Experts in medical genetics often talk about a "founder effect." This refers to a genetic trait or disease that has a high frequency in a contemporary population, because the gene was introduced by a founder into a small, often geographically or socially isolated group of people whose numbers then rapidly expand. For hundreds of years, the Ashkenazic Jews of Germany and middle and eastern Europe experienced sudden periods of population contraction (Crusades, pogroms, holocaust) followed by concentration in restricted areas (ghettos, Pale of Settlement) where, like their ancestors in Goshen, the Jewish people temporarily multiplied to large numbers. It is therefore not surprising that the Jewish people, when dispersed and scattered, and dwelling in small, isolated pockets among foreign nations, have become susceptible not only to assimilation and persecution, but also to a variety of hereditary genetic illnesses. Without any thought of exonerating the assailants, theologians might interpret the history of Ashkenazic Jewry not as the "founder effect," but rather as the "Founder" effect recounted in the Torah as the price to be paid for sins of rebellion and senseless hatred. "The L-rd will multiply plagues to afflict you and your descendants with severe recurring illnesses, pernicious persistent sickness." (Deuteronomy 28:59) The Biblical commentator Rashbam comments on the word ne'emanim: prolonged, self-perpetuating, from generation to generation. This surely must refer to genetic disease!

In 1894, the Dreyfus affair shook the Jewish world and put to permanent rest the illusion that western culture could suppress that most intractable of hereditary, psychosocial diseases, namely anti-Semitism. Subsequently, and within our lifetimes, the Jewish people have suffered all of the pain and suffering depicted in the Biblical admonitions. Contemporaneously, we have also identified a number of hereditary, genetic disorders that are particularly prevalent in various Jewish sub-populations. Among Ashkenazic Jews, the most common of these is Gaucher Disease (pronounced go-shay) which, coincidentally or otherwise, was first described in Paris, in 1882, just twelve years before Dreyfus.

What is Gaucher Disease?

Gaucher Disease is named for the young French medical student who first described the disorder (which he mistook for a malignancy) in a 32 year old woman with an enlarged liver and spleen. Nearly half a century elapsed before the true nature of Gaucher Disease as a metabolic storage disorder began to be understood. In 1934, a complex, fatty substance called glucocerebroside was isolated from the swollen spleen of a Gaucher patient. In 1965, my mentor, Dr. Roscoe Brady and his co-workers proved that the accumulation of glucocerebroside is due to the hereditary deficiency of a single essential enzyme called glucocerebrosidase.

What's so important about glucocerebrosidase?

Special cells in the body called macrophages remove worn-out cells and other unwanted debris by degrading them to simple molecules for recycling. This digestive process takes place in a cell compartment called a lysosome. The enzyme glucocerebrosidase is 1ocated within lysosomes, and is responsible for breaking down glucocerebroside which comes from membranes of senescent red and white blood cells. People with Gaucher Disease lack the normal form of glucocerebrosidase, and are unable to digest glucocerebroside, which then accumulates within the macrophage. The enlarged, swollen macrophages, engorged with the undigested fatty material, have a characteristic microscopic appearance. They are called Gaucher cells, and for many years, the diagnosis was dependent on finding the hallmark cells in the liver, spleen, and bone marrow. As more and more Gaucher cells accumulate, they crowd the normal liver, spleen and bone marrow cells, leading to swelling of organs, disruption of the bone marrow and of the blood cells normally produced therein, and contribute to the destruction of the bones that house the diseased marrow.

How is the body affected?

Although Gaucher cells may be in any organ, they are most numerous in those body organs in which macrophages are most active: the liver, spleen, bone marrow, and lungs. In Type I Gaucher Disease, which is the most common variant, the brain is not involved and neuromental development is normal. Types II and Ill occur much more rarely, and to no greater extent among Jews than among the general population. Both these variants are associated with neurological deterioration and dysfunction. Type II disease, also referred to as the infantile variant, is particularly devastating and invariably fatal within the first two years of life. Although reminiscent of Tay-Sachs disease, it is unrelated.

Even with the more commonly encountered Type I Gaucher Disease, which may be present in as many as one in every 600 Ashkenazic Jews, patients differ greatly as regards the age of onset and severity of symptoms. We don't fully understand the reason for this variability, which can be striking even among affected siblings. We know that Gaucher Disease is associated with a number of different genetic mutations and that the type of mutation does, to some extent, influence the physical manifestations of the disease. However, even among people with the same genotype, the clinical picture can differ dramatically.

