Gaucher Disease —
A Layman’s Overview

There is rich content on this website – this post is an effort to explain Gaucher disease in its simplest terms – “A Layman’s Overview”.  We will explain the disease in a logical progression, from the basic genetics (how a child gets the disease) through the potential outlook for a cure.

 First The Genetics

Let’s begin by understanding that genes within the body provide certain functions necessary for good health.  In other words, every gene has a job to do. Second, every gene in the body comes as a “pair”, meaning that there are two that provide the same function. Think of a pilot and a co-pilot who fly a plane. Collectively, they have a job to do – fly the plane. Every person’s body is composed of thousands of pilots and co-pilots (i.e. genes) each with their own instructions on where to fly the plane.  Of the thousands of genes that we have, each of us has approximately 10 genes that have a co-pilot that does not know how to fly (defective). This is referred to as carrier status. It does not cause health problems because a person who is a carrier still has the pilot (the healthy side of the pair) who knows how to fly a plane and provides the necessary function for the body. In summation, everyone reading this newsletter is a carrier of some genetic defect because we all have approximately 10 co-pilots on various genes that do not know how to fly.  Again, carriers carry the gene (defective co-pilot) for the disease, but do not have the disease because the pilot is healthy.

 How Is The Disease Passed On To Children?

Let’s take Gaucher disease as an example.  There are those of us who are carriers of a defective “Gaucher” gene – i.e. the co-pilot on the Gaucher gene cannot fly.  As stated above, we are healthy. We choose to marry and have children.  Because each of us has hundreds of thousands of genes the odds are remote that we choose a spouse who also has a Gaucher co-pilot that cannot fly. Therefore, the odds of finding a spouse who of their 10 recessive genetic defects, happen to also have one on the Gaucher gene, are highly remote. We then marry and have children.  For every gene in the body our child receives one half of the pair from the mother, and one half of the pair from the father.  In the situation where both the mother and father carry the defective Gaucher gene, there is a 25% chance that the child inherits the defective gene from both parents. Here is what can happen: A) If the child receives the pilot from the mother and co-pilot from the father, the child is healthy (remember, the pilot can fly), but is also a carrier for Gaucher disease.  If the child receives the co-pilot from both the mother and father, we now have two co-pilots for the Gaucher gene who are unable to provide the necessary bodily function. In this situation the child has the disease – Gaucher disease.  Therefore, similar to many other lysosomal diseases (Tay-Sachs – Niemann Pick – Batten’s – Krabbe – Mannosidosis –Fucosidosis – Sialidosis – Mucolipidosis etc.) Gaucher disease is an inherited genetic disease.

 What Is The Bodily Function?

The Gaucher gene instructions (of the pilot and co-pilot) are to deliver throughout the body an enzyme called glucocerebrosidase (“gloo-ko-sere-bro-si-dase).  This enzyme is responsible for digesting and removing from the body a portion of old worn-out cells. It is part of the recycling process – to grow new cells – and remove old cells. Because the individual inherited the two co-pilots (two defective Gaucher genes), the body does not produce the appropriate enzyme necessary for this cleansing process. Without the enzyme the older worn-out cells are not removed from the body.  They begin to accumulate. We call these cells Gaucher cells.

 What Happens When Gaucher Cells Accumulate?

Gaucher cells most often accumulate in the spleen, liver, and bone marrow.  They may also collect in other tissues, including the lymphatic system, lungs, skin, eyes, kidney, and heart.  Frequently, an organ that contains Gaucher cells becomes enlarged and does not function properly, resulting in clinical symptoms associated with the disease.  The symptoms we have addressed here are the systemic symptoms – meaning everywhere in the body excluding the central nervous system (brain). We will address brain related symptoms later.

 There Three Types Of Gaucher Disease

There are three types of Gaucher disease – Type 1 – Type 2 – Type 3. Type 1 Gaucher disease affects the systemic system only – the entire body excluding the central nervous system (brain). These patients do not have any neurological affects from the disease.  However, Gaucher Type 2 and Type 3 patients have neurological (brain) involvement.

 Is There a Treatment?

