With this issue, Moment launches JewishHealth: Your Guide to Intelligent Living. Use this guide to stay informed about a wide spectrum of issues that may affect you and your family. In this first edition, we focus on rare genetic diseases that occur more often in Jews of Ashkenazi and Sephardic descent than in the general population.
This section edited by Adele Schneider, MD, FACMG, Medical Director, Victor Center for Jewish Genetic Diseases, Philadelphia, PA
ASHKENAZI GENETIC DISEASES
AUTOSOMAL RECESSIVE DISORDERS
One in 5 individuals of Ashkenazi Jewish (Eastern European) descent is a carrier of a mutation in a gene for one of several diseases that occur more often in this population (see list below). Many of these diseases are disabling or may result in the early death of a child. A carrier is a healthy person whose only risk is to pass on the gene mutation to his or her offspring. These diseases occur when a fetus inherits two mutated genes, one from each parent. This is called autosomal recessive inheritance in which there is a 25% chance, with each pregnancy, of 2 carriers of a gene mutation for the same disorder having an affected child. Since carriers show no sign of the diseases, many generations can pass with healthy carriers who are not identified and most affected children are born to families with no history of having a child with the disorder. A simple blood test can determine if you are a carrier of any gene changes for one or more of these diseases. It is recommended that carriers seek genetic counseling to discuss reproductive options which include prenatal testing.
Bloom Syndrome
Bloom Syndrome is a chromosome breakage syndrome that predisposes people to multiple cancers and leukemia at a young age. Short stature, a sun-sensitive facial skin rash and increased susceptibility to infections occur.One out of every 100 Ashkenazi Jews is a carrier for this disease. Males with Bloom syndrome are usually infertile, and fertility appears to be reduced in women. These individuals usually die at an early age, but some have survived until their forties.
Canavan Disease
Apparently normal at birth, babies with Canavan disease begin to lose skills around 4 months of age and progressively decline. They develop an enlarged head, decreasing muscle tone and motor activity, progressive loss of visual responsiveness, and mental retardation , feeding difficulties and seizures. Children with Canavan disease frequently die in childhood but may live into adolescence and their 20s with improved medical care. One in 40 Ashkenazi Jews is a carrier of a gene change for Canavan disease.
Familial Dysautonomia
Familial Dysautonomia (FD), also known as Riley-Day Syndrome, is a disease that causes the autonomic and sensory nervous systems to malfunction. The autonomic nervous system controls bodily functions such as swallowing and digestion, regulation of blood pressure, body temperature and the body's response to stress. The sensory nervous system helps the body to taste, recognize hot and cold and identify painful sensations. The hallmark of FD is the lack of overflow tears with emotional crying. Children with FD may have difficulty feeding, have low muscle tone at birth and suffer frequent infections and poor growth. One in 30 Ashkenazi Jewish individuals is a carrier of a mutation in the FD gene. Before 1960, approximately 50 percent of patients died before age five, but today that same percentage reaches age 30.
Fanconi Anemia Type C
Fanconi Anemia Type C is a disease associated with short stature, bone marrow failure with a reduced number of all types of blood cells in the body and a predisposition to leukemia and other cancers. Some children may have limb, heart or kidney abnormalities and learning difficulties or mental retardation. Patients rarely reach adulthood. The carrier rate in the Ashkenazi Jewish population is ~1 in 89.
Gaucher Disease, Type 1
This panethnic disease is not age or gender specific and is caused by an enzyme deficiency. There is no cure, and both parents must carry the Gaucher gene in order to pass it to their offspring. It is the most prevalent Lysosomal Storage Disorder (LSD), with an incidence of about 1 in 20,000 live births and the most common genetic disease affecting Ashkenazi Jewish people with a carrier frequency of approximately 1 in 10. 1 in 450 have Gaucher disease. Treatments are available for this painful, debilitating and sometimes fatal disease.
Mucolipidosis (ML IV)
Mucolipidosis is a progressive neurological disorder. Children with ML4 begin to exhibit developmental delay during the first year of life Motor delays and mental retardation range from mild to severe. The earliest sign is corneal clouding which usually develops between three and five years of age. Blindness may develop in later years. Patients’ ages range from one to 45 years of age. Prognosis and life expectancy are unknown. Recently, a few very mildly affected children with ML IV have been diagnosed. The carrier rate for ML IV is 1 in 125 in the Ashkenazi Jewish population.
Neimann-Pick Disease, Type A
Children with Niemann-Pick disease usually appear normal at birth. The first signs of the disease appear at about three to five months of age. Progressive loss of early motor skills, feeding difficulties, and a large abdomen occur at this time. These children usually do not live past two to three years of age. The carrier rate for Niemann-Pick among Ashkenazi Jews is 1 in 90.
