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Annual Guide to Jewish Genetic Diseases

Bloom’s Syndrome

Definition: Bloom’s syndrome is a recessive disorder characterized by growth deficiency, sun sensitivity, immunodeficiency, and a predisposition to diabetes and cancer. Genes in people with Bloom’s syndrome are more likely to mutate, causing chromosomes to break. In a survey of Bloom’s syndrome cases in Israel in the 1970s, the carrier frequency of the mutation in the Ashkenazic Jewish population was estimated to be about one in 120. A more recent survey by a team of researchers in New York is estimating a frequency of one in 107 among Ashkenazic Jews, resulting in the disease manifesting itself in about one in 500,000 births.

Symptoms: The major symptoms of Bloom’s syndrome are short stature and low birthweight. A rash on exposure to the sun is also common.

Testing: Prenatal carrier screening is available.

Treatment: There is no treatment for the underlying cause of Bloom’s syndrome. Therefore, medical intervention is primarily preventative, with advice to stay out of the sun to prevent rashes. Adults with Bloom’s syndrome should be more cautious than others in their surveillance for cancer. A new center for the treatment of Bloom’s syndrome was established this year at Ohio State University.

Canavan Disease

Definition: Canavan disease, which is carried by one in 40 Ashkenazic Jews, is a disease of the brain and central nervous system. Canavan patients have a deficiency of the enzyme aspartocyclase, which is necessary for normal brain development, and therefore they cannot generate myelin, which insulates nerve cells and allows transmission of nerve impulses.

Symptoms: The disease is first clinically evident when, at 3 to 6 months old, a child fails to achieve developmental milestones. Symptoms include poor muscle tone, increased head circumference, lack of head control and reduced visual responsiveness. Over time, mental functioning deteriorates and some experience seizures. Testing: With a simple blood test, DNA-based carrier screening and prenatal tests are now available at genetic centers. The American College of Obstetricians and Gynecologists recommends that all Ashkenazic Jewish couples be tested for Canavan disease.

Treatment: At present, gene therapy is being evaluated as a possible treatment for Canavan disease. There is no cure. Most children born with Canavan disease die before 10 years of age.

Congenital Hyperinsulinism

Definition: Congenital hyperinsulinism (H.I.), sometimes referred to as nesidioblastosis or persistent hyperinsulinemic hypoglycemia of infancy (PHHI), is a rare autosomal recessive genetic defect occurring in the Ashkenazic Jewish population, among others. About one in 100 Ashkenazic Jews is a carrier. The disease affects the body’s sulfonylurea receptors in the pancreas, which control the secretion of insulin to regulate the levels of glucose in the bloodstream.

In individuals with congenital hyperinsulinism, the sulfonylurea receptor system is blocked, so the beta cells of the pancreas keep pumping insulin at full output. This causes blood-sugar levels to plummet, which can result in seizures, brain damage and death.

Symptoms: Congenital hyperinsulinism usually presents itself shortly after birth and varies in severity. When the blood-glucose levels fall too low, an infant may become lethargic, suddenly turn blue or experience seizures. Testing: A blood-glucose test will show that very low levels of the sugar and intravenous dextrose solution may be sufficient to raise the concentration to stable levels.

Treatment: Initial treatment is usually given with high concentrations of intravenous dextrose and/or glucagons, then with the drugs diazoxide and octreotide. If the defect is severe, medical therapies are ineffective and the only successful treatment to date is partial or full removal of the pancreas. When drug treatment fails, surgery must be done as soon as possible as the instability of the disease in infants is extremely dangerous and difficult to manage. Following surgery, most children do quite well — some needing little follow-up and others needing some continued treatment, although not with the same urgency as before. Long-term prognosis is usually good, with a significant percentage of patients developing insulin-dependent diabetes. Children’s Hospital of Philadelphia researches and treats many hyperinsulinism cases. Other centers are in Toronto, Paris and Jerusalem. A site on the World Wide Web that has information about H.I. is