Yes. In 1991 the FDA approved a new drug that is referred to as Enzyme Replacement Therapy. This genetically manufactured enzyme is infused into the body and supplements the deficient enzyme the Gaucher gene did not produce enough of. Enzyme replacement therapy, although not a cure, has helped to control the non-neurological, or systemic symptoms (i.e. enlarged liver, enlarged spleen, etc.). This drug is extremely expensive, and for most patients, it has to be infused bi-monthly. Despite the cost and inconvenience, it has greatly improved the quality of life for those patients with Type 1 Gaucher disease whose disease does not affect the brain. However, the drug is ineffective for Type 2 patients, and is only effective for the non-neurological symptoms of Type 3 patients.

 Gaucher Type 2 and Type 3 (The Brain Is Affected)

With Gaucher Disease Type 2 and Type 3 symptoms generally appear in infancy or early childhood.  Children with Type 2 and Type 3 Gaucher disease have all of the systemic symptoms mentioned earlier (enlarged liver, enlarged spleen, etc.) that Type 1 patients have. However, unlike Type 1, the central nervous system (brain) is also affected. 

Neurological Symptoms: Abnormal Eye Movements – Inappropriate Balance – Swallowing Problems – Myclonus (twitching) – Seizures, Etc. 

Type 2: Gaucher disease Type 2 is the most severe form of the disease with symptoms that become apparent from birth to one year of age. Generally, the child displays multiple neurological symptoms. These children generally pass away from 1 to 3 years old.

Type 3: Gaucher disease Type 3 is less severe than Type 2, and often times displays only one initial neurological symptom. These children generally display neurological symptoms from one to seven years old. Often one neurological symptom will present itself, and then over time the disease will progress to multiple neurological symptoms. It is important to note that:

1. No child is the same.
2. There is a range of neurological problems – from minimal to severe.
3. Neurological problems can present all at once, or slowly over a period of many years.
4. Some Type 3 children display only one neurological symptom and do not progress.
5. Brain symptoms are significantly more serious, and in many cases, cause death. 

Why Doesn’t The Enzyme Replacement Work For These Children?

The problem is that the replacement enzyme does not help the brain. The reason is that there is a filter of sorts referred to as the Blood-Brain Barrier that protects the brain. The replacement enzyme is not able to cross the blood-brain barrier. In 1991, when enzyme replacement therapy was approved it was viewed as a “turning point” for Gaucher disease.  It certainly was a turning point for the vast majority of Gaucher patients, mostly adults, who have Type 1 disease. 

 Research Slowed

In 1991, after the discovery of the replacement enzyme serious research on Gaucher disease slowed significantly. As a parent of a Type 3 child, I became very discouraged when I learned there was little, if any research being conducted on how the brain is affected in Type 2 and Type 3 children. This is where you, our donors, have made a tremendous difference. Because of you there is now research, and thus new hope for these children.

Is There Now Research That Matters?

Absolutely! Let me break it down into five areas:

1. Brain Neurons – Just a few years ago researchers did not know how the neurons in the brains of these children were impaired, and in some cases destroyed.  Because of the research you have funded, we now are in the process of understanding the exact molecular mechanism that causes brain problems.

2. Brain Locations – Research that you have funded is now determining the exact locations in the brain that are affected, and correlating these locations with clinical symptoms displayed by children. Thus, we are well on our way in determining HOW, and WHERE.

3. Three Dimensional Structure – Dr. Tony Futerman at the Weizmann Institute of Science in Israel has determined the 3 Dimensional Structure of the glucocerebrosidase enzyme. With this, it may be possible to create an enzyme replacement therapy with smaller molecules, one that may be able to pass through the Blood-Brain Barrier. 

4. 26 Lysosomal Diseases – Gaucher is only one of twenty six lysosomal diseases that affect the brains of children. Research centers are sharing scientific results and finding interesting similarities. Could a cure for one be a cure for all?

5. Parkinson’s Disease – Researchers at the National Institutes of Heath have found similarities in the brain between some forms of Parkinson’s disease and Gaucher disease Type 2 and Type 3. We have always believed that our research would have overlapping and positive benefits for other diseases that affect the brain.

Conclusion

We are researching the mystery of the brain, and research discoveries could well lead to cures for numerous childhood brain disorders.