NGF : Gaucher Disease

12 août 2005

Vous trouverez des articles traitant du même sujet dans la catégorie "A propos de la maladie de Gaucher".

Liens utiles à la fin des catégories.

Ghislaine SURREL

maladies-lysosomales-subscribe@yahoogroupes.fr

Gaucher Disease

Gaucher Disease is the most common lipid-storage disorder, and is the most common genetic disease affecting Jewish people of Eastern European ancestry.

Gaucher Disease results from a specific enzyme deficiency in the body, caused by a genetic mutation received from both parents. The disease course is quite variable, ranging from no outward symptoms to severe disability and death.

Fortunately, testing is available to identify potential parents who are carriers of the gene and to accurately diagnose those people who have the disease. And even more fortunately, an effective enzyme replacement therapy is available for one of the variants of the disease.

Prevalence and Transmission of Gaucher Disease

Gaucher Disease is an inborn error of metabolism. Inborn metabolic disorders are those conditions resulting from a specific malfunction in one or more of the body's many individual chemical processes. Although there are at least 34 mutations known to cause Gaucher Disease, there are 4 genetic mutations which account for 95% of the Gaucher Disease in the Ashkenazi Jewish population, and 50% of the Gaucher Disease in the general population. These can be identified through a blood test.

The carrier rate for the mutations which cause Gaucher Disease may be as high as 1 in 14 Jewish people of Eastern European ancestry, and 1 in 100 of the general population. Gaucher Disease is transmitted as an autosomal recessive; that is, it occurs equally among males and females, and both parents must carry the mutation for the child to have the disease. If both parents are carriers, then there is a 1 in 4 chance that the child will have Gaucher Disease, a 1 in 2 chance that the child will not have the disease but will be a carrier, and a 1 in 4 chance that the child will neither have the disease nor be a carrier.

Symptoms of Gaucher Disease

In 1882, a French physician named Philippe Charles Ernest Gaucher (pronounced: go-SHAY) first described a clinical syndrome in a 32-year-old woman whose liver and spleen were enlarged. The most common symptoms of Gaucher Disease are enlargement of the liver and spleen, anemia, reduced platelets (resulting in easy bruising and long clotting times), bone pain ("bone crises"), bone infarctions often leading to damage to the shoulder or hip joints, and a generalized demineralization of the bones (osteoporosis). The weakening of the bones can then lead to spontaneous fractures. The course of the disease is quite variable, ranging from no overt symptoms to skeletal problems, liver or spleen damage, bleeding, or other problems. There are indications of an increased risk of multiple myeloma, a type of slow growing cancer in the bones, in older individuals with Gaucher Disease. Because enzyme therapy has only been available since 1991, there are no data regarding this finding in individuals who are receiving the enzyme replacement therapy.

The characteristics just listed refer primarily to the Type 1 form of the disease. This is often called the adult form, although the cause is present from the time of conception. Type 1 Gaucher Disease occurs worldwide in all populations, but is most prevalent in the Ashkenazi Jewish population (the Jews of Eastern European ancestry). Within this population, Type 1 Gaucher Disease occurs at a rate of 1 in 450 live births, and is the most common genetically-based disease affecting Jewish people.

There are other forms of Gaucher Disease which, in addition to the liver, spleen, and bone complications characteristic of Type 1 Gaucher Disease, also result in acute neurological symptoms. Type 2 Gaucher Disease, called the acute neuropathic form, is characterized by brainstem abnormalities and is usually fatal during the first three years of life. Type 2 Gaucher Disease shows no ethnic predilection, and occurs rarely, with an incidence of 1 in 100,000 live births. Type 3 Gaucher Disease, the chronic neuropathic form, also shows no ethnic predilection, and is estimated to occur in 1 in 50,000 live births. The neurologic symptoms of Type 3 Gaucher Disease are slowly progressive and appear later in childhood than the symptoms of Type 2 Gaucher Disease. Neurologic symptoms of Type 3 Gaucher Disease include incoordination, mental deterioration, and myoclonic seizures. There is a subclassification of Type 3, called Norbottnian Gaucher Disease, named for the region in

Sweden

where it has been identified. The slowly progressive neurologic symptoms of Norbottnian Gaucher Disease may not occur until early adulthood.

Testing for Gaucher Disease

Gaucher Disease can be detected through a simple blood test. There are Gaucher specialists throughout the country who can diagnose, evaluate and recommend proper treatment. The testing process can be done at a hospital, Gaucher specialist’s office, or through your family physician. Your physician can draw blood that would then be sent to a specific laboratory for testing.