Definition: Dystonia is a neurological disorder characterized by involuntary muscle contractions, sometimes with intermittent spasms or tremors. It can affect any part of the body but does not affect intellect. It is rarely fatal. In 1997, researchers in the United States identified a mutation in the DYT1 gene as being responsible for the most serious form of the disease, an idiopathic torsion dystonia (ITD) called Oppenheim’s Dystonia. This is an early-onset generalized form of dystonia that usually strikes a child around the age of 6 and progresses over the next few years to commonly involve much of the body’s skeletal muscles. Although rare compared with other forms of dystonia, it is three to five times more prevalent in Ashkenazic Jews than in the general population. The estimates vary for the prevalence of the gene in the Ashkenazic population, ranging from one in 900 to one in 3,000.

Symptoms: Dystonia manifests itself in sustained, involuntary contractions of the muscles in one or more parts of the body. ITD typically starts in one part of the body, usually a foot or a leg. It often spreads to other parts, including the back, neck or arm.

Testing: There is now a simple blood test for DYTI, and hopefully that testing soon will be available for other forms of the disease. The diagnosis of dystonia also rests on neurological examination. Prenatal diagnosis can be determined from samples of amniotic fluid from the pregnant woman’s womb.

Treatment: There is no cure for dystonia, but treatment generally exists in three tiers with oral medications, botulinism toxin injections and surgery. These therapies can be used in conjunction with each other or alone. Complementary care, such as speech and physical therapy, also may play a role in treatment management depending on the disease’s form. With the mapping of the gene code, gene or enzyme therapy might become a possibility.

Familial Dysautonomia

Definition: Familial dysautonomia (F.D., also known as Riley Day syndrome) is a progressive neurogenetic disorder that affects the sensory and autonomic nervous systems. It is estimated that about one in 27 Ashkenazic Jews is a carrier of the F.D. gene.

Symptoms: Unable to control essential bodily functions, individuals with F.D. suffer from episodes of cyclical vomiting accompanied by high blood pressure and increased heart rate, sweating and fever. These “autonomic crises” are one of the most devastating symptoms of this disease. Problems with both high and low blood pressure, as well as with breathing (apnea and aspiration pneumonias), result in early death. Infants and young children with F.D. experience delayed speech and motor development, difficulty suckling and feeding, and low muscle tone. As they age, poor growth, back curvatures (scoliosis and lordosis) and decreased sensation to pain and temperature become evident. Two hallmarks of F.D. are the inability to produce tears, which leads to severe eye damage, and the lack of certain taste buds on the tongue, which gives it a relatively smooth or shiny appearance. Intelligence is usually normal in affected individuals; however, learning disabilities are common.

Testing: In January 2001, the two mutations that cause the disease were identified. A carrier test is now available. The reliability of the blood test is greater than 99%.

Treatment: In 2004, researchers at Fordham University discovered that a form of Vitamin E (tocotrienol) can be used to treat F.D. Patients who have begun using tocotrienol have reported significant improvement. Additional projects include studies involving pacemakers and clinical trials of new drugs that hopefully will be able to alter the genetic error that causes the disease.

Fanconi Anemia

Definition: Fanconi anemia is a fatal, recessive disorder that causes bone marrow failure and possible birth defects. One in 87 people of Ashkenazic Jewish ancestry carries a defective Fanconi anemia gene. If both parents carry a defect in the same Fanconi anemia gene, each of their children has a 25% chance of having the disease. Patients usually do not reach adulthood.

Symptoms: Patients may feel fatigue and have frequent infections, nosebleeds or bruises. Blood tests may show a low white or red blood cell or platelet count or other abnormalities. Sometimes Fanconi anemia can be seen at birth through physical defects, such as missing thumbs, kidney problems, or an undersized head or sex organ. Testing: Carrier testing is available. The only definitive test for suspected patients is a chromosome breakage test. Some of the patient’s blood cells are treated in a test tube with a chemical that affects the DNA, causing Fanconi anemia cells to show chromosome breakage. These tests can be performed pre-natally.

