Diseases Seen More Frequently in the Ashkenazi Jewish Population:
Individuals with Bloom syndrome have short stature, sun-sensitive facial skin lesions, an increased susceptibility to infections and respiratory illness, and an increased predisposition to gastrointestinal cancers and leukemia. Some individuals with Bloom syndrome also have mental retardation. Individuals with Bloom syndrome usually die at an early age, but some have survived until their forties. Men with Bloom syndrome are usually infertile, and fertility appears to be reduced in women.
Bloom syndrome is a rare disease that is most common in the Ashkenazi Jewish population. Approximately one out of every 100 Ashkenazi Jews is a carrier of this disease, which is caused by a change in a gene located on chromosome 15.
Bloom syndrome is considered a "chromosome breakage" disease. This means that affected individuals have an increased rate of breakage and rearrangements of their chromosomes. Chromosomes are the structures in each of the cells in our body that contain our genes. Genes produce proteins and guide the development and maintenance of the body.
Early diagnosis of this disease can be helpful in monitoring and treating the manifestations of Bloom syndrome. Affected individuals should have increased cancer surveillance and should also decrease their exposure to sunlight and X-rays, which may cause damage to their chromosomes.
Canavan disease is a severe degenerative disease of the central nervous system. Most children with Canavan disease appear normal at birth. It is not until three to five months of age that their parents might notice subtle differences in the child. For instance, the child may be unable to perform motor tasks, such as rolling over. Grasping and visual inattentiveness or tremors are frequently noted. These children eventually become blind and have problems with swallowing. They frequently die in childhood but may live into adolescence or even early adulthood.
Canavan disease is caused by the lack of an enzyme called aspartoacylase (ASPA). ASPA is essential in the breakdown of N-acetylaspartic acid (NAA). Without ASPA, NAA builds, leading to brain damage, mental retardation, and the other problems seen in this disease.
Currently, there is no cure for Canavan disease. There are some treatments available for managing and relieving the complications associated with Canavan disease. These include physical and occupational therapy, a feeding tube when eating becomes difficult for the child, and certain medications for seizures and relief of pain. Research is presently being conducted to determine the safety and efficacy of gene therapy for this disorder. Approximately one in 40 Ashkenazi Jews is a carrier for this disease gene, located on chromosome 17.
Cystic fibrosis (CF) is a disease seen with equal frequency in the general Caucasian population and Ashkenazi Jewish population. This disease affects about 30,000 children and adults in the United States; approximately one in 25 Caucasians carries a defective gene for the disease. Due to an abnormality in salt transport in people with CF, abnormally thick mucus is produced in the lungs causing difficulty breathing and increasing the frequency of serious lung infections. The pancreas is unable to produce important enzymes necessary for the proper absorption and processing of fats.
CF has a variety of symptoms. The most common are: very salty-tasting skin; persistent coughing, wheezing or pneumonia; excessive appetite but poor weight gain; and bulky stools. The standard diagnostic test for cystic fibrosis measures the amount of salt in a person’s sweat. A high salt level indicates that a person has CF.
CF is not yet curable, but in recent years, researchers have learned a great deal about the CF gene located on chromosome 7 and have developed many new treatments. CF treatment depends on how advanced the disease is and what organs it affects. Chest physical therapy, antibiotics, inhalation treatments, vitamin supplements, and enriched diets are a few of the many treatment options.
Dihydrolipoamide Dehydrogenase Deficiency
DLD deficiency presents in early infancy with poor feeding, frequent episodes of vomiting, lethargy and developmental delay. As the disease progresses, affected individuals develop seizures, enlarged liver, blindness and ultimately suffer an early death. DLD deficiency is also known as Maple Syrup Urine disease – Type 3.
In the Ashkenazi Jewish population, approximately 1 in 96 people are carriers of a mutation in the DLD deficiency gene, which is located on the long arm of chromosome #7.
There is currently no treatment or cure available for DLD deficiency. Dietary intervention was reported to be helpful in one patient, but other interventions are controversial.
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 and 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 disease is also known as HSAN III (hereditary sensory and autonomic neuropathy, type III).
The hallmark of FD is the lack of overflow tears with emotional crying. Children with FD may have difficulty feeding. They also may be unable to feel pain, and can break bones or burn themselves without realizing they’ve been injured.
The disease is caused by mutations in the IKBKAP gene. An estimated one in 30 Ashkenazi Jews carries the FD gene change, found on chromosome 9. Carriers don’t display any symptoms or warning signs of FD.