The NGF is committed to keeping the public informed about all aspects of Gaucher Disease, treatment options and services available for Gaucher patients and treaters. In furtherance of that commitment, the NGF would like to inform you about a change that has taken place in the availability of clinical laboratory testing services for Gaucher Disease. Generin Laboratories closed on

December 31, 2004

In an effort to help treaters minimize delays in services to Gaucher patients, below, please find a list of labs that provide Gaucher-related testing. Other labs may also provide Gaucher testing, therefore, we have listed a website that you can visit for full information on labs in the United States.

Genetic Testing Website: www.genetests.org

Should you have any questions, please feel free to call Sharon Adams at 1-800-925-8885, or email her at Sharon@gaucherdisease.org.

An enzyme assay test measures glucocerebrosidase (GC) activity in leukocytes, fibroblasts, or urine. Individuals who are affected with Gaucher Disease will have very low levels of enzyme activity. There are four common mutations of the GC gene: N370S, L444P, 84gg and IVS2[+1]. DNA analysis for these four mutations detects 90% to 95% of the mutations associated with Gaucher Disease in the Ashkenazi Jewish population, and 50% to 75% of the associated mutations in the general population. Neither disease type nor severity of disease is defined by enzyme assay. DNA analysis is used in combination with the enzyme assay test to diagnose Gaucher Disease and is helpful in defining the subtype.

Carrier Testing
Approximately 1 in 60,000 people have Gaucher Disease. However, among Jews of Eastern European (Ashkenazi) descent, one in 450 people will have the disorder, and the carrier rate is approximately 1 in 14. Carrier status can be detected through a simple blood test. The testing process can be done at a hospital, Gaucher specialist’s office, or through your family physician. Laboratory assay tests use chromosomes, DNA, RNA, and genes to determine the genetic status of a person who is at high risk for a particular condition. For detailed information on genetic testing, please contact one of these testing sites. In addition to Gaucher Disease, these sites also do testing for Fabry, MPS 1 and Pompe.

Testing Centers

U of

Washington

Seattle

(203)
987-2216

Baylor

School

of Medicine,

Houston

(800)
411-4363

Cincinnati
Children's
Hospital
(513)
636-4507

Emory University,
Atlanta, GA
(800)
200-1524

Genzyme
Genetics,
Cambridge, MA
(800)
848-4436

Mt.Sinai

School

of Med., NYC (866)
322-7963

NYU

School

of Med., NYC
(212)
263-8344

U of A
Birmingham, AL
(205)
934-4973

Yale

Univ.

New Haven

(203)
785-3412

Gaucher

Enzyme

DNA Mtn
Analysis

DNA
Sequencing

Biomarkers

Chito

ACE

TRAP

Prevention and Treatment of Gaucher Disease

Carrier testing is reliable and readily available.

An enzyme replacement therapy is available, which provides the missing enzyme. Much outcome assessment has yet to be completed, but indications are that the symptoms can be entirely reversed in children with Type 1 Gaucher Disease. It would be important to begin treatment before there is significant organ or bone damage. Current data strongly suggest that enzyme replacement therapy is an effective treatment for Type 1 Gaucher Disease in all age groups, with a treatment effect occurring most readily in children, and over a longer period of time in adults. It is not clear whether the neurological symptoms of Gaucher Disease respond to the enzyme replacement therapy, but initial reports have been disappointing.

Standard of Care
The current treatment for Gaucher Disease is Cerezyme, however, due to many variables, method of care for each individual may vary. For information about specific Standards of Care for Gaucher Disease, please feel free to contact Dr. Robin Ely Berman at ngf@gaucherdisease.org or 800-428-2437 Ext. 521 or contact any of the NGF Medical board members listed below.

Dr. John Barranger
University of

Pittsburgh

jbarrang@helix.hgen.pitt.edu
(412) 624-4623

Dr. Roscoe Brady
National Institutes of Health
bradyr@ninds.nih.gov
(301)724-3700

Dr. Gregory Grabowski
Cincinnati Children's Hospital
grabg0@chmcc.org
(513)636-7290

Dr. Henry Mankin
Massachusetts General Hospital
hmankin@partners.org
(617) 724-3700

Dr. Pramod Mistry
Yale University
pramod.mistry@yale.edu
(203) 785-3412

Dr. Gregory Pastores
New York University Medical Center
gregory.pastores@med.nyu.edu
(212) 263-7635

Zavesca - Specific Prescription Parameters

The FDA has stated that "Zavesca® is indicated for the treatment of adult patients with mild to moderate type I Gaucher disease for whom enzyme replacement is not a therapeutic option (e.g. due to constraints such as allergy, hypersensitivity, or poor venous access)."

