GENETIC DISEASE E-MAIL DISCUSSION LIST --------------------------------------------------------------------------- TAY-SACHS DISEASE Tay-Sachs Disease is a congenital, metabolic defect resulting from the lack of an enzyme, hexosaminidinase-A. This leads to developmental delay beginning as early as the third to sixth month, which rapidly proceeds to neurologic degeneration. There are infantile, juvenile, and adult-onset forms of the disease. Late Onset Tay-Sachs Disease has a distinctly different course than Tay-Sachs Disease presenting in infancy. There is no specific treatment for Tay-Sachs Disease, although research is progressing at a number of centers. One can identify carrier states (the disease is transmitted in an autosomal recessive fashion) by a relatively simple blood test (N-acetylglucosaminidase). Both parents would need to have the trait for the disease for the offspring to have a chance of developing it. There are couples where one of them has had a positive or indeterminate test result, only to have his or her partner test normal, which obviates the need for further testing, which is occasionally done of white blood cells. The adult-onset form of Tay-Sachs Disease may cause profound mental changes, and must be distinguished from a number of neurological and psychiatric disorders. Some signs of adult-onset disease may include: ataxia (unsteady gait), dysarthria (inability to move smoothly), muscle weakness, and recurrent psychosis. These are slowly progressive. This disease is found 100 times more frequently in Ashenazi Jews than in other ethnic groups. There are 4 mutations which account for 95% of the mutant genes iin the population. French Canadians have a different mutation causing this disease. Tay-Sachs & Allied Diseases Association: http://mcrc2.med.nyu.edu/murphp01/taysachs.htm --------------------------------------------------------------------------- GAUCHER DISEASE In 1882, a French physician named Philippe Charles Ernest Gaucher first described a clinical syndrome in a 32-year-old person 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. The characteristics just listed refer primarily to the Type I form of the disease. This is often called the adult form, although the cause is present from the time of conception. Type I 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, Gaucher Disease occurs at a rate of 1 in 450 live births, and is the most common genetically-based disease affecting Jews. There are other forms of Gaucher Disease, which have acute neurological symptoms, such as seizures, mental retardation, or death. Type 2 disease, called the acute neuropathic form, shows no ethnic predilection, and occurs rarely, with an incidence of 1 in 100,000 live births. Type 3, the chronic neuropathic form, is estimated to occur in 1 in 50,000 live births. There is a subtype of Type 3, called Norbottnian Gaucher Disease, named for the region in Sweden where it has been identified. 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 10 Jews 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. 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 builds up. Gaucher Disease is, therefore, a lipid storage disease. 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). Unfortunately, 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 human cost of these events is the loss of function when a hip or shoulder becomes infarcted or a long bone fractures, and the great pain experienced during reduced blood flow to the bones ("bone crises"). There are 4 items of good news: * Carrier testing is reliable and readily available. * An enzyme replacement therapy is available, which provides the missing enzyme. Much of the outcome assessment has yet to be completed, but indications are that the symptoms can be entirely reversed in children with Type I Gaucher Disease. The data are not yet complete with adults, but it would be important to begin treatment before there is significant bone damage. It is not clear whether the neurological forms of Gaucher Disease respond to the enzyme replacement therapy. * 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. * There is an organization for the coordination and dissemination of all sorts of information: National Gaucher Foundation, 11140 Rockville Pike, Suite 360 Rockville, Maryland 20852, USA Toll-free from within the U.S.: 800-925-8885 From Elsewhere: 301-816-1515 fax: 301-816-1516 On the World Wide Web, the Gaucher Disease Homepage is located at: http: //www.gaucherdisease.org --------------------------------------------------------------------------- ESSENTIAL PENTOSURIA --------------------------------------------------------------------------- FAMILIAL DYSAUTONOMIA Familial dysautonomia (FD) is a rare genetic disease that results from the abnormal development of the nervous system, particularly the sensory and autonomic systems. Dys-auto-no-mia literally means the dysfunction of the autonomic nervous system. The autonomic nervous system controls involuntary functions, such as swallowing, temperature and blood pressure regulation. Individuals with FD cannot regulate these autonomic functions. In addition, they have problems in perceiving various sensations, such as pain and heat. One of the most striking manifestations is the inability to produce overflow tears with emotional crying. Severe eye problems are common because of the resulting dry eye and the absence of corneal response to foreign objects in the eye. Feeding problems are one of the earliest signs as many infants have an abnormal suck at birth. Difficulties in feeding can persist and result in poor weight gain, as well as repeated pneumonia due to misdirected swallows. Other common manifestations are indifference to pain (including minimal or no response to bone fractures or blood drawing), inappropriate perception of heat and taste, excessive sweating, labile blood pressures (both episodic hypertension and postural hypotension), gastrointestinal problems, poor speech and motor incoordination. Many children have stunted growth and scoliosis (curvature of the spine). Forty percent of the children are prone to repeated attacks of vomiting. Intelligence is usually normal. Many patients complete college programs and can be expected to function independently if treatment is started early and major disabilities are avoided. Treatment has had a dramatic impact on improving the prognosis of this disorder. Prior to 1960, about 50% of patients