Annual Guide to Jewish Genetic Diseases

Published August 15, 2003, issue of August 15, 2003.
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The Forward presents this section to provide information on some of the more serious Jewish genetic diseases. There are about 20 “Ashkenazic diseases,” not counting the higher rates of at least four cancer-related genes. The diseases are more prevalent in the Eastern European Jewish population because of centuries of endogamy, literally, “marrying within.”

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FAMILIAL DYSAUTONOMIA

DEFINITION: Familial dysautonomia (FD), 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 Ashkenazi Jews is a carrier of the FD gene.

SYMPTOMS: Unable to control essential bodily functions. Individuals with FD suffer from episodes of cyclical vomiting with high blood pressure and heart rate, sweating and fever, called “autonomic crises,” one of the most devastating symptoms of this disease. Problems with both high and low blood pressure as well as breathing problems (apnea and aspiration pneumonias) result in early death. Infants and young children with FD have delays in 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 FD are the inability to cry tears, which can lead to severe eye damage, and the lack of certain taste buds on the tongue, giving 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, and a carrier test is now available. The reliability of the blood test is greater than 99%.

TREATMENT: The first treatment ever suggested for FD was announced on May 26 of this year. This exciting breakthrough by researchers at Fordham University revealed that a form of Vitamin E (tocotrienol) improves IKAP gene function, which is affected by the FD mutation. Significant improvements have been reported by patients who have begun using tocotrienol, and the treatment holds promise for improving the health and quality of life for those afflicted with FD.

CANAVAN DISEASE

DEFINITION: Canavan disease, carried by one in 35 Ashkenazi Jews, is a disease of the brain and central nervous system. Canavan patients have a deficiency of the enzyme aspartoacyclase, which is necessary for normal brain development, and therefore cannot generate myelin, which insulates nerve cells and allows transmission of nerve impulses.

SYMPTOMS: The disease is first clinically evident when a child is 3 months to 6 months old. The most obvious symptoms are lack of head control, poor muscle tone, increased head circumference and reduced visual responsiveness. Affected infants fail to achieve developmental milestones and later on lose those milestones, causing mental retardation.

TESTING: With a simple blood test, DNA-based carrier screening and parental tests are now available at genetic centers. The American College of Obstetricians and Gynecologists recommends that all Ashkenazi Jewish couples be tested for Canavan.

TREATMENT: At present, gene therapy is being evaluated as a possible treatment for Canavan disease. The only treatments are for relieving discomfort.

CONGENITAL HYPERINSULINISM

DEFINITION: Congenital hyperinsulinism (HI), sometimes referred to as nesidioblastosis or persistent hyperinsulinemic hypoglycemia of infancy (PHHI), is a rare autosomal recessive genetic defect occurring within the Ashkenazic population, among other populations. About one in 100 Ashkenazi 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 HI, 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: HI 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 very low levels of sugar, and intravenous dextrose solution may not be sufficient to raise the concentration to stable levels.

TREATMENT: Initial treatment is usually with high concentrations of intravenous dextrose and/or glucagon, then with the drugs diazoxide and octreotide. If the defect is severe, medical therapies are ineffective. 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 eventually 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 Internet for information about HI is www.sur1.org.

TAY-SACHS DISEASE

INFANTILE-ONSET TAY-SACHS

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 this disease is present in about one in 27 Ashkenazi Jews in America. About one in 250 Sephardi Jews and people not of Jewish descent are also carriers.

SYMPTOMS: The disease usually is not clinically evident until a child is 4 months to 8 months old, when peripheral vision is lost and an abnormal startle response is observed along with delayed 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 present 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 determines 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 and substrate deprivation 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 detected in less than 200 patients. The prevalence of the late onset gene among Ashkenazi Jews is not known.