The NGF believes that Zavesca® should only be recommended by physicians who are expert in the diagnosis, treatment, and management of Gaucher Disease.The National Gaucher Foundation’s Medical Advisory Board is currently discussing more precise clinical recommendations for the use of Zavesca® in the overall management of Gaucher Disease.

Further study is still necessary to evaluate the clinical effectiveness of Zavesca® , the drug’s side effect profile, and its possible use for the treatment of Type 3 Gaucher Disease.

Persons who believe they may be candidates for Zavesca® should consult the physician who is helping to manage the Gaucher Disease, and may consult with the NGF Medical Director, Dr. Robin Berman for further consideration.

Human trials have begun with a gene therapy, using technology developed for other diseases, which will give the Gaucher patient the ability to produce the enzyme not produced by the defective gene.

Research is ongoing into various treatments and supplemental therapies for Gaucher Disease.

Clinical Course of Gaucher Disease

The symptoms associated with Gaucher Disease result from the accumulation of a fatty substance, a lipid called glucocerebroside. This lipid is a byproduct of the normal recycling of red blood cells. When the gene with the instructions for producing an enzyme to break down this byproduct is defective, the lipid accumulates. Gaucher Disease is, therefore, a lipid storage disease, and is the most common disease of this type. The lipid is found in many places in the body, but most commonly in the macrophages ("big-eater" cells) in the bone marrow. There it interferes with normal bone marrow functions, such as production of platelets (leading to bleeding and bruising) and red blood cells (leading to anemia).

The presence of glucocerebroside seems to also trigger the loss of minerals in the bones, causing the bones to weaken, and can interfere with the bone's blood supply, causing areas of bone-death, or "infarctions". The most immediate human cost of Type I Gaucher Disease is related to the loss of function when a hip or shoulder becomes infarcted or a long bone fractures, the great pain experienced during reduced blood flow to the bones ("bone crises"), abdominal problems related to massive enlargement of the liver and spleen, poor blood clotting, and anemia. Type 2 and Type 3 Gaucher Disease result in severe neurological impairment or early demise.

Current Gaucher Disease Research and Clinical Trials

Cedars-Sinai Medical Center, Los Angeles, CA
Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Genzyme Therapeutics, Cambridge, MA
Massachusetts General Hospital, Boston, MA
National Institutes of Health, Bethesda, MD
National Institutes of Neurological Disorders and Stroke, Bethesda, MD
New York University School of Medicine, New York, NY
Shaare Zedek Medical Center - Gaucher Clinic, Israel
University Hospital, Tamarac, FL
University of Massachusetts, Worcester, MA
Yale University, New Haven, CT

Cedars-Sinai

Medical

Center
,
Los Angeles

CA

Name of Study: Clinical Trial for Children with Gaucher

Disease

Hospital

or Research Facility:

Cedars-Sinai

Medical

Center

Chief Investigator: William Wilcox, MD, PhD

Telephone number: (310) 423-6673

Email: william.wilcox@cshs.org

Cincinnati Children’s Hospital Medical Center

Study: "A Phase II, Randomized, Double Blind, Placebo-Controlled, Multicenter Study of the Safety and Efficacy of Zoledronic Acid for Improvement of Bone Mineral Density in Patients with Gaucher Disease Who Are Beginning Enzyme Replacement Therapy with Cerezyme^®"

Patient Survey Regarding Enzyme Replacement Therapy

Genzyme Therapeutics

Cambridge

Massachusetts

Study: "A Multicenter, Randomized, Dose Frequency Study of the Safety and Efficacy of Cerezyme^® (imiglucerase for injection) Infusions Every Four Weeks Versus Every Two Weeks in the Maintenance Therapy of Patients with Type 1 Gaucher Disease"

Study: "A Multicenter Study of the Efficacy of Cerezyme^® (imiglucerase for injection) in Treating Skeletal Disease in Patients with Type I Gaucher Disease"

Massachusetts General Hospital Boston, MA

Name of Study: A questionnaire based computerized review of clinical, sociologic and psychological status of 123 patients with Gaucher disease.

Hospital:

Massachusetts General

Hospital

;

New York

University

School

of Medicine

Chief Investigator: Dr. Henry J. Mankin; Dr. Gregory Pastores

Telephone Number: (617) 726-2735