died before five years of age. Currently, about 50% of patients reach 30 years of age. The greatest impact on treatment has been the increased use of gastrostomy and fundoplication to avoid aspiration pneumonia and maintain adequate nutrition and hydration. Some other important treatment methods have been the use of diazepam and chloral hydrate to control intractable vomiting attacks, and artificial tears to supplement decreased eye moisture. In addition, blood pressure regulation is enhanced by giving extra fluid and salt, physical therapy to improve leg muscles, and fludrocortisone in some patients. The disease is inherited as an autosomal recessive trait and afflicts boys and girls equally. It only occurs in Ashkenazi Jewish families. It is estimated that one out of every 30 Ashkenazi Jews in America is a carrier. Although population screening is not yet available, prenatal diagnosis and carrier identification are available. These advances were made possible by the localization of the FD gene to chromosome 9q31-33. Diagnosis of FD is made when an individual meets the following criteria: lack of overflow tears, absence of fungiform papillae on the tip of the tongue, absent deep tendon reflexes and an abnormal histamine test (lack of an axon flare following intradermal injection). Sural nerve biopsies have clarified the diagnosis in questionable non-Jewish patients. A Familial Dysautonomia Treatment and Evaluation Center has been established at the New York University Medical Center. For information, contact Dr. Felicia B. Axelrod, Director, 530 First Avenue, Suite 3A, New York, NY 10016 USA; or telephone 212-263-7225. Information on the Web is available at the Familial Dysautonomia Homepage, at Http: //www.med.nyu.edu/fd/fdcenter.html --------------------------------------------------------------------------- FACTOR XI DEFICIENCY Factor XI deficiency is an autosomal recessive inherited disorder, occurring at increased frequency among Ashkenazi Jewish people. The symptoms of heterozygotes (carriers) can be as severe as those of homozygotes (those with two copies of the mutant gene). Symptoms can include minor bleeding episodes, protracted bleeding after surgical procedures, abnormal prothrombin consumption, and prolonged recalcification time. Factor XI is produced only in the liver and there has been a documented case of it being transmitted by a liver transplant. The carrier rate may be as high as 1 in 8 Ashkenazi Jewish people. Factor XI is one of a number of proteins that are involved in the clotting process. There is a cascade effect of protein activation that must take place for proper clotting to occur. If there is a defect in any one of these proteins, there will be decreased efficiency of blood clotting. The severity of the symptoms depend upon whether the mutant gene codes for a defective protein which would lead to decreased function, or whether the mutation leads to an inability to code for a protein at all, which would then lead to more severe symptoms. --------------------------------------------------------------------------- CANAVAN DISEASE Canavan disease, also known as spongy degeneration of the brain, was first described by Myrtelle M. Canavan in 1931. This disease is characterized by the progressive loss of white matter --- giving the brain a spongy, degenerative appearance. Affected infants appear normal after birth. Later they are found to be hypotonic (floppy), fail to achieve head control and become developmentally delayed by five to eight months of life. Characteristic features include mental retardation, hypotonia, a large head and head lag. The severity and life expectancy of patients with Canavan disease vary. Some children die in the first year of life, while others survive beyond their teens. There is no treatment available other than supportive care. A procedure for direct implantation of the necessary gene into the brains of affected individuals was attempted with two children during early 1996. Evaluation of the effectiveness of this procedure is the subject of ongoing evaluation. Until 1988 the diagnosis required brain biopsy to show spongy degeneration of the white matter. In 1987, it was discovered that children with Canavan disease excrete increased amounts of a compound known as N-acetylaspartic acid (NAA) in their urine, and have deficient activity of the enzyme aspartocylase. Following that discovery, many cases of Canavan disease were diagnosed by the increased NAA in the urine. Because the enzyme test does not work in blood samples, a skin biopsy is required for carrier testing. Prenatal diagnosis based on measurement of the enzyme activity is unreliable since the enzyme activity is very low in normal chorionic villi or normal amniocytes. Three mutations causing Canavan disease in Ashkenazi Jewish individuals have been identified. These findings now permit accurate carrier testing and prenatal diagnosis of Canavan disease in the Jewish population. If the recently attempted gene transfer procedure proves to be successful, Canavan Disease will become the first brain-based genetic disorder to be so treated. The Canavan Foundation can be reached (212) 873-4640 or (877) 4-CANAVAN; or by e-mail at canavandisease@aol.com. The Foundation's website address is http://www.canavanfoundation.org. --------------------------------------------------------------------------- TORSION DYSTONIA The tragedy of dystonia, a disease affecting movement control, may be best described through the brief case history of a young girl. Early development was quite normal, but at age six she complained of difficulty walking. Medical evaluation revealed no explanation, and the condition was mistakenly considered psychological. But the torsion spasms progressed and by age 10 she could hardly walk. At age 11, the dystonia was generalized, her limbs were fixed in a twisted posture, and she was confined to a wheelchair. By age 12, she required help for all her daily living activities; she could not feed or dress herself or get in and out of bed unassisted. However, her voice and her mind remained normal. In one of its inherited forms, dystonia is more common in Ashkenazi Jews. In this form (transmitted as an autosomal dominant trait) the disease generally appears between the ages of six and 16 years, and has a fairly rapid rate of progression. The sustained, twisting spasms may be limited to one limb at first but often spread to other limbs and the