Let me tell you about some typical patients. There is Rivka who, when 3 years old, is found to have a large liver and spleen by the pediatrician. By age 6, she's very small for her age, and has a large protuberant belly, spindly arms and legs, and multiple bruises. Kids give her a hard time because she's always too tired to play and she looks weird. Then there's 11 year old Reuven and his 15 year old brother, Shimon. Reuven looks a lot like Rivka, and isn't much taller. He misses lots of school days because his arms and legs always hurt. Shimon, since his Bar Mitzvah, has been in the hospital twice with high fever and severe excruciating pain in a red, swollen leg (a bone crisis). Yaakov has had aseptic necrosis, or bone death, of both hips, and walks with a marked limp. Rachel, now 29 years old, had delayed onset of puberty and repeated severe nosebleeds. In 1981, her spleen was removed. The bleeding stopped, but she then developed collapse of the hips and had unsuccessful hip replacement surgery. She now spends most of her time in a wheel chair and has never had children. Dina, on the other hand, also had a splenectomy during her first pregnancy. She delivered uneventfully and has two other children. However, at age 36, she fractured her distal femur near the knee. Repeated surgery and attempted knee replacement failed because of the development of chronic infection, and her knee continues to drain. She gets around on crutches, and is a very successful counselor for abused women.

There's 52 year old Dr. Shtarker who learned that he had Gaucher Disease when he failed his army physical. Although his bone x-rays were abnormal, he always insisted he felt fine, until he fell playing racquetball and fractured his thigh. Mrs. Miltz first found out she has Gaucher Disease at age 65. Her spleen is slightly enlarged, but except for aches and pains that she blames on arthritis, she feels great. Mr. Eli was also in his late 60's when he was diagnosed. His platelet count was quite low, but he changed little over ten years of observation. One day, on his way to a card game, he tripped and fell on his head. He began to bleed around the brain and was taken to surgery. Because the neurosurgeon couldn't stop the bleeding, he had an emergency splenectomy. Unfortunately, although his blood counts are now normal, Mr. Eli never regained full mental acuity, and is now in a nursing home. Finally, there's Moshe who made a point of never going to the doctor. At age 80, he developed a mild speech problem, which the doctor attributed to a large hemangioma of the lip. Serendipitously, he was found to have a slightly' enlarged spleen and Gaucher Disease was diagnosed. His blood counts are barely abnormal, and he continues fully active as a condo politician and senior handball champion.

In truth, every individual Gaucher patient has a unique story. Given the degree of clinical variability, it should not be surprising that the management of Gaucher Disease presents a significant challenge in diagnosis, prognosis, and treatment. In fact, we suspect that there are significant numbers of Ashkenazic Jews with Gaucher Disease who are yet to be diagnosed.

How do you get Gaucher Disease?

Gaucher Disease is an inherited disorder, passed on from parents to children by the transmission of an abnormal gene. Genes contain the blueprints that the body's cells use to produce proteins and enzymes. An individual normally inherits one copy of each gene from each parent. Therefore, each cell contains two genes capable of directing the production of an enzyme such as glucocerebrosidase. In an inherited, recessive disorder such as Gaucher Disease, if a person is endowed with at least one normal gene, from either parent, that person will manufacture sufficient enzyme to lead a perfectly normal life. However, that healthy person with one normal and with one abnormal gene can still pass that abnormal gene to his children. That is why such an individual is cal led a "carrier."

Should two carriers marry and have children, there is a 25% chance that a child will have Gaucher Disease. There is also a 25% chance that the child will be normal and have two normal genes. The odds are 50% that the child will be another carrier. Remember, though, that we are discussing probabilities. In real life, it's possible, but unlikely, three children in a row could have Gaucher Disease. The more children one has, of course, the greater is the likelihood that the distribution will approach the predicted proportion.

If a carrier marries someone with Gaucher Disease, the odds of having a Gaucher child rise to 50%. In this marriage, all the children who do not have Gaucher Disease must be carriers. On the other hand, if a carrier marries a genetically normal person, no child will be born with Gaucher Disease, but 50% of the children will likely be carriers. Should two Gaucher patients marry and have children, all will be born with Gaucher Disease.

How many people have Gaucher Disease?

