Annual Guide to Jewish Genetic Diseases

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.”


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, low birth weight, immune system deficiencies, poor appetitive and esophageal reflux. A facial rash due to exposure to the sun is also common.

Testing: Prenatal carrier screening is available and recommended. (Bloom’s Syndrome is on the panel of disorders the Jewish Genetic Disease Consortium recognizes and recommends testing for.)

Treatment: There is no treatment for the underlying cause of Bloom’s syndrome. Therefore, medical intervention is primarily preventive, with advice to stay out of the sun to prevent rashes. Individuals with Bloom’s syndrome should be more cautious than others in their surveillance for cancer. A new center for the research of Bloom’s syndrome was established by the Bloom’s Syndrome Foundation in 2006 at Ohio State University Comprehensive Cancer Center.


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, stem cell 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.), also referred to as persistent hyperinsulinemic hypoglycemia of infancy (PHHI), or less commonly as nesidioblastosis, 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 impaired, so the beta cells of the pancreas keep secreting insulin, regardless of the blood sugar level. This causes dangerously low blood-sugar levels, 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 very low levels of sugar and intravenous dextrose solution may be sufficient to raise the concentration to stable levels.

Treatment: Initial treatment usually includes high concentrations of intravenous dextrose and/or glucagon, then treatment with the drugs diazoxide and octreotide is trialed. 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 need little follow-up and others need 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. The Children’s Hospital of Philadelphia researches and treats many hyperinsulinism cases. Other centers are in Paris and Jerusalem. A site on the World Wide Web that has information about H.I. is www.sur1.org.


Dystonia

Definition: Dystonia is a neurological disorder characterized by involuntary muscle contractions, sometimes with intermittent spasms or tremors. It may affect a specific body area or be generalized throughout multiple muscle groups. In 1997, researchers in the United States identified a mutation in the DYT1 gene as being responsible for one of the most serious forms of the disease, called primary torsion dystonia (PTD) or Oppenheim’s Dystonia. This is an early-onset generalized form of dystonia that usually strikes a child around the age of 9 and progresses to commonly involve much of the body’s skeletal muscles. Although relatively rare compared with other forms of dystonia, it is three to five times more prevalent in Ashkenazic Jews than in the general population. Prevalence estimates for 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. PTD typically starts in one part of the body, usually a foot or a leg. It often spreads to other parts, including the trunk, back, neck or arm.

Testing: There is now a simple blood test for DYTI, and testing may soon be available for other forms of the disease. Preimplantation and prenatal diagnosis is possible for PTD caused by the DYT1 mutation. The diagnosis of dystonia rests primarily on neurological examination.

Treatment: There is no cure for dystonia, but treatment may include oral medications, botulinum toxin injections, and surgery. These therapies can be used in combination or alone. Complementary care, such as speech and physical therapy, also may play a role. Significant progress is being made in the development of novel therapeutics, including gene therapy.


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 Ashkenazic Jews is a carrier of the FD gene.

Symptoms: Unable to control essential bodily functions, individuals with FD 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, unregulated heart rate, pulmonary and respiratory problems (apnea and aspiration pneumonias) as well as impaired renal function, result in early death. Infants and young children with FD experience delayed speech and motor development, difficulty suckling and swallowing, and low muscle tone. As they age, poor growth, back curvatures (scoliosis and kyphosis) and decreased sensation to pain and temperature become evident. Two hallmarks of FD 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, two mutations that cause the disease were identified. A third mutation is responsible for a single case of FD. Carrier testing is available for the two most common mutations. The reliability of the DNA blood test is greater than 99%.

Treatment: Treatments are supportive and preventative. Supportive therapies include medications to maintain and regulate cardiovascular, respiratory, and gastrointestinal function, as well as pacemakers. Surgical interventions include fundoplication, gastrostomy (feeding tubes), spinal fusion, and tear duct cautery. 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 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. Many 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 for C gene (common in Ashkenazic Jews). 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 in some patients. 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 cancers. For more information visit fanconi.org.


Gaucher Disease

Definition: Gaucher Disease (pronounced “go-shay”) is an inherited disorder caused by a defective gene which prevents the body from producing sufficient amounts of an important enzyme, glucocerebrosidase. That enzyme plays a critical role in the complex process the body uses to remove and recycle worn-out cells. The disease course is quite variable, ranging from no outward symptoms to severe disability and death. Gaucher Disease affects all ethnicities, but Jewish people of Ashkenazi descent are affected in greater numbers. Approximately 1 in 15 are carriers and 1 in 450 have Gaucher Disease. Among the general population, approximately 1 in 100/200 are carriers, while about 1 in 60,000 have the disease.

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 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. One out of 100 Ashkenazic Jews 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 severely limited. Many patients experience corneal clouding.

Testing: Carrier testing is available. ML4 soon might be added to the basic battery of diseases screened for in the United States. It is one of the nine tests screened for at many labs in the US, though the American College of Obstetricians and Gynecologists does not include ML4 on their screening panel of four diseases. 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.


Niemann-Pick

Definition: Niemann-Pick disease includes several subtypes, two of which (types A and B) 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 unprocessed 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. Additional variants of this enzyme deficiency exist, ranaging between types A and B in degree of severity. These depend on how much active acid sphingomyelinase is present in the cells to process the fats.

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 as well as boney changes.

Testing: For Niemann-Pick disease, type A, carrier screening can be done by DNA analysis for the 3 common Ashkenazi Jewish mutations. This detects approximately 95% of carriers in this population. If the partner of a known carrier is not of Ashkenazi Jewish ancestry, comprehensive gene sequence analysis is now available to screen for possible mutations (see below). If both members of the couple are found to be carriers, DNA analysis can then be used for prenatal testing. Acid sphingomyelinase enzyme levels were previously used for prenatal testing at limited non-U.S. laboratories. Couples are urged to seek genetic counseling and carrier testing by DNA analysis before embarking on a pregnancy.

DNA analysis for intermediate Niemann-Pick disease, types A/B and B is now clinically available at several laboratiories in the United States. This is done by full sequence analysis of the acid sphingomyelinase gene in comparison to the known normal structure of the gene. This type of testing is time consuming, so individuals and couples are again encouraged to seek genetic counseling and testing well in advance of a pregnancy.

Treatment: Though there is no effective treatment for those with Type A at this time, bone marrow transplants have been performed, with encouraging results, for those with Type B. Those with Type B may also be helped by enzyme replacement and gene therapies.


Infantile Onset Tay-Sachs/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 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 lo nger.

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, stem-cell therapy, substrate deprivation therapy and pharmacological chaperone 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 diagnosed 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. Many affected people often go 10 or more years 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. Researchers 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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Annual Guide to Jewish Genetic Diseases

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