trunk. The mind is not affected and patients usually are intelligent and mature. The disease can strike non-Jewish families as well, but at a much lower frequency. The abnormal gene causing dystonia in the Ashkenazi Jewish population and in seven non-Jewish families has been localized to the long arm of chromosome 9. This gene has been excluded from at least five non-Jewish patients, indicating the occurrence of at least one other gene causing dystonia in these patients. Dystonia can also be brought about from environmental causes, such as drug reaction, encephalitis or trauma to the head. The earliest description of familial dystonia may have been in 1907 by a psychiatrist-in-training who reported on two brothers and a sister who were hospitalized for "hysterical" torsion spasms. One brother committed suicide in the institution, the sister eventually died of the disease, but the second brother was discharged after several years and later married and had an affected son and daughter. Dystonia is expressed in only 30% of people who carry the abnormal gene. Symptoms occur in about one in every 3,000 Jewish individuals, but one in about 900 actually has the disease gene. Because the gene is not always expressed, the disorder may occur in individuals with no previous family history. In a geographic analysis, it was found that 86 percent of the Jewish carriers of the gene have origins freom Russia, Poland, Lithuania or the Ukraine. Genealogic research has shown that the dystonia gene in the Ashkenazi Jewish population came about from a single mutation about 400 years ago. Life expectancy is usually normal. Some medications have been found to be useful in a proportion of patients, particularly children. Injections of certain drugs into contracting muscles in order to weaken them can be helpful in those who have dystonia limited to only one or two parts of the body. Brain surgery may be useful in some cases of severe intractable dystonia. With the recent chromosomal localization of the gene to chromosome 9q34, it is likely that the gene will be isolated in the future. Genetic screening tests, including prenatal diagnosis, can already be performed on Ashkenazi Jewish individuals. A Dystonia Research Center has been established at the Columbia Presbyterian Medical Center. For further information, contact Dr. Stanley Fahn, Director, 710 West 168th Street, New York, NY 10032, USA; or telephone 212-305-5295. Dystonia Medical Research Foundation: 312-755-0198 (voice) 312-803-0138 (fax) Web: http://www.dystonia-foundation.org E-Mail: dystonia@dystonia-foundation.org --------------------------------------------------------------------------- ABETALIPOPROTEINEMIA --------------------------------------------------------------------------- BLOOM'S SYNDROME To date, over 170 individuals have been recognized as affected with this syndrome since it was first described in 1954 by the New York City dermatologist David Bloom. Bloom's Syndrome is inherited as an autosomal recessive trait. Once a couple has an affected child, there is a one in four risk for affected offspring in each future pregnancy. The mutant gene is very rare in most populations but is more frequent in Ashkenazi Jews, where the carrier rate may be greater than 1 in 110. Carriers of the mutant gene are normally developed and healthy. Affected individuals --- homozygous for the Bloom's syndrome mutant gene --- typically have the following features: (a) an unusually small size at birth but otherwise a normal degree of maturation; (b) shortness of stature after birth, only rarely reaching 5 feet; (c) redness of the skin and face, mainly the bridge of the nose and the adjoining upper cheek areas, the lower eyelids, and the lower lip; and (d) increased numbers of respiratory tract and ear infections, some of which are life-threatening. The skin problem, which is aggravated by sun exposure, varies in severity, being quite disfiguring in some affected persons but mild or even absent in others, but it generally improves with age. Mental ability is usually normal, although mild deficiency has occurred in a few affected persons. Diabetes occurs in about 10% of patients. Infertility is the rule in men with Bloom's Syndrome, and fertility appears to be reduced in women. The risk of cancer is much greater than normal throughout life, of the variety of sites and types that affect the general population. The diagnosis of Bloom's syndrome can be confirmed or ruled out by a cytogenetics laboratory, as cultured blood and skin cells show a diagnostic pattern of chromosome breakage and rearrangement. No test for the carrier state is yet available, but will be once the Bloom's syndrome gene is identified. Efforts to isolate the gene are underway in several laboratories. No treatment is known for the growth restriction. Respiratory infections require prompt antibiotic treatment. Adults with Bloom's syndrome should be more attentive than others in their surveillance for cancer, maintaining close contact with a physician knowledgeable about the syndrome, and paying particular attention to symptoms that could be early evidence of a treatable neoplastic condition. --------------------------------------------------------------------------- NIEMANN-PICK (A+B+C) DISEASE The first case of infantile-onset Niemann-Pick disease was first described in 1914 by the German neurologist Albert Niemann. Subsequently, five subtypes have been identified, but only Types A and B are prevalent in the Ashkenazi Jewish population. Type A disease is a severe neurodegenerative disorder of infancy. By six months of age, affected babies experience feeding difficulty, recurrent vomiting and enlargement of the spleen and liver which causes the abdomen to appear distended. Some have a cherry-red spot on the retina of the eye. Death usually occurs by two to three years of age due to infections which the emaciated and neurologically impaired child cannot overcome. Type B disease is a milder disorder with no neurologic involvement. Affected individuals develop enlarged livers and spleens in childhood which usually bring them to medical attention. With adolescence and adulthood, the major symptoms are associated with pulmonary disease due to involvement of the lungs. Patients with Type B disease may survive into the fourth and fifth decades of life. The specific biochemical defect in both Types A and B Niemann-Pick disease is the deficiency of the enzyme, acid sphingomyelinase, which