should be given a lower priority for this group of patients [18
]. This false perception may be perpetuated by the atypical presentation we have delineated in N370S/N370S GD. Moreover failure to recognize this previously undefined presentation may contribute to diagnostic delays of many years, which could result in severe complications, a number of which are preventable or ameliorated by currently available enzyme therapy, the standard of care for GD1 [22
]. In our study, we found that nearly 25% of patients experience diagnostic delays from 1 to 30 years after the onset of symptoms. In a recent study, we found patients with N370S/N370S GD are most likely to suffer diagnostic delays associated with disabling complications, that are preventable or reversible by timely therapy [21
Our data underscore the importance of evaluating individual domains of disease activity to reliably assess the effects of GD. This approach permitted delineation of divergent manifestations of N370S GD on the viscera and hematologic profile versus the skeleton. We have found the HS to be a useful instrument to assess the diversity and severity of skeletal involvement in GD. Bone disease in GD is a complex, multidimensional process, involving osteopenia, marrow expansion, lytic lesions, avascular necrosis, fracture, and/or collapse. HS can be derived simply from plain films. Although the MR bone marrow burden score proposed by Maas et al. [26
] appears to be a sensitive tool to assess marrow disease, the advantage of the HS is that it ascertains severity of all of the diverse aspects of GD bone involvement and it may reflect the natural history of bone involvement.
Among the entire cohort, the risk of developing multiple myeloma, non-multiple myeloma hematologic malignancies, and other cancers is increased. It is of interest to note that among GD1 patients who developed cancers, the diagnosis of cancer preceded ERT in 70% of patients in keeping with many previous reports suggesting this association is an intrinsic feature of the disease in some patients. The association of GD with cancers has been reported for more than 3 decades in case-reports and small case-series [7
], but the data are not consistent, and there are no genotype correlations or natural history studies. There are numerous case reports of multiple myeloma and GD [9
]. Analysis of data of 2742 patients within ICGG Gaucher Registry demonstrated a 6-fold increased life time risk of multiple myeloma but not of other cancers [6
]. The study suffered from incomplete ascertainment since the objective of the registry is to track treatment responses, and it comprises a predominantly younger population, i.e., 65% of patients were younger than 40 years old, an age at which cancer complications are less frequent and an age at which multiple myeloma does not occur. Findings similar to the ICGG Registry were reported in a single center study [10
]. A more recent study by Landgren et al., found no increase in overall cancer risk in a cohort of 1,525 patients identified in the VA system with an ICD code for lipidosis [27
]. However, the diagnosis of GD in this study was flawed, because patients were identified based on diagnostic codes (272.2 or 272.7) that represents all lipidoses (such as primary hypercholesterolemia and all lipid storage diseases, such as Fabry disease and Niemann-Pick disease) as well as GD [27
The high incidence of sequential polyclonal gammopathy, MGUS, and multiple myeloma suggests important interactions between pathologic glycolipid-laden macrophages and the adaptive immune system in the pathogenesis of GD. This finding together with increased risk of cancers reported by us and others [7
] as well as coexistence of multiple cancers among seven patients in our study, suggest that alterations of the cellular milieu in GD create a microenvironment conducive to malignancy.
The pathways linking GD and cancer are not known, but several features of GD may offer clues to the pathogenesis of malignancy that will undoubtedly be the focus of future scientific investigations. It has been suggested that accumulation of glucocerebroside and related lipids in tissue macrophages results in chronic stimulation of the immune system and consequent lymphoproliferation including CD1d-mediated imbalances in regulatory and NKT cells [24
]. Another factor promoting malignancy in GD may be endoplasmic reticulum (ER) stress [30
]. Recent studies suggest that N370S glucocerebrosidase is likely a protein folding mutation and thus may contribute to ER stress [31
]. There are clearly several putative and likely additive or synergistic mechanisms to promote malignancy in GD.
Our findings have the potential to further improve patient monitoring and management as well as highlight areas of future scientific investigation. First, our findings underscore the importance of monitoring patients with GD for gammopathies and especially for development of multiple myeloma in patients older than 50 years. The finding of increased risk of non-myeloma hematologic malignancies and other cancers not related to GD severity emphasizes the need to have a high index of suspicion in routine monitoring adult GD patients even though their GD may appear indolent. Furthermore, our results and those of others should encourage further investigations to determine whether the carrier state for GD is a risk factor for the development of multiple myeloma. Additionally, it will be of great interest to determine whether the new generation of patients who tend to begin ERT early in the course of their GD will have an altered cancer risk.
Cancer risk data in our study of predominantly Ashkenazi Jewish patients were derived from a comparison with the US White population as well as the Israeli population. Finding valid cancer incidence rates to serve as a reference for our GD patient population or indeed for any other GD patient population is challenging. As previously stated, most cases of GD in our cohort are of Ashkenazi Jewish ancestry. This ethnic group corresponds demographically to Caucasians who are represented in the US SEER database as non-Hispanic Whites. However, this group has a variety of unique characteristics, which can influence their cancer risk estimates. Cancer rates are determined by behavioral exposures, by genetic constituents, and most likely by their combination. For example, the high prevalence of founder mutations in the BRCA gene in the Ashkenazi Jewish population leads to higher probability of developing breast cancer and to younger age at detection of this cancer [32
]. Thus, it is unclear to what degree cancer rates from the SEER program would represent the expected cancer rates in the Ashkenazi Jewish population.
To further refine our analysis, we compared cancer rates in our study to those for Jews from the National Israeli Cancer Control Center and our initial findings were confirmed. However, it is important to note that disease rates are also dictated by other parameters, such as the degree of screening and differences in health behaviors between countries. For example, the use of hormone replacement therapy in post-menopausal women and prostate specific antigen to screen for prostate cancer in Israel are much lower compared with the US (G. Rennert, unpublished observations). A comparison of cancer incidence rates between European–American born Israeli Jews and SEER non-Hispanic Whites shows the rates in the latter to be 2–3-fold higher for leading cancers, such as lung cancer and prostate cancer [33
]. Thus, such an adjustment is also imperfect.
Our study is not a prospective study. Because of heterogeneity in clinical outcomes of N370S/N370S GD and its relatively slow natural course, it is not feasible to determine an accurate natural history by prospective follow-up of a cohort of untreated patients over many years. However, despite this difficulty, it remains important to estimate the natural history for counseling, enabling optimal lifelong monitoring of disease progression, and directing costly therapies effectively. We used quantitative determination of disease severity at age of evaluation prior to commencing ERT in a cross-sectional study of consecutively evaluated patients to define the natural history of our patient population. Every patient was included and there was no selection of patients for disease severity.
In conclusion, our observational study reveals the progressive nature of GD due to N370S homozygous mutation with the brunt of the disease on the skeleton in adult patients. Uniquely, this lysosomal storage disease is associated with an increased risk of multiple myeloma and other malignancies. Adults with N370S/N370S GD should be carefully monitored for disease activity in all domains, especially the skeleton and there should be a high index of suspicion for cancers. There should be further exploration of cancer risk in GD patients representing the spectrum of genotypes, age, and disease severity, to develop an evidence-based cancer screening strategy in this population and to evaluate the eventual impact of various therapies [34
]. As with Parkinsonian syndrome [3
] and pulmonary hypertension [5
] associated with GD, the risk of cancer in individual GD patients in the clinic is low and therefore patients should be reassured. However, it is hoped that these emerging insights into the nature of GD will enhance delivery of sophisticated personalized medicine to this group of patients.