Treatment: Researchers are still looking for a cure for this disease. Although there is no definitive cure, there exists a range of treatment possibilities. Androgens, effective in approximately half of F.A. patients, stimulate the production of red blood cells and often platelets; however, after years of use they fail to be effective. Hematopoietic (blood-stimulating) growth factors such as G-CSF are also used. Gene therapy trials are underway as a possible means of treatment, but currently stem cell transplantation is the only long-term cure for the disease’s blood defects. Patients always will carry the defective gene and are susceptible to leukemia, as well as to head, neck, gastrointestinal and gynecological disorders.

Gaucher Disease

Definition: Gaucher disease results from defects in a gene that is responsible for an enzyme called glucocerebrosidase. This enzyme helps the body break down particular kinds of sugary fat. In people with Gaucher disease, the body is not able to produce this enzyme properly and the fat cannot be broken down. The sugary fat accumulates, primarily in the liver, spleen and bone marrow. Among Ashkenazic Jews, Gaucher disease is the most common genetic disorder. About one in 13 individuals is a carrier. Some one-tenth to one-third of those with the disease show symptoms.

Symptoms: The major signs and symptoms are an enlarged liver and spleen, low blood counts and bone pain and fracture. Patients may have increased bleeding and anemia-induced fatigue.

Testing: Carrier testing is available. A simple blood test is used to determine whether a person experiencing symptoms has Gaucher disease. Chorionic villus sampling and amniocentesis can be used to diagnose Gaucher disease during early pregnancy.

Treatment: In the spring of 1991, enzyme replacement therapy became available as the first effective treatment for one of the variants of the disease. The treatment consists of a modified form of the glucocerebrosidase enzyme that is administered intravenously. Initial results suggest that the enzyme replacement therapy reverses the symptoms of Gaucher disease, allowing individuals to enjoy a better quality of life. In July 2003, the FDA approved the the drug Zavesca for patients with type 1 Gaucher for whom enzyme replacement is not an option.

Mucolipidosis Type 4

Definition: ML4, first described in 1974, is characterized by the deficiency of a transport protein that plays a crucial role in psychomotor development. It is the most recently recognized genetic disorder affecting Ashkenazic Jews; one out of 100 is a carrier.

Symptoms: Children with ML4 begin to exhibit developmental delays during the first year of life. Motor and mental retardation can be mild to severe. Patients with ML4 have severely impaired ability in crawling, walking, talking and in learning basic skills. Vision is also limited severely. Many patients experience corneal clouding. Testing: Carrier testing is available. ML4 soon might be added to the basic battery of diseases screened in the United States. A diagnosis of ML4 is made in mildly to moderately retarded Jewish children who also have corneal clouding. Prenatal diagnosis, which has been successful through amniocentesis, must be performed at centers that have experience with specialized techniques.

Treatment: No specific treatment is available; care focuses on support therapies, such as speech or physical therapies, and medical management to improve quality of life. The recent discovery of the gene eventually may lead to gene therapy or other forms of treatment.


Definition: Niemann-Pick disease includes several subtypes, two of which stem from a deficiency of acid sphingomyelinase, an enzyme that breaks down a fatty substance called sphingomyelin. As a result of the enzyme deficiency, the unbroken-down fat accumulates, mainly in the spleen, lymph nodes and brain. About one in 90 Ashkenazic Jews is a carrier of Niemann-Pick Type A, which is neuro-degenerative and leads to death by 2 or 3 years of age. Type B is a milder disorder that does not affect the brain but results in complication of the liver, spleen, lungs and bone marrow.

Symptoms: Type A begins in the first few months of life, and symptoms might include feeding difficulties, an abnormally large abdomen at the age of 3 to 6 months, and progressive loss of early motor skills. The symptoms for Type B may include abdominal enlargement and respiratory complications.