normally degrades sphingomyelin. Affected individuals with Type A disease have little or no (5% of normal) sphingomyelinase activity, whereas Type B patients have 5-10% of normal activity, thereby accounting for their milder manifestations. The enzyme defect leads to the accumulation of the fatty substance. sphingomyelin, primarily in the liver, spleen, lymph nodes and brain. Recently, the acid sphingomyelinase, which is located on chromosome 11, was isolated. Analyses revealed that three common mutations in the gene (L302P, fsP330, and R496L) were responsible for over 90% of the lesions causing Type A disease in Ashkenazi Jews. Another mutation (delta-R608) was found to be a common cause of the enzyme defect in Jewish and non-Jewish Type B patients. Both Types A and B Niemann-Pick disease are inherited as autosomal recessive traits. Each parent is a carrier of the disease-causing gene and the carrier couple have a 1 in 4 risk for an affected child with each pregnancy. It has been estimated that approximately two-thirds of all infants with Niemann-Pick Type A disease are of Ashkenazi Jewish descent. Niemann-Pick Type B disease is less frequent among Ashkenazi Jews. The incidence of both types in the Ashkenazi Jewish population is estimated to be between 1:20,000 and 1:30,000 births per year. The frequency of carriers for Types A and B disease is estimated to be about 1 in 60 Ashkenazi Jewish individuals. Both Types A and B disease are rare in non-Jews. The diagnosis of affected individuals with Type A or B disease can be made by demonstration of the enzyme defect or the specific mutation(s) in the acid sphingomyelinase gene. Prenatal diagnosis can be reliably made by determination of acid sphingomyelinase activity or specific DNA mutations in chorionic villi obtained in the first trimester of pregnancy, or amniotic cells obtained by amniocentesis in the second trimester. Screening of Jewish individuals to determine if they are carriers of the Niemann-Pick gene is now available using DNA techniques. For more information or patient referral, contact The Mount Sinai Center for Jewish Genetic Diseases at the Mount Sinai Medical Center (Dr. R. J. Desnick, Director), Fifth Avenue at 100th Street, New York, NY 10029 USA. Telephone: 212-241-6944 --------------------------------------------------------------------------- COHEN'S SYNDROME --------------------------------------------------------------------------- BETA-THALASSEMIA Thalassemia is an inherited characteristic of the blood. It reduces the amount of hemoglobin the body can make, thereby causing anemia. The trait is primarily found in people of Mediterranean, African, Southeast Asian, Asian and Indian descent, including Sephardic Jews. It is rare in Northern Europeans. There are two forms of thalassemia: Thalassemia trait. People with thalassemia trait are generally healthy but if two people with thalassemia trait both pass the trait to their child, the child will have thalassemia major. It is estimated that more than two million people in the United States carry the thalassemia trait. Thalassemia major. This is a very serious blood disorder which begins early in childhood. Children who have thalassemia major cannot produce sufficient hemoglobin. They need frequent blood transfusions and medical treatment. The World Health Organization recognizes Thalassemia as the most prevalent inherited genetic blood disorder in the world. There are over 300,000 patients worldwide. Thalassemia Major is sometimes called Mediterranean Anemia, Cooley's Anemia, or Homozygous Beta Thalassemia. For more information, please contact: Cooley's Anemia Foundation California Chapter 19410 Hinsdale Avenue Torrance, CA 90503 USA OR... Cooley's Anemia Foundation National Headquarters 129-09 26th Avenue, Suite 203 Flushing, NY 11354 USA Call 1-800-522-7222 toll-free from within the U.S., or visit the Thalassemia Web Page at Http: //pages.prodigy.com/thalassemia. --------------------------------------------------------------------------- BRONCHIECTASIS --------------------------------------------------------------------------- MUCOLIPIDOSIS IV Mucolipidosis IV (ML IV), first described in 1974, is the most recently recognized Jewish genetic disease. To date, over 70 patients, most of Ashkenazic Jewish descent, have been reported. Children with ML IV are normal at birth and develop signs of central nervous system deterioration during the first year of life. Sitting is delayed and most patients do not walk. Motor and mental retardation is usually mild to moderate, and slowly progressive. Some patients may become more severely retarded in the second or third year of life. The earliest sign is clouding of the corneas, but about 30% of patients only develop corneal clouding between three and five years of age. Other eye findings may include strabismus (crossed eyes), and in some patients retinal degeneration develops which may lead to blindness in later years. There is no involvement of the skeleton nor is there urinary mucopolysaccharide excretion. Patients currently range from one to 30 years of age. Prognosis beyond this age and life expectancy are not known. Recently, a few very mild patients with ML IV have been described, which raised the possibility of other mild undiagnosed patients. The name, ML IV, derives from the presence of diagnostic storage bodies (cytoplasmic inclusions seen under the electron microscope) in almost every cell of these patients. The storage bodies are similar to those observed in the mucopolysaccharide and lipid storage diseases; thus, the designation mucolipidosis. The diagnosis should be considered in mildly to moderately retarded Jewish children who have corneal clouding. The demonstration of the characteristic storage bodies in a conjunctival biopsy by electron microscopy supports the clinical diagnosis. The specific biochemical and genetic defects which cause ML IV are not known. Current research has focused on a possible defect in the metabolism of phospholipids and gangliosides. Further research is required to identify the specific enzyme abnormality which then will permit the development of precise methods for diagnosis including the identification of carriers of the gene which causes ML IV. The disease is inherited as an autosomal recessive trait. Although both parents are normal, they must be carriers of the disease-causing gene. Such carrier couples have a 25% risk for an affected child with