One Test, Eleven Answers

In every ethnic, demographic, or racial group, there are certain inherited disorders that occur more frequently than in the general population. Such is the case for Ashkenazi Jewish individuals whose ancestors lived in Central or Eastern Europe . If you and/or your spouse are of Ashkenazi Jewish descent, you have the opportunity to be screened for eleven inherited life-threatening diseases that are more prevalent among Ashkenazi Jews. These genetic diseases include:

• Tay-Sachs
• Familial Dysautonomia (FD)
• Canavan Disease
• Niemann-Pick
• Gaucher Disease (Type I)
• Cystic Fibrosis (CF)
• Fanconi Anemia (Type C)
• Bloom Syndrome
• Mucolipidosis type IV
• Maple Syrup Urine Disease
• Glycogen Storage (type 1a)

The Genetic Disease Foundation has spearheaded an awareness campaign to educate physicians and their patients about the availability of screening for these eleven diseases for individuals and couples of Ashkenazi Jewish descent. For such individuals and couples, the physician can order one simple blood test to determine if either carries a gene mutation that can cause any of these diseases in their children.

Testing availability.

Screening for any of the eleven diseases can be performed individually at many labs throughout the US as well as outside the US . The Genetic Diagnostic Laboratory of Mount Sinai School of Medicine can do screening for all eleven diseases on one blood sample (a total of 5 tubes of blood), as well as select diseases. For patient testing call The Jewish Genetic Disease Screening Program of Mount Sinai School of Medicine at 212-241-6947 or contact any of the other major US laboratories performing carrier testing for Jewish Genetic Diseases (click on Diagnostic Testing Laboratories on the GDF Home Page for a list with contact information).

What Is Genetic Screening?

Genes are the basic units of heredity passed from parent to child. They occur in pairs, and we inherit one member of each pair from our mother and the other from our father. A change in a gene, known as a mutation, can cause that gene not to work properly, which can lead to disease.

Certain diseases are caused when both genes of a pair have mutations. This type of disease is called a recessive disease. In order to have a child with a recessive disease, each parent has a gene that works properly and a gene that does not. The parents are known as carriers and do not have any health problems related to that gene. Genetic screening can identify carriers by a simple blood test to determine if a couple is at risk to have a child affected with a specific disease.

What if both partners are carriers?

If both partners in a couple are identified as carriers for the same disorder, they have a 25% risk with each pregnancy to have a child affected with that disease. They also have a 50% chance that the child will be a carrier, and therefore normal like the parents, and a 25% chance that the child will not inherit a non-working gene from either parent. If a couple is at risk to have a child with any of the diseases for which we screen, prenatal diagnosis is available to determine whether or not the fetus is affected. Diagnosis is possible through either chorionic villus sampling (CVS) at 10-12 weeks of pregnancy or amniocentesis in the second trimester of pregnancy. In addition, new technologies are creating other reproductive options. When a carrier couple is identified, a genetic counselor can provide information and support that may be helpful in making important family planning decisions.

Ideally, both members of a couple should be screened prior to starting a family or as soon as you learn of your pregnancy to allow all available options to be considered. An individual may decide to be screened for each of the eleven diseases or for select diseases.

Diseases for which screening is available.

The following is a list of the eleven diseases for which screening is available for individuals and couples of Ashkenazi descent with a brief description of each, including frequency of occurrence and detection rate. A summary table is at the end.

Tay-Sachs Disease is a disorder in which the central nervous system progressively degenerates. It is caused by the absence of a vital enzyme called hexosaminidase A. Without this enzyme, a fatty substance builds up abnormally in cells especially in nerve cells of the brain. This destructive process begins in the affected fetus early in pregnancy, although the disease is not apparent until the child is several months old. This degeneration causes loss of coordination, seizures, difficulty swallowing, and poor pulmonary function. Symptoms usually appear at about 6 months of age. Eventually, children with Tay-Sachs disease become blind, severely mentally retarded, paralyzed, and unaware of their surroundings. There is no treatment, and average life expectancy is 3-5 years.