Tay-Sachs Disease
This is the most well-known of the Jewish genetic diseases and screening since the 1970s has lowered the incidence of Ashkenazi Jewish babies born with Tay-Sachs by 90 percent. However, it has not eliminated carriers who are healthy and have no signs of the disease. Babies born with Tay-Sachs disease appear normal at birth, and symptoms of the disease do not appear until the infants are about four to six months of age. Children begin to lose previously attained skills, such as sitting up or rolling over. They gradually lose their sight, hearing and swallowing abilities and become unresponsive. They develop a “cherry red spot” in the back of the eye, which used to be how the diagnosis was made before testing was available. Children usually die by the age of four. The carrier rate in the Ashkenazi Jewish population is 1 in 25. Tay-Sachs also has a higher carrier rate in other populations such as the Irish, French Canadian and Cajun populations. As the Ashkenazi Jewish community is intermarrying, the Jewish gene pool is changing so it is important that Tay-Sachs testing is done with enzyme levels and DNA mutations for the most accurate result. A more rare type of Tay-Sachs disease is Late onset Tay-Sachs where the progression of symptoms is slower and milder and these individuals, while disabled, may live into their 60’s and 70s.
Cystic fibrosis (CF)
Although it is not an Ashkenazi Jewish genetic disease, CF has a carrier rate amongst all Caucasians, including Ashkenazi Jews, of approximately 1 in 25. Cystic fibrosis is a disease that makes the body produce an abnormally thick, sticky mucus because cells in the lungs and pancreas fail to transport salt in the body where it needs to go. The thick mucus also blocks digestive enzymes from reaching the intestines where they are supposed to break down and digest food. While severity is variable, most affected individuals face frequent lung infections with persistent coughing, fat malabsorption, poor growth, and infertility in males. The median age of survival is in the mid-30s. CF does not affect intelligence. CF is not yet curable, but in recent years many new treatments have been adopted and these have helped maintain better health for people with CF. CF treatment includes chest physical therapy, antibiotics, inhalation treatments, and enriched diets with oral enzymes to help digest the food.
Maple Syrup Urine Disease (MSUD)
MSUD is a disorder of amino acid metabolism named for the characteristic maple syrup smell of the urine in those with the disease. The condition is variable and affects newborns with irritability, poor feeding, lethargy, seizures, and coma. With early detection and careful dietary control, normal growth and development are possible. MSUD can be detected by routine newborn screening that is done in most medical centers. Treatment for MSUD involves lifelong dietary control. The carrier rate in the AJ population is 1 in 81.
Glycogen Storage Disorder Type 1a (GSD1a)
This disorder occurs when the body is missing an enzyme that is needed for the liver to convert sugar from its storage form (glycogen) to the form that can be used by the body to produce energy (glucose). Individuals with GSD1a cannot maintain their blood glucose levels and develop hypoglycemia (low blood sugar) a short time after eating. Treatment for GSD1a involves providing the body with an outside supply of glucose on a continual basis. If left untreated, affected individuals will develop seizures, enlarged liver, slow growth and short stature. Disease management involves lifelong diet modification to maintain the blood sugar level. The carrier rate is 1 in 71 in the Ashkenazi Jewish population.
AUTOSOMAL DOMINANT DISORDERS
An autosomal dominant disorder needs only one abnormal gene of the pair of genes for the disorder to manifest. The gene is often inherited from one parent who has the disease. Some of these conditions are highly variable even within the same family. Some dominant diseases occur due to a new mutation in the affected individual and neither parent carries the gene. This occurs more often when the father is over 40 years of age.
Torsion Dystonia
Torsion dystonia
is inherited as an autosomal dominant trait. It is a progressive disorder of involuntary muscle contractions characterized by involuntary twisting and repetitive muscle movements and postures with wide variation in age of onset and severity. It may present with writer’s cramp or be a generalized movement disorder with significant associated disability. There is no cure for Torsion Dystonia, but there are treatments available that may alleviate some of the symptoms. Of those who carry the gene mutation for Torsion Dystonia that occurs more often in the AJ population, only 30% will manifest the disorder during their lifetime and the severity cannot be predicted. Gene testing is available.
Breast cancer
A small percentage (7-10%) of breast and ovarian cancers are hereditary. A hereditary cancer syndrome refers to a cluster of specific cancers that occur more often in affected families. The characteristics of a hereditary cancer syndrome include: individuals in three or more generations affected with cancer, early age of onset of cancer, bilateral cancer, multiple cancers in one individual and multiple cancers in a family.
Recently, two genes have been discovered, BRCA1 and BRCA2, that have been associated with hereditary breast and ovarian cancer syndromes. BRCA1 and BRCA2 are called tumor suppressor genes. This means that the function of these two genes is to play a role in controlling the rate at which a cell grows and divides. If a cell loses the function of these genes, then it will no longer have the control mechanism in place to regulate cell division, and therefore that cell would grow out of control, thus forming a tumor.
Alterations in both, BRCA1 and BRCA2 are associated with a significantly increased cancer risk. A woman found to have an alteration in the BRCA1 gene has a lifetime risk to develop breast cancer of 80-85%, a lifetime risk of ovarian cancer of 20-40%, and a small increase in the risk for colon cancer (from 6% to 10%). Men found to have an alteration in BRCA1 also have a small increase in risk for colon and prostate cancers.