Currently, there is no cure for FD. The lifespan of those affected with FD is often shortened. Treatments aim at controlling symptoms and avoiding complications. Treatment strategies can include using special feeding techniques and special therapies, medications, artificial tears, respiratory care and orthopedic management.
Familial Hyperinsulinism is characterized by hypoglycemia which can vary from mild to severe. It can be present in the immediate newborn period through the first year of life with symptoms such as seizures, poor muscle tone, poor feeding and sleep disorders. If left untreated, it can lead to irreversible neurological damage or death. In the more severe forms, dietary control only gives minimal improvement, and removal of the pancreas may be necessary.
Mutations in several genes have been associated with Familial Hyperinsulinism. Two founder mutations in the ABCC8 gene, located on chromosome number 11, have a carrier frequency of 1 in 66 in the Ashkenazi population.
Franconi anemia is an inherited disorder characterized by a bone marrow failure in the first decade of life resulting in reduced numbers of all types of blood cells in the body. Individuals with Fanconi anemia are usually smaller than average. Other symptoms associated with the disease may include missing bones in the thumbs and arms, increased risk for cancer and leukemia, brown coloring to the skin, and kidney problems. Ultimately, Fanconi anemia affects all systems of the body. Patients rarely reach adulthood.
Fanconi anemia is considered a "chromosome breakage" disease. This means that individuals affected with this disease have an increased rate of breakage and rearrangements of their chromosomes. Chromosomes are structures in each of the cells in our body that contain our genes. Genes produce proteins and guide the development and maintenance of the body.
Early diagnosis of this disease can lead to increased surveillance for leukemia and other cancers. Steroid therapy and bone marrow transplantation may be helpful in increasing the number of cells in the body. Affected individuals should avoid X-rays, chemotherapeutic agents, and other environmental exposures that may cause damage to their chromosomes.
Approximately one out of 89 Ashkenazi Jews is a carrier for this disease gene, which is located on chromosome 16.
There are three different types of Gaucher (pronounced go-shay) disease (type I, II, III). Type I is the most common form of the disease; an estimated one in 14 Ashkenazi Jews is a carrier. The gene is located on chromosome 1. The signs and symptoms of Gaucher disease vary greatly and can appear at any age. The most common symptom of type I Gaucher disease is painless enlargement of the spleen and/or liver with absence of central nervous system involvement. Other symptoms may include bruising, bone pain, frequent nosebleeds, and a lack of energy. Also, children with type I Gaucher disease are often shorter than their peers and may have delayed puberty.
People with Gaucher disease lack an enzyme called glucocerebrosidase and are unable to break down a fatty substance in their cells. This fatty substance builds up in the liver, spleen, bone marrow and other areas of the body. This build-up leads to the medical complications of Gaucher disease.
Although there is no cure for Gaucher disease, there are some treatments available for managing and relieving the symptoms. Enzyme replacement therapy is an effective form of treatment, but is quite expensive and time-consuming. The treatment consists of a modified form of the glucocerebrosidase enzyme given intravenously. A newer therapy oral therapy, miglustat, is available for those patients who are not suitable candidates for enzyme therapy. These therapies can lead to improved quality of life for affected individuals and their families.
Glycogen Storage Disorder
Glycogen storage disorder - Type Ia (GSDIa) is due to insufficient production of an enzyme that is needed by the liver to convert sugar from its storage form (glycogen) to the form that can be used by the body to produce energy (glucose). People with GSD cannot maintain their blood glucose levels and develop hypoglycemia (low blood sugar) within a few hours after eating. Untreated, GSD1a causes seizures, liver and kidney dysfunction, poor growth, and short stature. Life expectancy can be greatly reduced if treatment is not initiated soon after birth. Treatment for GSD involves providing the body with an outside supply of glucose.
Two specific mutations in the gene causing GSD1a are carried by approximately one in 71 Ashkenazi Jews, and the gene is found on chromosome 17.
Joubert Syndrome 2 is characterized by structural mid- and hindbrain malformations. Affected individuals have mild to severe motor delays, developmental delay, decreased muscle tone, abnormal eye movements, and characteristic facial features. Additionally, there may be variable degrees of kidney abnormalities and retinal problems.
One specific change in the TMEM216 gene on chromosome #11 was found to occur in approximately 1 in 92 Ashkenazi Jewish individuals.
