Gaucher disease (Type I)

Gaucher Disease is the most common of the lipid storage diseases. It is caused by a
deficiency of the enzyme glucocerebrosidase, which leads to a collection of fatty material in
the spleen, liver, kidneys, lungs, brain, and bone marrow. It has three subtypes, with Gaucher
Disease Type I being the most prevalent. It is also the most common genetic disease among
Ashkenazi Jews in North America. A genetic defect in the enzyme, that normally breaks
down the chemical glucocerebroside in the cell, allows this substance to accumulate
excessively in the liver, spleen, and lymph nodes, giving rise to the symptoms associated with
Gaucher Disease Type I.

Symptoms

Typically, the first sign of this disorder is an enlarged spleen. Anemia, low blood platelets,
consequent fatigue, bruising, and a yellow fatty deposit on the white part of the eye are also
symptoms. Skeletal weakness and bone disease may occur, leading to collapsed hips,
shoulders, and spine.

Inheritance Patterns

Gaucher Disease Type I is an autosomal recessive disorder.

Diagnosis and Testing

A blood or skin test is performed to confirm a diagnosis of Gaucher Disease Type I. This
blood test measures the amount of the enzyme glucocerebrosidase and compares it to normal
enzyme activity levels. If the disorder is present, low levels of this enzyme will be present as
well. Carrier testing can also be performed. In the Ashkenazi Jewish population, four
common mutations (N370S, L444P, 84GG, and IVS2) account for roughly 95% of all
nonfunctional Gaucher genes. If a mutation is found, the individual is a carrier. If none of the
four mutations are found, there is still a chance that the individual is a carrier because other
mutations could be present. A small percentage of non-Jewish individuals carry one of these
common mutations.

Treatment

Enzyme replacement treatment given intravenously every two weeks can dramatically
decrease liver and spleen size, reduce skeletal abnormalities, and reverse other manifestations
of the disease. For patients who cannot be treated with enzyme replacement therapy, an
enzyme inhibiting medication, miglustat, can be taken orally and has demonstrated some
benefit. Successful bone marrow transplantation cures the non-neurological manifestations
of the disease. However, this procedure carries significant risk and is rarely performed in
Gaucher patients. Surgery to remove the spleen may be required on rare occasions (if the
patient is anemic or when the enlarged organ affects the patients comfort). Blood transfusion
may benefit some anemic patients. Other patients may require joint replacement surgery to
improve mobility and quality of life.
Gaucher disease (Type I) results from an enzyme deficiency that causes a fatty substance to
accumulate in the liver, spleen, and bone marrow. Symptoms include anemia, easy bruising,
impaired clotting, bone and joint pain, and other orthopedic problems.

Symptoms may appear in childhood or much later in life. Some patients may suffer from
chronic ill health, while others may experience few, if any, of the disease manifestations.
Enzyme replacement therapy has been developed in recent years and has been highly
effective in reversing some symptoms and reducing the severity of others.

Type I Gaucher is the most prevalent Jewish genetic disease, with a carrier frequency of
about 1 in 15. Screening will detect approximately 95% of cariers.

More information:

Information on Gaucher Disease from the Mount Sinai School of Medicines

Comrehensive Gaucher Treatment Center

History of Gaucher Disease

In 1882, Phillipe Gaucher, a French physician, first described the clinical disorder that now
bears his name. His astute medical thesis describing a 32-year-old woman with a remarkably
enlarged spleen ("splenomegaly") and the hallmark large, peculiar cells present within it
stimulated interest in the medical community. The eponym "Gaucher Disease" was
introduced by Nathan Brill, the Mount Sinai pathologist who first suggested the familial
nature of the disorder and was the first to diagnose a case during life. Along with his Mount
Sinai colleagues, Drs. Mandelbaum and Libman, Nathan Brill extensively described the
anatomic and morphologic pathology of the disease. Throughout the century following its
discovery, the scientific and medical communities have continued to advance our
understanding of the clinical and pathologic findings, metabolic disorder, familial
transmission, and genetic defect of the disease. Based on these studies, diagnosis and
treatment of Gaucher disease are possible and represent a cornerstone in the era of molecular
medicine.

Clinical Manifestations of Gaucher Disease

There are three subtypes of Gaucher disease. There is a wide variability in the pattern and
severity of disease involvement between and within each subtype. All three variants of
Gaucher disease are inherited "storage" diseases but are distinguished by the presence or
absence of neurologic complications (Table I).

