Annual Guide to Jewish Genetic Diseases

There are about 20 known “Ashkenazic diseases,” though more are being discovered all the time. Here are diseases that are commonly screened for in Jewish couples who are planning to have children. In many of these diseases, Ashkenazic Jews are more likely to be carriers than the population at large. The list also includes four disorders known to be more prevalent among Sephardic Jews.

†= Information courtesy of the Chicago Center for Jewish Genetic Disorders

• Bloom’s Syndrome

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.

• Canavan Disease

Canavan disease, which is carried by one in 40 Ashkenazic Jews, affects 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.

• Congenital Hyperinsulinism (Familial Hyperinsulinism)

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.

• Cystic Fibrosis†

Cystic fibrosis (CF) is a progressive multi-system disorder caused by abnormal function of the CFTR protein, which causes the body to produce thick, sticky mucus in the lungs and digestive system. CF is no more common among Ashkenazi Jews than among other Caucasians, and is in fact one of the most common genetic disorders among Jews and non-Jews alike.

• Dystonia

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.

• Factor XI Deficiency†

Factor XI is a coagulation enzyme which binds to platelets to stop bleeding. Deficiency of Factor XI causes a (usually) mild bleeding disorder that can become more serious after surgery, tooth extraction or injury.

Factor XI deficiency was originally called hemophilia C, and is also known as plasma thromboplastin antecedent (PTA) deficiency. Hemophilia A is Factor VIII deficiency and hemophilia B is Factor IX deficiency.

• Familial Dysautonomia

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.

Intelligence is usually normal in affected individuals; however, learning disabilities are common.

• Fanconi Anemia

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.

• Gaucher Disease

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.

• Glycogen Storage Disease, Type I†

Glycogen is a carbohydrate that serves as one of the primary fuel reserves for the body’s energy needs. Stores of glycogen power the body during times of fasting and exercise. Glycogen storage disease type I (GSD I) is caused by an enzyme deficiency that prevents the body from completely breaking down the stored glycogen into glucose, which the body metabolizes. This progressive buildup of glycogen can cause impaired growth, bleeding problems and enlarged liver and kidneys. There are two main subtypes of GSD I, caused by mutations in two different genes. GSD Ia is the most common subtype in Caucasians, with a relatively high carrier frequency in Ashkenazi Jews.

• Joubert Syndrome†

There are several types of Joubert syndrome, caused by mutations in different genes. Joubert syndrome 2 is most common in Ashkenazni Jews, and is caused by a mutation in the TMEM216 gene. It is a rare neurological disorder characterized by multiple brain abnormalities, including the absence or underdevelopment of the cerebellar vermis — an area of the brain that controls balance and coordination.

• Maple Syrup Urine Disease†

Maple syrup urine disease (MSUD) is named for the characteristic sweet smell of the urine in affected children. It is caused by genetic mutations that prevent the body from breaking down three specific amino acids in the body. These products then build up to toxic levels, leading to the manifestations of the disease. MSUD is caused by mutations in four different genes. There are several forms of this disease, and the classic severe form is most common in Ashkenazi Jews.

• DLD

Dihydrolipoamide dehydrogenase deficiency is a type of maple syrup urine disease. Beginning in early infancy, it presents as persistent lactic acidosis, or the buildup of amino acids in tissue to toxic levels, with recurrent episodes of vomiting and abdominal pain. This condition is also characterized by poor feeding, vomiting, lethargy, low muscle tone, and developmental delay. If untreated, it can lead to seizures, coma, and death. Dietary modifications can be implemented, but unfortunately are not always effective.

Dihydrolipoamide dehydrogenase deficiency is caused by mutations in the DLD gene, which manufactures a protein necessary for several enzyme complexes which are essential for producing energy in cells.

• Mucolipidosis IV

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.

• Niemann-Pick

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.

• Nonclassical† Adrenal Hyperplasia

NCAH results from a defect in an enzyme necessary for the conversion of cholesterol to cortisol, which is the body’s primary stress hormone. Mutations in this gene are also responsible for the much more severe salt-wasting and simple virilizing types of adrenal hyperplasia which present shortly after birth. The non-classical type presents at any time after birth and exhibits much milder symptoms.

• Nonsyndromic Hearing Loss and Deafness†

Nonsyndromic hearing loss refers to non-progressive mild-to-profound sensorineural hearing impairment (which means the impairment stems from problems within the ear’s nerves) that is not associated with any other medical problems or physical abnormalities. There are many known causes of nonsyndromic hearing loss, many of which are genetic. DFNB1 accounts for fifty percent of all congenital, autosomal recessive nonsyndromic hearing loss. DFNB1 is most often caused by mutations in the GJB2 gene, which encodes the connexin 26 protein, and less frequently by mutations in the GJB6 gene, which encodes the connexin 30 protein. One specific mutation in the GJB2 gene is found most commonly in Ashkenazi Jews.

• Spinal Muscular Atrophy†

Spinal muscular atrophy (SMA) causes degeneration of motor neurons, the nerve cells in an area of the spinal cord known as the anterior horn. When the motor neurons break down, so does the link between the brain and the voluntary muscles — those which we control. As the link between the brain, spinal cord and muscles breaks down, the muscles that are used for activities such as crawling, walking, sitting up and moving the head are used less and less and become weaker, or shrink (atrophy).