About 1 in 25 Ashkenazi Jewish individuals is a Tay-Sachs carrier. The gene is also relatively common in the French Canadian population and the Cajun community in Louisiana . Tay Sachs disease can occur in Jews of Sephardic origin and in the non-Jewish community.

Carrier screening involves analysis of the enzyme responsible for Tay-Sachs disease. The detection rate for carriers is approximately 99%.

Familial Dysautonomia (FD) is a severe disease of the autonomic nervous system. Autonomic nerves control functions such as swallowing, sweating, and the ability to cry with tears and to sense pain. Individuals affected with FD are incapable of producing overflow tears with emotional crying. Frequent manifestations of FD include inappropriate perception of heat, pain, and taste, as well as, labile blood pressures and gastrointestinal dysmotility. Other problems experienced by individuals with FD include excessive sweating, dysphagia and vomiting, aspiration and frequent pneumonia, speech and motor un-coordination, labile blood pressures (episodic hypertension and postural hypotension), poor growth and scoliosis. Affected individuals usually are of normal intelligence. FD patients can be expected to function independently and major disabilities avoided if treatment is begun early.

The carrier frequency in the Ashkenazi population is 1/35. Testing for two common mutations provides a carrier detection rate of 99.5%.

Canavan disease is a progressive disease of the central nervous system for which there is no treatment. Symptoms, which begin in infancy, include poor head control, generalized weak ness and enlarged head size. Affected infants also develop seizures, regression of early development milestones and severe mental retardation. Canavan disease is typically fatal in childhood and there is no treatment.

The carrier frequency in the Ashkenazi Jewish population is about 1 in 40. Testing involves analysis of common mutations in this gene and the detection rate is about 97%.

Niemann-Pick Disease , Type A is a severe neurodegenerative condition of infancy that cannot be treated. It is caused by the deficiency of the enzyme, acid sphingomyelinase, which results in an abnormal accumulation of the fatty substance, sphingomyelin primarily in the liver, lung, lymph nodes and brain. Five subtypes of Niemann-Pick disease have been identified, but only Type A is more frequent in Ashkenazi Jewish populations. By six months of age, affected babies with Type A disease experience feeding difficulty, recurrent vomiting and enlargement of the spleen and liver, which causes the abdomen to appear distended. Some have a characteristic "cherry-red spot" in the retina of the eye. Death usually occurs by two to three years of age, due to infections such as pneumonia.

Approximately 1 in 70 Ashkenazi Jewish individuals carries the Niemann-Pick disease gene. Testing for the common mutations allows a detection rate for carriers of about 95%.

Gaucher disease (Type 1) results from the deficiency of the enzyme acid B-glucosidase, and the subsequent accumulation of its unmetabolized substrate called glucosylceramide. This substance is deposited in unique cells known as Gaucher cells in the spleen, liver and bone marrow. Type I Gaucher disease is characterized by enlargement of the spleen and liver as well as blood abnormalities, including anemia, easy bruising, and impaired clotting. In addition, there are orthopedic problems, such as bone and joint pain and an increased susceptibility to bone fracture. The age of onset of symptoms is variable, with some individuals showing symptoms in childhood and others remaining relatively symptom-free into their 50s or 60s. The severity of symptoms varies among patients. 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 disease is the most common genetic disorder in the Ashkenazi Jewish population, with a carrier frequency of about 1 in 19. Analysis of common mutations allows a detection rate for carriers of about 95%.

Cystic fibrosis (CF) is a progressive, lifelong condition in which the glands that produce mucus, sweat, and intestinal secretions do not function properly. This dysfunction results in thick mucus accumulation in the lungs, leading to breathing difficulty and infection. CF also causes poor digestion, and males with this disease are usually infertile. There is no cure for CF. Supportive treatments are available to help improve quality of life, and average life expectancy has improved over the years. While some babies with CF still die in infancy, many patients with CF live into their 20s and 30s.