Table I

Clinical Features Type I Type II Type III

Clinical Onset Childhood/Adulthood Infancy Childhood

Hepatosplenomegaly + + +

Hematologic Complications + + +
Skeletal Involvement + - +

Neurologic Involvement - + +

Survival Variable < 2 yrs 2nd - 4th decade

Ethnic Predilection Ashkenazic Jewish Panethnic Northern Swedish

Type I Gaucher Disease

Type I disease is the most common form of Gaucher disease and does not directly involve the
nervous system. In the United States, there are estimated to be 20,000 or more patients with
Type I Gaucher disease. This disease is the most common genetic disorder in Jewish
individuals of Central and Eastern European ancestry (Ashkenazic Jews). Approximately one
in eighteen Ashkenazi carry the gene for this disease. However, Gaucher disease is not
restricted by geographic or cultural boundaries and has been found in all ethnic groups.

The clinical manifestations usually become apparent in childhood or early adulthood, when
patients initially show an enlarged spleen or develop hematologic problems (anemia and/or
low platelet count) or orthopedic (bone) complications. Gaucher cells in the bone marrow
may lead to symptoms of bone and joint pain, fractures, and other orthopedic problems.
Accumulation of Gaucher cells in the spleen and liver leads to enlargement of these organs as
well as blood abnormalities such as anemia and thrombocytopenia (low platelet count) with
subsequent easy bruisability and impaired blood clotting.

Since there is marked variability in the severity of Type I disease, even among family
members, it is difficult to predict the future severity and extent of complications in individual
patients. Some patients are severely affected in their teens, while others are relatively
asymptomatic when diagnosed in their 50s or 60s. Although there is no "classic" predictable
disease course, prognosis generally depends on the severity at diagnosis and the occurrence
interval between disease complications in each patient.

Type II Gaucher Disease

Type II disease has its onset in infancy and is a fatal neuro-degenerative disorder with death
occurring in the first or second year of life. Extensive liver and spleen enlargement is present,
but oculomotor (eye movement) abnormalities may be the first noted findings. Other findings
may include rapid head thrusts, bilateral fixed strabismus and or neck muscle hypertonia,
limb rigidity, and seizures. It is very rare and does not have a predilection for any particular
ethnic or demographic group.

Type III Gaucher Disease

Type III disease is intermediate in severity between Types I and II in that the neurologic
symptoms occur but present later and in a milder form than in Type II. The first symptoms
are usually the enlargement of the liver and spleen with eventual eye movement disorders.
Some patients progress to have further neurologic involvement including dementia, ataxia,
and spasticity. The prototype form of this disease has been found in population isolates in
northern Sweden. Again, this form of the disease can occur in all ethnic and demographic
groups.

Each of these three types of Gaucher disease is genetically distinct and "breeds true" in
affected families - that is, the type of Gaucher disease occurring in a specific family remains
the same through successive generations.

Metabolic Defect
All three Gaucher variants are inherited "storage" diseases. They result from the deficiency of
an enzyme, acid beta-glucosidase, that is necessary for the breakdown of a particular fatty
substance, glucosyl ceramide. Normally, glucosyl ceramide is present in very small amounts
in all body cells where it is produced, broken down, and then re-synthesized daily, allowing
for the normal growth of cells. In Gaucher patients, glucosyl ceramide cannot be broken
down properly. It therefore becomes abnormally stored in those cells normally assigned to
metabolize this substance. These enlarged, abnormal cells are known as Gaucher cells.

The major manifestations of Gaucher disease are the result of the abnormal accumulation of
Gaucher cells, primarily, in the bone marrow, spleen and liver. Only in patients with Types II
and III Gaucher disease does the accumulation also occur in the central nervous system.

Genetics
The gene for acid beta-glucosidase, the defective protein/enzyme responsible for the
deficiency in Gaucher disease, was identified and characterized in 1989. Analysis of this gene
has led to the recognition of more than 60 gene alterations (mutations) that cause Gaucher
disease. Four of these mutations account for about 90-95 percent of disease-causing changes
among Jewish patients but for only 50-75 percent of the mutations among non-Jewish people.
The use of molecular genetic analysis in patients to identify the exact error in the acid beta-
glucosidase gene (the patient's "genotype") can, in general, be used as an aid in predicting the
severity of involvement (the patient's "phenotype").

Familial Transmission
Gaucher disease is a genetic disorder that is transmitted in an autosomal recessive fashion.
An affected individual must inherit two recessive Gaucher genes one from each parent, in
order to have Gaucher disease. Individuals with only a single Gaucher gene are known as
"carriers". Carriers are completely normal with respect to Gaucher disease. Carrying only one
recessive gene for Gaucher disease has no bearing on one's health, though it may have
reproductive implications. With prenatal diagnosis, it is now possible to ascertain early in
pregnancy whether the fetus of a "carrier couple" is affected by Gaucher disease.

If two carrier individuals have children, there is a 25 percent chance with each and every
pregnancy of having a child with Gaucher disease.