each pregnancy. The prenatal diagnosis of this disease has been successfully accomplished by finding the characteristic storage bodies in cultured amniotic cells obtained by amniocentesis early in pregnancy. The prenatal diagnosis is difficult and must be performed in centers with experience in the specialized techniques required for this disease. At present, no specific therapy is available. Optimal supportive care and medical management can significantly improve the quality of life for affected children. Families with affected children should seek genetic counseling and be offered the option of prenatal diagnosis for future pregnancies. For 1996, the ML4 Foundation has committed to funding over $140,000 in medical research grants to the National Institutes of Health, Bethesda, Maryland, New York University Medical Center, New York City, Wolfson Institute, Holon, Israel and Hadassah Hospital, Jerusalem, Israel. At New York University, Dr. Edwin Kolodny, Chief, Department of Neurology, NYU School of Medicine, and his team have made impressive progress in identifying a significant part of what they believe to be the ML4 gene. At the National Institutes of Health, Dr. Brady and his team are working to improve diagnostic techniques for ML4 and to identify definitively an enzyme deficiency in ML4 cells. NIH is collaborating with Dr. Ehud Goldin, who divides his time between NIH and the Wolfson Institute, Holon, Israel. Recently, NIH embarked upon a 3 year clinical study of ML4. All ML4 children in the United States have been invited to participate in comprehensive annual evaluations by teams of specialists. At the conclusion of the study, a paper summarizing the findings will be published. This should lead to the diagnosis of new cases of ML4 or the correct diagnosis of cases that currently are misdiagnosed as "cerebral palsy" or "unknown developmental delay". At Hadassah Hospital, prenatal screening techniques have been vastly improved and families with an affected child now can attempt to have more children without undue worry that they also will have ML4. Contributions to sustain this research are gratefully accepted. All checks should be made payable to the ML4 Foundation, 719 East 17th Street, Brooklyn , New York 11230, USA. You may reach the ML4 Foundation by E-Mail at ML4www@aol.com --------------------------------------------------------------------------- CYSTIC FIBROSIS Although cystic fibrosis is found in all populations, one mutation is found almost exclusively among Ashkenzi Jews. In the homozygous state, cystic fibrosis causes an increased presence of chlorine in exocrine glands - primarily the lungs, liver and pancreas - which cause them to become swollen, forming cysts. In the heterozygous (carrier) state, the CF gene is related to diabetes and male infertility due to a congenital absence of the vas deferens (the tubes that bring sperm out of the testes). The symptoms of CF and the results of the carrier state vary according to the mutation - the mutation carried by most Ashkenazi Jews is considered to be particularly strong and can cause the most severe outcome. The link between infertility and CF has only come to light in the past two or three years. Many men have found out that they are carriers for CF only because of a diagnosis of this type of infertility. In these men, sperm are usually viable and can be extracted directly from the testes and then can be combined to fertilize the egg using in vitro fertilization techniques. So far this procedure has been done with about 70 couples worldwide. --------------------------------------------------------------------------- FAMILIAL MEDITERRANEAN FEVER Familial Mediterranean Fever is an ethnically restricted genetic disease commonly found among Arabs, Armenians, Balkans, Jews originating from North African countries, and Turks. Closely following the pattern of autosomal recessive inheritance, FMF is recognized by two phenotypically independent manifestations: (1) acute, short-lived painful, febrile attacks, accompanied by peritonitis, pleuritis, or arthritis, and (2) nephropathic amyloidosis, which can lead to terminal renal failure even at a young age. Manifestations appear early in life, evident in two-thirds of patients before age two. Although the gene for FMF has been located on the short arm of chromosome 16, the exact pathogenesis of the disease remains unclear. However, the lack of adequate suppression of the inflammatory response to C5a, a complement protein involved with the inflammatory response of the immune system, has been cited as a possible molecular basis for FMF. The identification of FMF is based on clinical findings and particularly family history, as no specific diagnostic test is yet available. However, usually the physical examination and laboratory results obtained from FMF patients experiencing episodes of recurrent acute peritonitis, one of the most common feature of FMF, are identical to those of acute appendicitis. Consequently, up to two-thirds of FMF patients undergo emergency appendectomy with the appendix being normal in most cases. Amyloidosis affects most untreated FMF patients. Its early stage is recognized by the appearance of proteinuria. Colchicine treatment introduced in 1973, in a dose of 1-2 mg/day on a continuous basis, has been found to prevent attacks in most patients and amyloidosis in all patients. However, amyloidosis is still encountered in medication-noncompliant patients and in those who acquired amyloidosis prior to initiation of colchicine. The mechanism of action of colchicine in preventing the attacks and amyloidosis of FMF has not been determined. However, it is evident that colchicine's action in preventing attacks is unrelated to its action in arresting the formation of amyloid, because in some patients who undergo colchicine therapy, the high rate of attacks does not change, but amyloidosis ceases to develop. Arrest of colchicine treatment not only precipitates abrupt exacerbation of the febrile attacks but also enhances development of amyloidosis. Consequently, suspension of colchicine treatment for several months or more prior to conception and during pregnancy, due to the poisonous effects of colchicine on microtubules, is not entirely practical. Colchicine has been shown to cause azoospermia in male patients and chromosomal nondisjunction in lymphocyte cultures. Many colchicine-treated patients planning pregnancy are offered care at a