SYMPTOMS: Symptoms are not consistent among patients. They include clumsiness, speech impediments, 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 currently in progress and in development hold a lot of promise. The first clinical trial in patients with LOTS is currently underway at two sites: The University Hospitals of Cleveland and New York University. This therapy is looking at the effects of enzyme inhibition therapy, which reduces the formation of fatty substances that cannot be broken down by the low hex A enzyme level. Preliminary results should be available in about one year. Stem cell therapy and gene therapy may both hold hope for treatment in the future, and some laboratories are currently investigating these therapies in mouse models. 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, similar to the enzyme replacement therapy that is now available for similar diseases, such as Gaucher and Fabry disease.

FANCONI ANEMIA

DEFINITION: Fanconi anemia is a fatal, recessive blood disorder that causes bone marrow failure and may cause birth defects. One in 87 people of Ashkenazic 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 Fanconi anemia. 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. Fanconi anemia may sometimes be seen at birth through physical defects, such as missing thumbs, kidney problems or an undersized head or sex organ.

TESTING: The only definitive test is a chromosome breakage test. Some of the patients’ 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 prenatally.

TREATMENT: Researchers are still looking for a cure for this disease. A number of treatments exist, ranging from a medication called Oxymetholone, used to stimulate hemoglobin, to a bone-marrow transplant. Patients will always carry the defective gene and are susceptible to malignancies such as leukemia and head, neck, gastrointestinal and gynecological cancers.

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. For 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 Ashkenazi 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 shows symptoms. This disease occurs in non-Jews, but is much rarer.

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

TESTING: 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. Indications are that enzyme replacement therapy reverses the symptoms of Gaucher disease, allowing individuals to enjoy a better quality of life.

MUCLOLIPIDOSIS TYPE 4

DEFINITION: Muclolipidosis (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 Ashkenazi Jews; one out of 100 Ashkenazi Jews are carriers.

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 abilities in crawling, walking, talking and learning basic skills. ML4 also severely limits vision. Many patients experience clouding of the cornea.

TESTING: Currently, 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. Carrier testing is available. ML4 may soon be added to the battery of diseases screened for in the United States.

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

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 Bloom’s syndrome 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 Ashkenazi Jews, resulting in the disease manifesting itself in about one in 50,000 births.

SYMPTOMS: The major symptom of Bloom’s syndrome is short stature and low birth weight. A rash upon exposure to the sun is also common.

TESTING: Prenatal carrier screening is available.

TREATMENT: There is no complete treatment, although staying out of the sun prevents the rashes. A possible treatment for Bloom’s syndrome is through gene therapy, but research in this regard has not progressed very far.

DYSTONIA

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 not a fatal disorder.

In 1997, researchers identified the DYT1 gene responsible for one form of the disease, early-onset generalized dystonia. The gene that causes this form of the disease is dominant, and a carrier has a 30% to 40% chance of developing symptoms. There are other types of idiopathic torsion dystonia (ITD), also described as dystonia musculorum deformans or generalized dystonia, which is more prevalent in Ashkenazi Jews than in the general population. Estimates for the gene’s prevalence in the Ashkenazic population vary, 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 in a foot or a leg. It often spreads to other parts of the body, including the back, neck or arm.

TESTING: There is now a simple blood test for DYTI, and hopefully that testing will soon be available for other forms of the disease. The diagnosis of dystonia also rests upon 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 treatments include drug therapy, botulinum toxin injections and several types of surgery. With the mapping of the gene code, gene or enzyme therapy may become a possibility.

NIEMANN-PICK DISEASE

DEFINITION: Niemann-Pick disease includes several subtypes, two of which stem from a deficiency of the 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 73 Ashkenazi Jews is a carrier.

Type A is a neurodegenerative disorder of infancy, and type B is a milder disorder that doesn’t affect the brain but results in involvement of the liver, spleen, lungs and bone marrow.

SYMPTOMS: Type A begins in the first few months of life, and symptoms may include feeding difficulties, an abnormally large abdomen at the age of 3 months to 6 months and progressive loss of early motor skills. Type A generally leads to death by 2 or 3 years of age. 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, specific DNA mutations in blood somes or by analyzing chorionic villi or amniotic cells early 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 these mice by bone-marrow transplantation and gene therapy.






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