If a carrier and a non-carrier have children, none of their offspring will have Gaucher
Disease, but each pregnancy bears a 50 percent chance of producing a carrier of the disease.
All of the children of a patient with Gaucher disease and a non-carrier will be unaffected
carriers.

If a patient with Gaucher disease and a carrier have children, on average, half will have the
disease and half will be carriers.

Probability of Each Child Risk of Each Risk of Each

Parent Parent
Not Being a Carrier or Child Being a Child Being
1 2
Affected Carrier Affected
carrier + carrier = 25% 50 % 25%
non-
carrier + = 50% 50% 0%
carrier
affected + carrier = 0% 50% 50%
non-
affected + = 0% 100% 0%
carrier

Diagnosis and Treatment

Diagnosis

Concerned couples and individuals can be tested for Gaucher disease. Testing is done by
blood sample analysis wherein the level of enzyme responsible for Gaucher disease is
measured and the Gaucher gene itself is analyzed at the molecular level.

Individuals who are carriers have an enzyme level that is intermediate between that of
affected patients and that of non-carrier individuals. Affected individuals have two Gaucher
genes and therefore have very low enzyme levels. Because an overlap exists in the range of
enzyme activity values between non-carriers and Gaucher disease carriers, enzyme testing
alone as a means of carrier identification is only about 90 percent accurate. Use of direct
genetic testing or molecular DNA analysis has provided increased (>98 percent) reliability
and accuracy to testing.

Prenatal Diagnosis

All types of Gaucher disease can be detected during pregnancy through procedures known as
"amniocentesis" or "chorionic villus sampling." Prenatal diagnosis is available for couples
who are at risk for having a child with Gaucher disease. Amniocentesis involves the insertion
of a needle through the abdominal wall and uterus into the amniotic sac surrounding the fetus.
A small amount of amniotic fluid is removed. This fluid, of fetal origin, contains fetal cells
that can be grown in the laboratory. Alternatively, a sample of the developing placenta can be
obtained and grown in the laboratory or studied directly. This procedure is called "chorionic
villus sampling" ("cvs"). When sufficient numbers of cells have grown (approximately two to
four weeks), they are studied biochemically and by DNA techniques. By measuring the level
of acid beta-glucosidase in these fetal cells, it can be determined whether or not the fetus has
Gaucher disease.
Treatment

The goal for management of Gaucher disease has been supportive and aimed at minimizing
future clinical complications. Management initially involves careful monitoring of blood-cell
values and orthopedic problems and appropriate medical intervention when problems
develop. The laboratory and radiologic findings must then be correlated with the patient's
general well-being, as assessed by a comprehensive physical examination.

Enzyme replacement therapy recently has been made available to combat and treat directly
the underlying problem in Gaucher disease. Originally, the enzyme was placentally derived
(Ceredase ). However, since 1994, Cerezyme , a recombinant form of acid beta-
glucosidose, has been approved by the FDA for the treatment of symptomatic Gaucher
disease. Several clinical studies have demonstrated the safety and efficacy of both enzyme
preparations in reversing the clinical manifestations of Gaucher disease. The therapy entails
the regular intravenous infusion of the enzyme, which has been biochemically modified to
target the Gaucher cell specifically. In conjunction with coordinated management of Gaucher
disease manifestations and complications, this therapy can lead to a greater improved quality
of life for affected patients and families.

Decisions regarding enzyme replacement therapy are complicated not only by the fact that
the minimal effective dose and optimal frequency of enzyme administration have not been
established but also by the extreme variability of clinical manifestations among patients, the
expense of therapy, and the required commitment on the part of the patient to regular
intravenous administration of the enzyme. Therefore, careful and coordinated management by
physicians with special expertise in Gaucher disease is required to tailor each individual's
treatment program in order to maximize benefit and well-being.

Research Projects
Researchers are currently directing their efforts toward the development of improved and
novel treatments. Studies are ongoing to determine the long-term safety and efficacy of
enzyme therapy, indications for the treatment of Gaucher disease, and the value of treatment
of asymptomatic patients.

Another area in which studies are now underway is the evaluation of bone marrow
transplantation for the treatment of this disease. Although this approach can cure Gaucher
disease, there is a high morbidity and mortality rate associated with this procedure; thus only
severely affected patients who have histocompatible sibling donors have been considered for
transplantation.

Gene therapy is another approach to the cure of Gaucher disease. By using any of several
techniques, a normal gene for acid b-glucosidase can be inserted in to the somatic cells of
Gaucher disease patients to correct the inherited enzyme defect. The basic strategy involves
the retrieval of stem cells from the patient through either bone marrow harvesting or
extraction from peripheral blood, and the subsequent introduction of the normal gene using a
retroviral vector. Stem cells are blood cells with the ability to propagate continuously; thus,
once the deficiency is corrected in these cells they become an internal and continual source of
the enzyme.