CF is found in all ethnic groups. It is most common among Caucasians, Jewish and non-Jewish alike, with a carrier frequency of about 1 in 25. By testing for some of the more common mutations, 96% of Ashkenazi Jewish CF carriers can be identified, as can 85% of non-Jewish Northern European CF carriers.

Fanconi Anemia (Type C) is a chronic disease associated with short stature, bone marrow failure, congenital malformations, and a predisposition to leukemia. For some children, the condition may also involve learning disabilities or mental retardation.

The carrier frequency in the Ashkenazi Jewish population is about 1 in 90. Testing for one common mutation provides a carrier detection rate of approximately 95%.

Bloom syndrome is a condition in which children grow poorly, have frequent infections, and may have learning disabilities. As adolescents and young adults, individuals with Bloom syndrome are predisposed to develop common cancers such as breast cancer, colon cancer, and leukemia.

The carrier frequency in the Ashkenazi Jewish population is approximately 1 in 100. Testing for one common mutation allows for a carrier detection rate that is greater than 95%.

Mucolipidosis Type IV (MLIV) is a severe neurodegenerative condition that is characterized by a variable degree of growth and psychomotor retardation. In addition, many patients have abnormalities of the cornea and retina , including pseudostrabismus (false appearance of crossed eyes) and/or retinal degeneration, which may lead to blindness in later years. There is no involvement of the skeletal system or urinary mucopolysaccharide excretion. Patients currently range from one to 45 years of age . Most patients never develop the ability to speak or walk and remain at the developmental level of 1 to 2 years of age.

The carrier frequency in the Ashkenazi population is approximately 1 in 125. Testing for two mutations provides a carrier detection rate of 96%.

Maple Syrup Urine Disease (MSUD) results from an enzyme deficiency which prevents the body from properly breaking down three essential amino acids, leusine, isoleusine, and valine. They are essential because they are used by the body to build proteins, and they are three of 11 amino acids that must be obtained as part of the daily diet since the body cannot synthesize them. Symptoms of MSUD manifest in the newborn period and can result in severe neurological complications and death. After ingesting dietary protein, infants show signs of neurological impairment including poor suck, irritability, lethargy, and, if untreated, will ultimately lapse into a coma. MSUD patients can be effectively managed with dietary restriction of the involved amino acids and the maintenance of strict biochemical control. State newborn screening enables early recognition of the disease, however, a significant proportion of treated individuals have impaired intellectual development or neurological complications, particularly as a result of delayed diagnosis, infection, or stress.

Although more than one gene has been found to result in MSUD, the primary gene responsible for the condition in the Ashkenazi Jewish population is the E1B gene. The carrier frequency of E1B in the Ashkenazi Jewish population is approximately 1/80. Screening for three mutations in the E1B gene provides a carrier detection rate of greater than 95%.

Glycogen storage disease Ia (GSD Ia) , also known as von Gierkes disease, results from a deficiency of the enzyme glucose-6-phosphatase (G6Pase). Symptoms usually present in infancy. Individuals with GSD Ia have difficulty controlling their blood glucose levels and within a few hours after eating the blood glucose level can drop dangerously low. This often results in chronic hunger, fatigue, and irritability that is especially noticeable in infants. Symptoms of hypoglycemia only begin to appear when the interval between feedings increases and the infant sleeps through the night or when an illness prevents normal feeding routine. If the blood sugar falls to a low enough point, some patients may experience seizures. Individuals with GSD Ia experience a variety of biochemical abnormalities and delayed growth and development. Although dietary restrictions has proven to be effective in the management of GSD Ia, related long term complications, including liver and renal problems, persist.

The carrier frequency for GSD Ia among the Ashkenazi Jewish population is at least 1/130, and may be higher among certain subpopulations. Screening for two mutations in the G6Pase gene provides a carrier detection rate of 95%.