special obstetric FMF-clinic established at the Sheba Medical Center in Tel Aviv, Israel. Primary infertility is much more common in patients with FMF than it is in the general population. In addition, the prevalence of pregnancy loss in women with FMF is considered to be high and patients with amyloidosis are advised not to conceive. Pregnancy during FMF complicated with amyloidosis and severe nephrotic syndrome may cause several maternal and fetal complications. Asymmetrical intrauterine growth retardation, superimposed preeclampsia, thromboembolic phenomena, resistant anemia, and renal failure only partially represent the possible complications. The overall positive effects of the systematic use of colchicine, a high protein diet, acetylsalicylic acid, and dipyridamole on the condition of pregnant women with FMF have been noted. Amniocentesis is carried out on all pregnant FMF patients and karyotype analysis is performed for the detection of any chromosomal abnormalities in the fetus. Moreover, all children born to FMF patients, with or without a history of colchicine use, are screened for teratogenic effects which may have been overlooked. The fate of many of these children is followed long after birth for research purposes. Those interested in more information regarding Familial Mediterranean Fever, should contact Dr. Avi Livneh or Dr. Deborah Zemer at the Sheba Medical Center located in Tel Aviv. Contact Information: Drs. Deborah Zemer and Avi Livneh Heller, Institute for Medical Research, Sheba Medical Center, Tel Hashomer, Israel FAX #:972-3-530-7002 --------------------------------------------------------------------------- CONGENITAL ADRENAL HYPERPLASIA 1. What is "CAH"? Classic CAH: Congenital adrenal hyperplasia (CAH) is an inherited disorder affecting the body's own production of steroid hormones in the adrenal glands. The adrenals are small glands which lie on top of the kidneys and serve to help regulate several bodily functions, including blood pressure and salt balance, among others. The term CAH actually describes a group of different enzyme deficiencies, but in its most common form the enzyme steroid 21-hydroxylase is missing or defective. In the most severe case of CAH due to 21-hydroxlase deficiency cortisol, a vital stress hormone, is lacking. This hormonal imbalance results in excessive production of sex hormones, mainly male hormone precursors (androgens), which masculinize the external genitals of girls before birth, beginning in the first trimester of gestation. These affected girls are born with ambiguous or male-like external genitals, although they have normal uterus and ovaries. Infant males with CAH-21 do not have malformed genitals. Most children born with this disease also lack a salt-retaining hormone, aldosterone, and as a consequence suffer life-threatening dehydration. Nonclassic CAH: A milder form of CAH-21 is characterized by the absence of major prenatal and neonatal hormonal problems. Rather, these individuals are diagnosed in later childhood, adolescence, or young adult life . Their symptoms include early appearance of pubic hair, acne, and premature rapid growth spurt with early cessation of growth. Irregular menstrual cycles and unwanted facial hair are the most often cited complaints of young women. 2. How common is CAH? Classic CAH-21 is found in 1:10,000 newborn infants worldwide. Because of the potentially serious consequences of this disease, several states in the U.S. and other countries now perform newborn screening tests for CAH. Classic CAH-21 is not unusually common among Jews, although another virilizing form of CAH, 11-hydroxylase deficiency, is common among Jews from Eastern countries (e.g., Iran and Turkey) and North Africa (e.g., Morocco). Nonclassic CAH-21 occurs in about 0.1 to 1% of people in the general population varying by ethnic group, but is even more common among Ashkenazi Jews (about 3%). Not all people with mild 21-hydroxylase deficiency experience enough symptoms to warrant their seeking medical treatment. Thus, in adult males particularly, this mild enzyme deficiency may be of little practical importance. 3. How is CAH treated? Classic CAH is treated by administering small daily oral doses of replacement hormones, usually hydrocortisone in infants and children, and if needed, the salt-retaining hormone, fludrocortisone. Salt tablets may additionally be prescribed, but cannot substitute for the hormone treatments. Medical therapy is life-long. Research studies are underway at the National Institutes of Health to explore alternative medical therapies. Girls born with abnormal external genitalia will usually undergo surgical repair in infancy. In the hands of experienced pediatric surgeons, these operations produce excellent results. Nonclassic CAH is treated with low dose cortisol-like drugs only when the physician feels that there are sufficient signs of hormonal imbalance to warrant steroid therapy. Some physicians will use alternative or adjunctive treatments for women with hirsutism and/or irregular menstrual periods. No surgery is required. 4. How does CAH affect a person's life? A child with severe CAH will have to take medication on a daily basis and continue throughout life. A bracelet or necklace is worn to alert health care personnel to the condition. In times of serious illness the dose of medication will need to be increased 2-3 fold for a few days. If dehydration occurs, (s)he may be hospitalized to receive intravenous fluids and steroid medications. It is very important to recognize and appropriately treat this condition, since children who suffer repeated bouts of dehydration leading to shock may suffer permanent brain injury or expire. Effects of repeated dehydration may be as subtle as mild learning disabilities, or more profound cognitive impairment. Despite these warnings, proper parental and medical supervision usually prevents such untoward events, and children with CAH lead normal and long lives. Prenatal diagnosis and therapy are available to couples who have already had a child severely affected child with CAH. Nonclassic CAH is not associated with life-threatening crises. Most often, this milder disorder affects somatic growth and puberty, but affected individuals are otherwise healthy. 