Although Gaucher patients may be found among all ethnic and racial groups, it is very rare in the general population, occurring in fewer than one in 50,000. Among Ashkenazic Jews, however, the frequency is much greater. As many as one in every 600 Ashkenazic Jews is believed to have some form of Gaucher Disease, and the frequency of the carrier state may be as great as one in 15-20, far greater than that of Tay-Sachs disease. Does that mean that we should encourage mass screening programs for Gaucher Disease similar to those which have been so successful in combating the transmission of Tay-Sachs? Most geneticists think not, especially because type I Gaucher Disease is almost never fatal at an early age and is often compatible with a long and productive life. Furthermore, unlike Tay-Sachs disease, an effective treatment is available for symptomatic Gaucher patients. However, it is advisable for family members and relatives of known Gaucher patients to be tested for carrier status. A simple blood test is all that is required. Appropriate diagnostic tests for Gaucher Disease should be offered to all relatives of Gaucher patients who have clinical findings that are associated with Gaucher Disease.

How is Gaucher Disease diagnosed?

Diagnosing Gaucher Disease is not always straightforward as some symptoms may resemble other diseases such as arthritis or even leukemia. When Gaucher Disease is suspected, the diagnosis can be established by a blood test showing a decreased activity level of glucocerebrosidase in white blood cells. Nowadays, it is rarely necessary to require a bone marrow sample purely for diagnostic purposes. Diagnostic testing for Gaucher Disease is easily available throughout the United States, Israel, and Western Europe. A number of Gaucher treatment centers work with the National Gaucher Foundation to provide free testing for individuals who are at risk for or suspected as having Gaucher Disease. Further information about treatment centers as well as recommendations for assessing the extent of disease and for monitoring the progress of the disease and the response to treatment is available at

Treatment of Gaucher Disease

Until 11 years ago, there was no specific treatment for Gaucher Disease and therapy was aimed solely at palliating symptoms: analgesics for bone pain, orthopedic surgery and insertion of prosthetic devices for bone deformities and fractures. Severe anemia was treated with blood transfusions and painful splenic enlargement by removal of the spleen. For patients with severe disease, pain, chronic fatigue, disability, depression, and even death were the only predictable outcomes.

Today, the outlook for Gaucher patients has dramatically improved due to the availability of enzyme replacement therapy. Glucocerebrosidase, commercially known as Cerezyme, is prepared by recombinant biotechnology from Chinese hamster ovary cells grown in large scale tissue culture, scrupulously purified, concentrated, and chemically modified so that it is preferentially taken up by the macrophage cells that are deficient in enzyme activity. It is administered intravenously to Gaucher patients safely with a low incidence of side effects. In almost all patients treated with enzyme replacement treatment (ERT), anemia, spleen and liver enlargement, and low platelet counts improve within 6-12 months of starting treatment. Improvement in bone disease also occurs, especially in children and adolescents who have not yet suffered permanent damage, but skeletal responses do seem to take more time. In children, growth and sexual maturation resume in a normal time frame. Nearly all patients on enzyme replacement therapy report a new sense of energy and well being.

Many questions remain to be answered. For example, what is the natural history of Gaucher Disease in untreated patients? Who needs to be treated? Which patients need to be started on a high dose, and who can be safely started on a lower dose? When can the dose be reduced? Is there a role for preventative treatment before symptoms become manifest? What is the best way to assess the effect of ERT on bone disease? Scientists and clinicians from the United States, Israel and Europe are working cooperatively with the Gaucher Registry and the International Cooperative Gaucher Group to answer these and other related questions. The United States National Gaucher Foundation also helps to coordinate these efforts, and to provide practical, up-to-date information for patients and their families.

Gaucher Disease is just one of a rapidly expanding list of genetic diseases. The information that will be mined from the Human Genome Project will certainly add exponentially to this list as well as offer the possibility of new therapeutic approaches. The progress in the treatment of Gaucher Disease holds forth the promise that medical solutions will, with God's help, eventually be found for many other disorders as well.

Yet, one wonders to what avail, if we are unable to overcome the challenge of the spiritual malaise and interpersonal divisiveness that beset us now more fiercely than at any time since the latter days of the second Temple. It will take more than just good science if we are to finally realize the blessing promised in Deuteronomy 7:15: "HASHEM will remove from you all types of sickness."

Dr. Neal Weinreb has been caring for patients with Gaucher Disease for 33 years. He is a member of the Young Israel of Hol1ywood-Ft. Lauderdale, FL, and has discussed Gaucher Disease at the annual International Jewish Medical Ethics Conference.