Gaucher disease Type I

Gaucher disease Type I

A triumph for science and the biotechnology industry

Michael Smith, left, and Dr. Manisha Balwani
Michael Smith, left, and Dr. Manisha Balwani

The story of Gaucher Type 1 is a story of triumph for science and for the biotechnology industry.

There are approximately 6,000 patients in the United States who have been diagnosed with Gaucher disease. Over the past three decades, Gaucher has changed from an untreatable and life-threatening disease to a treatable and manageable chronic condition, and it is possible that people who have been diagnosed with it can live a normal life. Scientific breakthroughs in biochemistry and genetics, and the development of medications to overcome the genetic defects, has enabled this impressive progress.

“My parents never knew they had the gene,” Michael Adam Smith said, but “they are both carriers.

“I was 18 years old, in my freshman year at Syracuse University, and had very bad knee pain. I had to use crutches because it was so bad. I went to various doctors, and they couldn’t figure it out.”

Mr. Smith, who is Jewish and grew up in Paramus, came home from college to consult with specialists, and he ended up at Sloan-Kettering Cancer Center in Manhattan. “They weren’t sure, and did diagnostic tests, including a bone biopsy, as the original thinking was cancer,” he said. “Leukemia.”

“They were talking about chemo — all the scary things,” he continued. “They didn’t know what it was. It really freaked out my parents. It wasn’t fun for me either.”

The doctors discovered an infection deep in his knee, which was treated with intravenous antibiotics. After other tests ruled out cancer, Mr. Smith finally was diagnosed with Type 1 Gaucher disease. “I was on IV at home for six weeks, and the leg is all fine now. It could have been significantly worse. I’m pretty healthy. I had the absolute best-case scenario, from my perspective.”

Besides the knee pain, Mr. Smith also suffered from lethargy, and, he reported, “my spleen and kidneys were very enlarged, three to four times their normal size.” Fortunately, he got the diagnosis of Type 1 Gaucher in 2009, a very opportune time. “I got into a clinical trial that was just starting,” he said. “The clinical trial was a great experience. They take good care of you.”

He joined the clinical trial at Mount Sinai, where a new drug developed by Sanofi Genzyme Corporation was being tested. Up to that point the treatment for Gaucher was intravenous infusion of a drug every two weeks. “The new medication in the clinical trial was in pill form, one or two pills a day,” Mr. Smith said. “I was in the clinical trial for a few years. It was a great success. Now I don’t often talk about Gaucher’s, as I consider it a background disease.”

According to the website of the National Gaucher Foundation (, 95 percent of Gaucher patients in western countries have Type 1 Gaucher. That form of the disease also happens to be the most common Jewish genetic disorder; it is estimated that about one in 450 Ashkenazi Jews have the disease.

Gaucher is caused by a mutation in the GBA gene, which makes an important protein, glucocerebrosidase, an enzyme, or biological catalyst, needed by cells. An astonishing one in 10 Ashkenazi Jews may be carriers of a mutation of the GBA gene. We inherit two copies of most of our genes — one from each parent — so a person who inherits one faulty copy and one healthy copy is a carrier, and does not have disease symptoms.

Those who inherit two flawed copies of the gene have the disease.

According OMIM, the official database of all human genetic variants (Online Mendelian Inheritance in Man,, the GBA gene is made up of 10,414 DNA base-pairs, or letters of the genetic code, that direct the formation of the enzyme glucocerebrosidase. That enzyme is a protein made up of 515 amino acid building blocks. In the N370S mutation, which is the most common GBA mutation in Ashkenazi Jews, there is one single base change in the entire DNA sequence that leads to production of a defective protein. When the mutated protein is made, a mistake appears at position 370 of its 515 amino acid residues. The amino acid asparagine (abbreviated N) is switched for serine (abbreviated S), hence the mutation is designated by the name N370S.

People with Gaucher Type 1 do not make enough functional glucocerebrosidase, an enzyme that is needed to destroy a fatty chemical called glucocerebroside. When that fatty chemical builds up in organs and bone marrow, it can lead to enlargement of the spleen and liver. That, in turn, reduces the production of blood cells, causing anemia and fatigue. Patients also make fewer blood platelets, which can affect blood clotting, and leads to frequent bruising, nose bleeds, and excessive bleeding after surgery or childbirth. When glucocerebroside accumulates it can also reduce blood flow to bones, hence the bone pain, degeneration of bones, and greater tendency for bone breakage.

The National Organization for Rare Disorders ( lists and describes Gaucher as a rare disorder, because there are relatively few cases in the United States. Since it affects small numbers of people it is considered an “orphan disease.” That is an important designation, because the Orphan Drug Act of 1983 provides incentives for pharmaceutical companies to develop drugs to treat such conditions; normally companies tend to be less interested in developing drugs for small numbers of patients.

Fortunately, despite the relative small demand, research on the disease has led to astounding success.

In 1991, Ceredase, the first successful drug for Gaucher, was developed and approved by the Food and Drug Administration. The drug is a form of the normal functional enzyme, derived from human placental tissue. When patients were infused with Ceredase the procedure provided them with the enzyme they were missing. It was a solution to the genetic defect. A few years later, recombinant DNA technology was used to develop a synthetic form of the enzyme, Cerezyme. Enzyme replacement therapy using Cerezyme became the standard of care for patients for the last two decades, and although it still is the drug of choice for many Gaucher patients, a new drug, Cerdelga, which the FDA approved in 2014, has proven to be a vast improvement for many patients. Cerdelga is in pill form and so does not require infusion. Cerdelga involves a new biochemical approach, substrate reduction therapy, which partially blocks the formation of glucocerebroside in the first place, leading to reduced buildup of the fatty chemical that causes all the problems.