5. Does CAH affect sexual and reproductive function? Before the advent of modern surgical techniques and effective medical therapies, girls with classic CAH were largely unable to have intercourse and bear children. As both surgical and medical treatments have improved, more women have married and borne children. Some studies suggest that girls with classic CAH have psychosexual problems, including disturbed gender identities, lesbiansism, asexuality, or adjustment disorders. A vital part of the early management of classic CAH girls and their families is psychological counseling. Sensitivity and awareness of the complexities of this disease for parents and the affected child may avert some, if not all, of these problems. The role of prenatal androgens on the developing human brain is still uncertain, and it would be too simplistic to ascribe these problems to a hormonal imbalance. Nonclassic CAH does not interfere with normal heterosexual relations, and affected girls and women do not require genital surgery. Some men and women with nonclassic CAH have reproductive problems. For men, these may include low sperm counts, which can be improved by steroid treatment. For women, infrequent ovulation may also be treated with steroids, with or without other hormonal therapies. Nonclassic CAH is not an especially common cause of infertility in the Jewish or general populations. 6. How is CAH inherited? CAH is an autosomal recessive trait. The cause is a mutation (genetic defect) in the gene coding for the steroid 21-hydroxylase enzyme. If one inherits defective genes from both parents, disease results. Disease severity depends largely on the type of mutations transmitted. If one has inherited two severely defective genes, the disease picture is usually quite severe. A combination of moderate and severe gene defects produce moderate disease. Either combination of mild and severe, or mild and mild, gene defects produce mild disease. Typically, the patient's disease is only as bad as the least defective gene. The gene defect most commonly found in the Ashkenazi Jewish population is a mild one. 7. Can someone with nonclassic CAH have a child with the classic disease? Yes, but the chances of this happening are not that great. Although most patients affected with nonclassic CAH carry two mildly defective genes for the enzyme steroid 21-hydroxylase, some may have a combination of one mild and one severe gene defect. If such a person marries another carrier of a severe gene defect, and if both transmit their severely defective 21-hydroxylase genes, the child will have severe CAH. Overall, the odds that this might happen is about 1:1,000, and perhaps somewhat lower among Ashkenazi Jews. While prenatal diagnosis and therapy are available to couples who have already had a severely affected CAH child (whose risk is 1:4 for having another such child), the much lower risk for the nonclassic parent makes these invasive measures unwarranted. 8. Does having CAH increase my chance of getting cancer or other bad diseases? There are no data suggesting that CAH predisposes to cancer, heart disease, diabetes, or osteoporosis. 9. What should I do if I think I have a form of CAH? If you or a member of your family thinks (s)he has CAH, you should be examined by a physician specializing in endocrinology (the study of glands and hormones). A pediatric endocrinologist should be chosen to examine a child. CAH may be diagnosed through simple early morning blood tests, or sometimes by a one hour adrenal stimulation test. Your doctor should send the blood to a laboratory experienced in hormonal measurements to detect whether you have an imbalanced hormonal profile consistent with this diagnosis. Families may seek genetic counseling (ask to be referred to a university-affiliated medical center) for questions about risk of having or carrying the disease, prenatal diagnosis and prenatal therapy. 10. Where can I get further information about CAH? The National Addison's Disease Foundation (516-487-4992) has lay information about all forms of adrenal diseases. The Magic Foundation (800-3MAGIC3) is a parent-run organization for family support and lay information about several childhood illnesses, including CAH. The Endocrine Society has brief fact sheets on various endocrine disorders, including CAH (http://www.endo-society.org/pubaffai/factsheet/cah.htm). Those desiring current medical literature may try accessing the National Library of Medicine via the World Wide Web (http://www.nlm.nih.gov, registration and small fees required). Alternatively, Online Mendelian Inheritance in Man provides an excellent summary of all known genetic diseases with literature citations (http://www3.ncbi.nlm.nih.gov/omim/, free). The MESH term to search for is "adrenal hyperplasia, congenital" or "adrenal hyperplasia, type III." It is suggested that you ask your physician to review any information you find through these mechanisms to help interpret the "medicalese." The Congenital Adrenal Hyperplasia FAQs were prepared by: Phyllis W. Speiser, MD Professor of Pediatrics,NYU School of Medicine Chief, Division of Pediatric Endocrinology, North Shore University Hospital, Manhasset, NY 11030, USA Phone: 516-562-4635 email: speiser@nshs.edu ____________________________________________________________________________ FANCONI ANEMIA Fanconi Anemia, named for Swiss pediatrician, Guido Fanconi, is one of the inherited anemias that lead to bone marrow failure (aplastic anemia). It is an autosomal recessive disorder. By that definition, FA is not tied to gender (autosomal). Both parents must carry the same defective gene (recessive) for Fanconi Anemia in order for it to occur in their children. There is a one in four chance with each pregnancy that a child will inherit the disease. Ultimately, FA affects all systems of the body. Patients rarely reach adulthood. Fanconi Anemia often reveals itself when children are between the ages of 3 and 12. They suddenly begin to feel extreme fatigue and have continual colds or viral infections. Frequent nosebleeds or easy bruising may be a first sign. At this point, blood tests may reveal a low white, red, or platelet cell count or a combination of deficiencies. However, Fanconi Anemia may also be evident at birth through a variety of physical defects. These could include any of the following: Thumb and arm anomalies--misshapen of missing thumbs, an incompletely developed or missing radius; kidney problems, skin discoloration (care-au-lait spots); small head or eyes; low birth weight; gastro-intestinal difficulties; heart defects; small reproductive organs in males, short stature