Alterations in the BRCA2 gene are also associated with an increased lifetime risk of breast cancer of 80-85%, an increased risk of ovarian cancer of 10-20% (less than with BRCA1), and a small increased risk of several other cancers, possibly including melanoma and pancreatic cancer. Men with BRCA2 mutations are also at increased risk for breast cancer, a relatively rare cancer in men. The risk for male breast cancer is approximately 6% in men found to have an alteration in BRCA2.
In the Ashkenazi Jewish population, three specific mutations (2 in the BRCA1 gene and 1 in the BRCA2 gene) occur more often. The overall frequency for an Ashkenazi Jewish individual to have one of these three mutations is approximately 1 in 40 or 2.5% of the Ashkenazi Jewish population. If you have a family history of cancer that you are concerned about, genetic counseling can help you understand your risks and whether gene testing is recommended for you.
OTHER DISEASES
Crohn's Disease
while slightly more prevalent among Jewish Caucasian populations than among other Caucasian populations, is not primarily considered a “Jewish disease”. The genetic cause of Crohn’s disease has not been identified yet so no testing is available.
SEPHARDIC GENETIC DISEASES
AUTOSOMAL RECESSIVE DISORDERS
Sephardic Jews, whose ancestry can be traced to North African and Mediterranean countries, including Spain and Greece, suffer from the same genetic diseases as other populations in these countries. The diseases are not as serious as Ashkenazi Jewish genetic diseases, but can cause significant health problems. The disorders in the Sephardic population also vary with your country of origin.
Beta-Thalassemia
Beta-Thalassemia is an inherited blood disorder that reduces the production of the beta subunit of hemoglobin and results in anemia. Thalassemia major, the most severe form, results from severe mutations on both beta globin genes. It also is called Cooley's anemia. Most affected children appear healthy at birth but they develop severe anemia and a large liver and usually need medical attention within the first two years of life . They grow slowly and often develop jaundice. Treatment is with regular transfusions and chelation therapy to prevent iron overload. Carriers of one mutated thalassemia gene have Thalassemia minor which is usually asymptomatic, though some have mild anemia. The less severe form, thalassemia intermedia presents later with milder anemia that sometimes requires transfusion. Thalassemia intermedia results from milder abnormalities in both beta globin genes. Beta thalassemia is reported most commonly in Mediterranean, African, and Southeast Asian populations. Roughly one in 30 people of Mediterranean descent carry the gene.
Familial Mediterranean Fever
Familial Mediterranean Fever is an inherited condition characterized by recurrent episodes of painful inflammation in the abdomen, chest, or joints. These episodes are often accompanied by fever and sometimes a rash. The symptoms and severity vary among affected individuals, sometimes even among members of the same family. Typically, episodes last 12 to 72 hours. The length of time between attacks is also variable. The first episode usually occurs in childhood or the teenage years. The carrier rate for FMF has been calculated to be as high as 1:3-1:7 in North African Jews, Iraqi Jews, Armenians, and Turks.
Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD)
This common human enzyme deficiency affects an estimated 400 million people worldwide. It confers protection against malaria, which probably accounts for its high gene frequency. G6PD deficiency is passed along in genes from one or both parents to a child. The gene responsible for this deficiency is on the X chromosome. People of Mediterranean heritage, including Italians, Greeks, Arabs, and Sephardic Jews, also are commonly affected. People with G6PD deficiency lack enough of the enzyme G6PD, which helps red blood cells function normally. This deficiency can cause hemolytic anemia, usually after exposure to certain medications, foods, or even infections. Most people with G6PD deficiency have no symptoms, while others develop symptoms of anemia only after red blood cells have been destroyed, a condition called hemolysis. In these cases, the symptoms disappear once the cause, or trigger, is removed. In rare cases, G6PD deficiency leads to chronic anemia. With the right precautions, a child with G6PD deficiency can lead a healthy and active life. Some substances can be harmful to people with this condition when consumed—or even touched—such as fava beans and naphthalene (a chemical found in mothballs and moth crystals) and should be avoided.
Glycogen Storage Disease, Type III (Cori’s Disease or Forbes Disease)
GSD III is a very variable disorder characterized by the storage of structurally abnormal glycogen, termed limit dextrin, in both skeletal and cardiac muscle and/or liver. Glycogen is one of the primary fuel reserves for the body's energy needs. During infancy and early childhood, patients with GSD III may have liver enlargement, low blood sugar and poor growth similar to those in GSD 1a. Hypoglycemia is rare in newborns with GSD III, but often manifests at age 3-4 months when many parents reduce feeding frequency. Muscular involvement usually is minimal during childhood but often becomes the major feature by young adulthood. Carrier rate is 1:37 in the Sephardic Jewish individuals of North African descent. Disease management involves lifelong diet modification to keep the blood sugar from dropping.
—Adele Schneider, MD, FACMG
Medical Director, Victor Center for Jewish Genetic Diseases
Philadelphia, PA
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