• Tay-Sachs:

•nfantile Onset Tay-Sachs

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.

•ate Onset Tay-Sachs

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.

• Torsion Dystonia†

Torsion dystonia (DYT1) is a progressive movement disorder characterized by sustained, twisting muscle spasms. With time, the frequency and duration of these spasms increases, leading to joint contractures and progressive disability. Spasms may be slow or rapid shock-like jerks, which are repetitive and may be rhythmic, and which are often made worse by voluntary movement, stress and fatigue.

Individuals with torsion dystonia have normal early development and normal intelligence. The disease is caused by a mutation in the TOR1A gene, but the underlying mechanism of the disorder is not well understood. Researchers believe that it may be caused by altered communication between the neurons in the brain.

• Usher Syndrome†

Usher syndrome comprises a group of diseases with a distinctive combination of hearing and progressive vision loss. The genes related to Usher syndrome provide instructions for making proteins that play important roles in normal hearing, balance, and vision. They function in the development and maintenance of hair cells, which are sensory cells in the inner ear that help transmit sound and motion signals to the brain. In the retina, these genes are also involved in determining the structure and function of light-sensing cells called rods and cones. Most of the mutations responsible for Usher syndrome lead to a loss of hair cells in the inner ear and a gradual loss of rods and cones in the retina. Degeneration of these sensory cells causes hearing loss, balance problems, and vision loss.

• Nemaline Myopathy†

There are several types of nemaline myopathy, caused by mutations in different genes. It primarily affects skeletal muscles, which are muscles that the body uses for movement. It causes muscle weakness (myopathy) throughout the body, but it is typically most severe in the muscles of the face, neck, and limbs. This weakness can worsen over time. The muscle problems associated with nemaline myopathy are caused by an abnormal buildup of thread-like structures (nemaline bodies) in certain muscle tissue.

• Walker-Warburg Syndrome†

Walker-Warburg syndrome (WWS) is a type of congenital muscular dystrophy characterized by brain and eye abnormalities and muscle disease, particularly weakness and atrophy of voluntary muscles. Mutations in different genes lead to different forms of WWS, and the forms vary in regard to muscles involved, ages of onset, and severity.

•SEPHARDI DISORDERS

• Beta Thalassemia†

Red blood cells rely on the protein hemoglobin to transport oxygen from the lungs to the rest of the body. When genetic mutations prevent the production of the beta chain, one of two structures necessary to complete a hemoglobin protein, red blood cells aren’t produced in sufficient quantities, leading to anemia. Beta thalassemia is the most common inherited single gene disorder in the world. This disorder covers a spectrum of anemias, ranging in severity from mild (intermedia) to severe (thalassemia major or Cooley’s anemia). Individuals with thalassemia intermedia have some residual beta chain production, whereas those with thalassemia major have none. Beta thalassemia is most frequently seen in humid climates with a high incidence of malaria, such as Africa, the Mediterranean, the Middle East and Asia. This is due to the fact that being a carrier is thought to confer some resistance to malaria.

• Familial Mediterranean Fever†

White blood cells require a protein called pyrin (also known as marenostrin) to help regulate inflammation, which in turn is a site-specific process that fights infection and repairs tissue. When mutations on the MEFV gene reduce the amount of pyrin manufactured, the body loses control of the inflammation process, which is then prolonged or inappropriate to the body’s condition. Familial Mediterranean fever (FMF) is an episodic condition which can also result in amyloidosis, or potentially dangerous buildup of protein in organs and tissues. It occurs most commonly in untreated Jews of Northern African and Iraqi ethnicity and in patients of Turkish heritage.

• G6PD Deficiency†

When the body doesn’t produce glucose-6-phosphate dehydrogenase (G6PD), an enzyme found in red blood cells, the red blood cells break down faster than they can be replenished. This results in hemolytic anemia, which can vary in severity from lifelong anemia to rare bouts to no symptoms. The anemia can also be induced by certain oxidative drugs, infections, severe stress or ingestion of fava beans. (The most severe form of the disorder is called favism, after the legume.)

G6PD deficiency is the most common known human enzyme deficiency, most frequently in areas with a high incidence of malaria, such as Africa, the Mediterranean and Southeast Asia. This is due to the fact that being a carrier for G6PD deficiency is thought to confer some resistance to malaria. Because the genetic mutations are sex-linked, most cases occur in males. Females who carry one mutation are generally not affected because the copy of the gene on the other X chromosome is functioning normally and compensates for the defect. Affected males can pass the mutation to a daughter, but it is unlikely that she would have symptoms, for this reason.

• Glycogen Storage Disease, Type III†

Glycogen is a carbohydrate that serves as one of the primary fuel reserves for the body’s energy needs. Stores of glycogen power the body during times of fasting and exercise. Glycogen storage disease type III (GSD III) is caused by an enzyme deficiency that prevents liver and/or muscle tissue from completely breaking down the stored glycogen into glucose, which the body metabolizes. This progressive buildup of glycogen can cause muscle wasting and organ failure. In the Sephardi community, GSD III is primarily found among Jews of North African descent.