as they grow. The severity of the disorder often escalates over time. Patients may experience chronic infection, bruising and bleeding episodes, and frequent hospitalization. A recent follow-up study of Fanconi Anemia "C" gene patients indicate that up to twenty-five percent of these patients will develop leukemia or other cancers. Approximately 50% of the patients with FACC mutations are Jewish, of Ashkenazi and Sephardi descent, and all have two copies of the same mutation. Jewish patients who have a mutation in FACC have a severe clinical picture, with multiple congenital abnormalities, and relatively early onset of hematologic disease. The Fanconi Anemia Research Fund offers support for families diagnosed with FA. In addition we raise funds for research looking for better treatments and ultimately a cure. Those wanting more information may contact us at: 800-828-4891, 541-687-4658, 541-687-0548 FAX, fafund@rio.com - email you may also visit our website at: http://www.rio.com/~fafund/FAHTML/FAHome ___________________________________________________________________________ BREAST and OVARIAN CANCER More than 10% of women diagnosed with breast cancer every year have a family history of the disease; that is, there is evidence that their cancer may be hereditary. Mutations in two different genes, BRCA1 and BRCA2, have been recently implicated in hereditary breast cancer. Mutations in the BRCA1 gene are believed to be responsible for nearly 50% of all inherited breast cancers and for over 75% of inherited breast/ovarian cancers. The BRCA2 gene is not yet fully characterized. It is estimated that from 1 in 300 to 1 in 800 individuals in the U.S. may carry mutations in the BRCA1 gene and the risk for breast cancer conferred by these mutations is 85% by age 70. Many different harmful mutations have been identified in the BRCA1 gene but two in particular, 5382insC and 185delAG, have been found rather frequently in cases of familial breast cancer. The 185delAG mutation has been present in all 10 of the families with breast cancer for which ethnic/religious origin has been reported and all 10 families are Ashkenazi Jewish. So far, only one other Ashkenazi family with breast cancer has been found to have a different mutation in the BRCA1 gene. A study of DNA samples for the 185delAG mutation in 858 unrelated Ashkenazi individuals, unselected for the presence of breast cancer or a positive family history of breast cancer, found that 8 individuals (age and sex unknown) were carriers for this mutation while none of the reference or control DNA samples were positive. This finding suggests a 0.9% (or 9 per 1,000 individuals) carrier frequency of this mutation in Ashkenazi individuals. The authors were careful to point out that this limited sampling may not be truly representative of the entire Ashkenazi population. Most of the samples were taken from individuals undergoing carrier testing for Tay-Sachs disease. None of the 858 samples had the other relatively common mutation, 5382insC. From this study, it was estimated that 16% of breast cancers and 39% of ovarian cancers diagnosed in Ashkenazi women before are 50 are due to 185delAG. By contrast, all known mutations in BRCA1, including 185delAG, only account for 4.1% of all breast cancers and 12% of ovarian cancers in the non-Ashkenazi population diagnosed before age 50. So the observed carrier frequency of just one BRCA1 mutation prevalent in Ashkenazi individuals is several times higher than all known BRCA1 mutations in the non-Ashkenazi population. These results are not surprising since genetic diseases with carrier frequencies of 1% or greater are not uncommon in the Ashkenazim: Tay-Sachs (3-4%), Gaucher (4-6%), Canavan (1.7-2%) and Niemann-Pick (1-2%). The authors do not recommend widespread population testing at this time. Rather, they feel that carefully planned pilot studies need to be conducted to answer critical questions. For example, what is the true age-related penetrance of the 185delAG mutation? What is the true carrier frequency in the Ashkenazi population? Part of the complexity in dealing with screening for a particular mutation such as 184delAG is that while most women will test negative, 10% or more will still develop breast cancer due to other causes. Recognition of the increased frequency of the 185delAG mutation in the Ashkenazi population suggests the realistic possibility of genetic screening in an adult population for predisposition testing for a disease with some potential for prevention. Despite the fact that the BRCA1 mutations are associated with a high risk of cancer, the carrier frequency is relatively low and is on a high background of breast cancer which occurs due to factors (genetic and environmental) other than mutations in BRCA1. References: * Hogervorst, F. et al.Rapid detection of BRCA1 mutations by the protein truncation test.Nature Genetics, 1995;10:208-212. * Struewing, J.P. et al.The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals.Nature Genetics, 1995;11:198-200. This summary was prepared by Georgirene D. Vladutiu, Ph.D.,Associate Professor of Pediatrics & Neurology, State University of New York at Buffalo, School of Medicine & Biomedical Sciences (05.05.96) *****The newsletter of the Cancer Genetic Counseling Program of the Yale Cancer Center may be found at: http://www.gaucherdisease.org/cancer.htm --------------------------------------------------------------------------- --------------------------------------------------------------------------- A source of legal support and advocacy for individuals with rare genetic disorders, provided AT NO COST to patients, is the International Patient Advocacy Association, Attorney Lenny van Pelt, Founder and Director, 800 Bellevue Way, MGM Building, Suite 400, Bellevue, WA 98004 USA. Telephone: 206-462-4037 (voice); 206-462-9532 (fax) --------------------------------------------------------------------------- --------------------------------------------------------------------------- Portions of this file have been contributed by subscribers to the Genetic-Disease E-Mail Discussion List. Some parts are from copyrighted material from the National Foundation for Jewish Genetic Diseases, Genzyme Corporation, the National Gaucher Foundation, and others who may contribute from time to time. Material from copyrighted sources is used with permission. (Last Updated: October 13, 2000) --------------------------------------------------