Rare Disease Report

Zachary Spigelman, MD: Ashkenazi vs Non-Ashkenazi Populations

FEBRUARY 05, 2016

Now we have more aggressive screening of young Ashkenazic, both couples and Jews for many disorders, Tay-Sachs, Canavan’s disease, things like that. But we’re finding with that, it’s the Ashkenazic Jew that is really not known, in other words, there’s a great deal of Ashkenazic/non-Ashkenazic mixture now that is missed. So it’s important to go back three generations in the family history to identify to see if that’s the case. The workup should be an initial, either blood spot test, which is quite simple and straightforward, which is literally blood on a paper to be sent in or glucocerebrosidase assays through blood samples sent to local labs to make sure that there isn’t a deficiency. However, the carrier rate with genetics in the Ashkenazic is as high as 1 in 12, and that means 1 in 12 patients will be carriers for this deficiency. Therefore, you can have a very frequent diagnostic presentation in the Ashkenazic group.
Now, what’s unknown is really I think the denominator in the non-Ashkenazic and that’s where this algorithm comes into play. And the algorithm actually was a thought by initially, Pram Mistry and Maria Cappellini, that enlarged spleens would be a much better approach to looking and diagnosing early disease than just waiting for the symptoms.1 And it turns out, their initial studies in Europe were right. The lead author on the paper is Dr. Motta, who looked at patients presenting with large spleens to hematologic clinic.2 And, of those patients, she found 196 patients and did blood spot tests which initially showed about 34 positives which when assayed in detailed, showed seven true deficiencies or seven cases of Gaucher’s. Now, the math suggests that taking non-Ashkenazic population, the frequency of disease is 1 in 40,000. Well, here you found in a splenomegalic population, 7 in 196 or about 3-4%.
The key to that is two-fold. One is clearly you’ve not only diagnosed seven, you’ve diagnosed seven families, and therefore you are going to find the issues and prevent problems, bony pain, stunting of growth, thrombocytopenia, and really a lot of fatigue with this disease which makes life miserable. However, the second part is this is truly a change in paradigm, which looks at how can we look at and screen for rare disorders and actually enrich the population so we can get to the therapies quicker. And here it takes a simple clinical test which is examining the spleen. And I’m advocating that we actually teach medical students to use ultrasound machines, which are very common, to do their examination and show the spleen enlargement because many people cannot actually do a good spleen exam or don’t have the time to. And in doing so, really have the true denominator for this.
The other lesson here learned is that this was a non-Ashkenazic population, basically. And here was a group that we never thought would have come up with as frequent a diagnosis. If we take each of those sentinel ideas in terms of their physical exams, or clinical symptoms, or clinical presentations and start to learn how to screen for each of the rare disorders earlier, we are going to be able to then call them out, focus, and get them treated earlier and prevent hopefully long-term disease.
What’s interesting is I think there’s going to be a lot of findings for the carrier stage. Very similarly, work with other lysosomal disorders, we found that patients who were supposed to have specifically a male disorder, the females were mimicking many of their symptoms and needed the same therapy. But in identifying that carrier state, we then identified a family as well. So, in the future, what I believe a lot of both international disease and American disease  are small snippets of phenotypic changes in their genetic background, decreases in enzymes which cause people to feel symptoms and result in more rapid cardiac disease, more frequent malignancies, just as myeloma is more frequent in Gaucher’s disease, and we’re going to be able to address it directly rather than having patients come in, leave undiagnosed, but know that it’s not a lethal disease immediately. I think eventually it will affect their mortality, but this has yet to be proven. But I think this study underlines that fact.


1. Mistry PK, Cappellini MD, Lukina E, et al. A reappraisal of Gaucher disease-diagnosis and disease management algorithms.  Am J Hematol. 2011;86(1):110-115.
2. Motta I, Filocamo M, Poggiali E, et al. A multicenter observational study for early diagnosis of Gaucher disease in patients with splenomegaly and/or thrombocytopenia. . Eur J Haematol. 2015. doi: 10.1111/ejh.12596. Epub ahead of print.

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