Michael Smith’s doctor, Dr. Manisha Balwani, associate professor of genetics and genomic sciences at Mount Sinai Icahn School of Medicine, specializes in treating patients with Gaucher disease.

“Almost all patients with Type 1 Gaucher can live a normal life with treatment,” Dr. Balwani said. “In Type 2 and Type 3 there are neurologic limitations that can’t be treated.” Both Type 2 and 3 are more severe, and neither is found at high incidence in Jewish populations.

While Mr. Smith’s parents originally did not know that they were carriers, many Jewish couples opt to test for carrier status for a host of genetic disorders. “The way we diagnose patients is changing,” Dr. Balwani said. “Almost all Jewish couples have preconception screening, so parents know if they are carriers.” Pregnancies are also screened for couples who are carriers, and if a couple learns their fetus has Type 1 Gaucher, they may choose to continue or to terminate the pregnancy. But having a therapy available that alleviates most symptoms is a game-changer. “In my experience, I’ve not had a couple who have chosen to discontinue the pregnancy,” Dr. Balwani said.

She explained that carrier couples also can opt for PGD, or preimplantation genetic diagnosis, in which the couple goes through in vitro fertilization, and embryos are tested in the laboratory. Healthy embryos are chosen for transfer and develop into a pregnancy, thus eliminating the risk of having a child with Gaucher.

Dr. Balwani and her colleagues are concerned about the cost of pharmaceuticals for treating Gaucher. “It’s one of the most expensive treatments,” she said. “We make sure the treatment is really justified.” It’s important to make the right diagnosis and decision about treatment, as “early treatment prevents irreversible complications,” she continued. The decision when to treat is done on a case-by-case basis, because some but not all patients need treatment right away. “If it is progressing we initiate treatment. For younger kids, we take the family’s opinion into account. If there’s a risk, we are more likely to insist on treatment.”

Dr. Balwani explained that there is a spectrum of severity for the disease and for its time of onset. If a patient has two copies of N370S, “it’s the milder end of the spectrum.” A person also could inherit one copy of N370S from one parent and a more severe mutation in the GBA gene from the other. In those situations, the disease tends to appear earlier and be more severe. The average age of onset for those with two copies of the N370S mutation is 20, but there are people who develop symptoms in their early teens and others do not develop them until they are in their 80s.  For late onset, “when diagnosis is in their 80s, with a slightly low platelet count, we just follow them,” Dr. Balwani said. Those patients are monitored but not necessarily treated.

As Michael Smith’s experience shows, not all physicians are aware of Gaucher, so they may miss the diagnosis. “It’s important to raise awareness of this disorder,” Dr. Balwani said. “Patients have been to hematologists without diagnosis, so it’s important for physicians to know. They need a complete assessment and follow up, and [it’s critical to] treat them before complications develop.”

Another surprising development is the discovery of a link between Gaucher and Parkinson’s disease. “Type 1 Gaucher patients have a higher risk of Parkinson’s disease,” she said, and “we don’t have good treatment for Gaucher-related Parkinson’s disease.” One study reported that 10 percent of Gaucher patients will develop Parkinson’s by they time they are 80, and other studies show even higher risks. Carriers also are at increased risk to develop Parkinson’s. This connection has led to research studies on the Parkinson’s protein and how it interacts with the GBA gene, and such research may lead to better understanding of the mechanisms of both diseases.

Michael Smith, who now is 27, takes just one pill a day, and although he’s a little lethargic at times, “It’s really not a scary disease,” he said. “I keep in my mind that I’m not perfectly healthy, but I don’t describe myself as being sick.”

Since it is a genetic disease, Mr. Smith’s family members have been informed and tested. His sister and their cousins do not have Gaucher. Mr. Smith says that Gaucher does not affect his social life. “I’m single and dating. If I had HIV I would feel strongly that I would have to tell my date right away. But Gaucher is not communicable, and doesn’t affect my quality of life. I think about it, but it’s not something I would mention on the first date. It’s not a red flag. It’s something like ‘I have blond hair and blue eyes.’

“I will have to consider it when I have a wife and want kids.”

Drug therapies for Gaucher are very expensive; treatment costs up to $200,000 a year. “It’s really great that there is a treatment because it’s an orphan disease, and not very common,” Mr. Smith said.

“I think it’s important for the government to ensure that orphan diseases are looked at. There is a responsibility to those who are not so fortunate. I’ve never needed anything in my life. My parents have good insurance. But there are people who can’t fend for themselves, so there has to be some incentive for Sanofi to make the drug, for the company to care.” After he aged out of his parents’ plan, “I was on Obamacare at age 26, and the drug was covered.

“In most other countries the government takes over coverage until a new job is found,” he continued. “No one should have to determine if healthcare is an option. The thought of that is chilling. I think that we’re supposed to be the best country in the world.”

Jewish Standard science correspondent Dr. Miryam Z. Wahrman of Teaneck is a professor of biology at William Paterson University of New Jersey and author of “The Hand Book: Surviving in a Germ-Filled World,” which provides tips on how to avoid infections.

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