Testing: Carrier testing can be done by DNA analysis, and prenatal diagnosis can be made by determining acid sphingomyelinase activity, DNA mutations in blood somes, or by analyzing chorionic villi or amniotic cells in pregnancy. Treatment: The acid sphingomyelinase gene has been used to produce large quantities of the human enzyme in the laboratory for future therapeutic evaluation. Mice with Niemann-Pick Type A have been generated, and studies have been initiated to treat them with bone marrow transplantation and gene therapy. Although currently there is no effective treatment for persons with the Type A form, bone marrow transplantations have been performed, with encouraging results, in patients with Type B Niemann-Pick. The development of enzyme replacement and gene therapies also maybe helpful for those with Type B.

**Tay-Sachs Disease Infantile Onset **


Definition: Tay-Sachs disease is caused by the congenital absence of a vital enzyme, Hexosaminidase-A. Without the enzyme, the body cannot break down one of its fatty substances, which builds up abnormally in the brain and progressively impairs the central nervous system.

The gene that causes the infantile form of the disease is present in about one in 27 Ashkenazic Jews in America. About one in 250 Sephardic Jews and people of non-Jewish descent are also carriers.

Symptoms: The disease is usually not clinically evident until a child is 4 to 8 months old, when peripheral vision is lost and an abnormal startle response is observed, along with delayed or reversed developmental milestones. By age 1, most patients begin to lose motor and coordination skills. Eventually, they become blind, mentally retarded and paralyzed. Death usually occurs by age 5. In juvenile Tay-Sachs, symptoms appear and progress in early childhood, and life expectancy is longer.

Testing: A blood test determines the amount of Hex-A in the cells and reliably predicts whether a person is a carrier. DNA testing is also available. If both members of a couple are carriers, they have a one-in-four risk of having an affected child. Amniocentesis or chorionic villus sampling can determine if the fetus is affected. If testing occurs during pregnancy, leukocyte analysis should be utilized to reduce the chances of an inconclusive result. Treatment: Only symptom control and discomfort relief are available. Current research includes gene therapy, skin-cell therapy, stem-cell therapy, substrate deprivation therapy and pharmacological chaparone therapy.

Late Onset Tay-Sachs

Definition: Late onset Tay-Sachs (LOTS) occurs in adolescents and adults and is the result of having only small quantities of Hexosaminidase-A rather than a complete absence. Since the first cases were described in the 1970s, the disease has been dianosed in fewer than 200 patients. The prevalence of the late onset gene among Ashkenazic Jews is not known.

Symptoms: Symptoms are not consistent among patients. They include clumsiness, slurred speech, unstable gait and balance, muscle weakness, tremors, memory impairment and mood alterations.

Testing: Same as for infantile-onset Tay-Sachs. In the past, many affected people were misdiagnosed as having muscular dystrophy or multiple sclerosis.

Treatment: While in the past, treatment has been focused on managing the varied symptoms of LOTS, new therapies in progress and in development hold a lot of promise. The first clinical trial for patients with LOTS, which looked at the effects of substrate inhibition therapy, was concluded earlier this year. Results were not consistently positive enough to proceed with an additional FDA application for the drug, although those patients who feel they have been helped by it can continue to take the medication, under their physician’s care. Currently a popular area of genetic disease research, pharmacological chaperone therapy is being looked at as a possible treatment for Tay-Sachs. Designed to combine selectively with the protein target, molecular chaperones compensate for the misfolding and instability of the original mutation and restore function of the protein or enzyme to its normal limits. Also on the horizon is enzyme replacement therapy, but the trick here is getting the Hex-A enzyme into the central nervous system once it is in the body. Investigators are currently looking at this option, which is analogous to the enzyme replacement therapy that is now available for other lysosomal storage diseases, such as Gaucher disease.

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