What Causes It?

In 1934, the French chemist A. Aghion discovered the chemical cause of the enlarged spleens and
liver: a buildup of a lipid (fatty substance) called "glucocerebroside."

This discovery led researchers to speculate why there was too much lipid - did people with Gaucher
disease make too much of the lipid for their bodies to handle? Or did their bodies not break it down
and dispose of it? The answer to this question came during the early 1960s, when Dr. Roscoe
Brady's group showed that people with Gaucher disease made the lipid normally but did not make
enough of the enzyme "glucocerebrosidase" to break it down and clear it out of the body.

In 1967, Brady's group developed a convenient diagnostic test for Gaucher disease which works by
measuring the activity of the enzyme glucocerebrosidase in white blood cells. The amount of
enzyme one's body makes directly relates to how severe a case of Gaucher disease one has. The
enzyme activity is also one way that may help to distinguish the three types of Gaucher disease
described in this chart.

The Three Types of Gaucher Disease

Type 1 Type 2 Type 3
Whom it Strikes young infants children/young
adults/adults adults

Distinguishing no nervous early later onset of

symptom system nervous nervous
problems system system
problems problems
Effects of disease varies from dies in becomes
mild to infancy severe
severe
Glucocerebrosidase some very little activity
Activity activity but little
much less activity
than normal

The next question of course was "Why do some people make too little enzyme?" The answer to this
question came in 1987, when the first gene mutation that causes Gaucher disease was discovered by
Dr. Shoji Tsuji and coworkers.

Gaucher disease turned out to be an "autosomal recessive" genetic disease. This means that both of
the glucocerebrosdiase genes a person inherits - one from the mother and one from the father --
must be mutated for the person to have the disease. A person with only one mutated gene is a
carrier. A carrier of Gaucher Disease is not affected but can pass the trait on to his/her children.

The inheritance diagrams below show how a child can be affected depending on the genetic
material s/he inherits from her/his parents.

G = mutated gene
g = normal gene
OPTION 01
 Parent 1 (a carrier) Parent 2 (a carrier)
Gg Gg

Possibilities for each child they have

GG two mutated genes; person with Gaucher disease

Gg carrier of Gaucher gene; no signs or symptoms

gG carrier of Gaucher gene; no signs or symptoms

gg two normal genes; normal enzyme activity, not a

carrier
OPTION 02
Parent 1 Parent 2
(a person with Gaucher (a person with normal
disease) genes)
GG gg
Possibilities for each child they have

GG carrier of Gaucher gene; no signs or symptoms

Gg carrier of Gaucher gene; no signs or symptoms

gG carrier of Gaucher gene; no signs or symptoms

Gg carrier of Gaucher gene; no signs or symptoms

OPTION 03
Parent 2
Parent 1 (a carrier) (a person with normal
Gg genes)
gg
Possibilities for each child they have

GG two mutated genes; person with Gaucher disease

Gg carrier of Gaucher gene; no signs or symptoms

gG carrier of Gaucher gene; no signs or symptoms

gg two normal genes; normal enzyme activity, not a

carrier

In the early 1970s, Dr. Brady's group devised an enzymatic test based on the enzyme's activity to
tell people if they were carriers or not, and a procedure for prenatal diagnosis. These tests give
people information about their genetic status so that they can prepare for the future.

Can We Prevent, Treat, or Cure It?

The third question that medical researchers try to answer is the most important, and often depends on the
answer to the question, "What causes it?" For Gaucher disease, physicians initially attempted to address the
symptoms that accompany the disease. They removed enlarged spleens, and performed liver transplants,
blood transfusions, and orthopedic procedures. Only bone marrow transplantation for people with Type I
Gaucher disease was sometimes successful. To be truly successful, a treatment would have to address the
cause of the disease, not just the symptoms.

In 1966, Dr. Roscoe Brady suggested a therapy for Gaucher disease based on replacing the enzyme. Using
human placentas, Dr. Peter Pentchev of Dr. Brady's team isolated a tiny sample of purified
glucocerebrosidase. In 1973, two patients received this enzyme; because of the good biochemical results,
Brady decided to develop a procedure to obtain larger quantities of the enzyme for further clinical trials.

A large-scale purification method was completed in 1977. The enzyme had to be treated with an alcohol to
make it stick to the purifying columns. But this preparation of the enzyme produced inconsistent results
during clinical trials. The alcohol had removed a lipid (fat) that activates the enzyme and targets it to the
affected cells, called macrophages. Dr. Brady's challenge was now to get the purified enzyme into the
targeted cells.

A diagram of Native mannose

term diagram

About this time, two facts became known. First, the enzyme has sugar side-chains attached to amino acid
backbone of its structure. Second, macrophages react with enzymes whose sugar chains end with the sugar
called "mannose." The problem was that the mannose on the sugar side chains of glucocerebrosidase was
inside of the chains, not on the end of the chains. The mannose therefore could not interact with
macrophages. Dr. Brady's team needed to develop a method to strip off some of the sugars on the ends of the
side chains to expose the mannose, which would allow the enzyme to bind to the macrophages.

In the first clinical trial with macrophage-targeted glucocerebrosidase, eight people with Gaucher disease
received a fixed dose of the modified enzyme. Only the smallest one - a child - experienced beneficial
effects. His hemoglobin and platelet counts increased; the size of his spleen and liver decreased; and the
damage to his bones lessened. The other seven people were adults and had not received enough of the
enzyme to improve their condition.

Brady's team then selected a different dose amount of replacement enzyme for a trial of twelve people with
Gaucher disease. All of these people had strikingly good clinical responses within a few months. For
example, their height and weight increased; their anemia improved; their liver and spleen sizes decreased;
and their bone damage lessened. Because of these findings, macrophage-targeted glucocerebrosidase was
approved as a specific treatment for Gaucher disease by the Federal Drug Administration on April 5, 1991.
Enzyme replacement therapy worked.

In a few short years, people with Gaucher disease were able to receive the enzyme replacement therapy at
home. Enzyme replacement therapy is an effective treatment for most people with Type 1 Gaucher disease.

Dr. Brady is conducting genetic research to provide a cure for all people with Gaucher disease. At the
National Institutes of Health in May 1995, a young man with Gaucher disease received the first gene therapy
for that disease. He received back his own cells into which the correct genes for making the enzyme
glucocerebrosidase had been inserted. He had no adverse reaction, proving the safety of the procedure.
Current trials are attempting to determine the efficacy of gene therapy for Gaucher disease.