Maple Syrup Urine Disease
Maple Syrup Urine Disease (MSUD) occurs when the body is missing an enzyme used to break down certain building blocks of proteins. Toxic substances accumulate in the body after ingesting protein causing brain dysfunction, seizures, and death if untreated. With lifelong strict protein restriction, children may survive, but often have mental retardation and may require frequent hospitalizations with illnesses. Their urine has an odor of maple syrup.
MSUD is carried by approximately 1 in 113 Ashkenazi Jews and the gene for MSUD is located on chromosome 6.
Mucolipidosis Type IV (ML IV) is due to the absence of a protein important in the transport of certain fatty substances (lipids) in the body. These lipids accumulate to toxic levels throughout the body, causing disease.
Children with ML IV appear normal at birth, but by approximately one year of age begin to show signs of motor and mental delays. ML IV also causes eye problems, including clouding of the corneas, strabismus (crossed eyes), and degeneration of the retina, which may lead to blindness. The children are ultimately mentally retarded and live shortened lives.
No treatment is currently available for ML IV; supportive care is used to treat the symptoms.
Although ML IV can occur in any ethnicity, it is more common in individuals of Ashkenazi Jewish descent. Approximately 1 in 100 Ashkenazi Jews is a carrier of ML IV. The gene is located on chromosome 19.
Nemaline myopathy is characterized by muscle weakness, decreased muscle tone, and depressed or absent deep tendon reflexes. Muscle weakness is usually most severe in the face, the neck, and the proximal limb muscles. There are several different forms of the disease, with some being more severe than others. In the more severe forms, respiratory distress and feeding and swallowing difficulties are common and can lead to early death.
There are six different genes in which mutations have been found to cause Nemaline Myopathy. A single mutation in the Nebulin gene, located on chromosome 2, has a carrier frequency of 1 in 108 in the Ashkenazi Jewish population. Affected individuals with mutations in the Nebulin gene often have a milder form of the disease, although rarely, they can be more severely affected.
In Niemann-Pick disease, harmful quantities of a fatty substance accumulate in the spleen, liver, lungs, bone marrow and sometimes in the brain. There are two types of Niemann-Pick disease, type A and type B. Type A is more common in the Ashkenazi Jewish population, with an estimated 1 in 90 carrier frequency. The gene is located on chromosome 11.
Individuals with Niemann-Pick disease lack a substance called acid sphingomyelinase (ASM). ASM usually breaks down another substance in the body called sphingomyelin. If ASM is missing from the body, sphingomyelin builds up in certain cells and causes damage to the central nervous system, liver and lungs.
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. There is no cure for Niemann-Pick disease. Children with Niemann-Pick type A usually do not live past two to three years of age.
Spinal muscular atrophy
Spinal muscular atrophy (SMA) refers to a group of diseases which affect the motor neurons of the spinal cord and brain stem, which are responsible for supplying electrical and chemical signals to muscle cells. Without proper signals, muscle cells do not function properly and thus become much smaller (atrophy). This leads to muscle weakness. Individuals affected with SMA have progressive muscle degeneration and weakness, eventually leading to death.
There are several forms of SMA, depending on the age of onset and the severity of the disease. Two genes, SMN1 and SMN2, have been linked to SMA types I, II, III and IV. Type I is the most severe form of SMA and is characterized by muscle weakness present from birth, often manifested by difficulties with breathing and swallowing, and death usually by age 2-3 years. Type II has onset of muscle weakness after 6 months of age, and can obtain some early physical milestones like sitting without support. Type III is a milder form of SMA, with onset of symptoms after 10 months of age. Individuals with Type III SMA often achieve the ability to walk, but may have frequent falls and difficulty with stairs. The weakness is more in the extremities, and affects the legs more than the arms. Type IV is the mildest form and is characterized by adult onset of muscle weakness.
SMA is most often caused by a deletion of a segment of DNA, called Exon 7 and Exon 8, in the SMN1 gene located on chromosome #5. Rarely, SMA is caused by a point mutation in the SMN1 gene. Carrier testing for SMA measures the number of copies of the deleted segment in the SMN1 gene. A non-carrier is expected to have 2 copies present (no deletion), while a carrier will have only 1 copy present (a deletion of one copy). However, carrier testing will not identify carriers of point mutations. Approximately 90% of SMA carriers in the Ashkenazi Jewish population can be identified with this testing method. It is estimated that 1 in 41 individuals, including Ashkenazi Jews, is a carrier for SMA.
Classical Tay-Sachs disease is an inherited, genetic disorder that causes progressive degeneration and destruction of the central nervous system in affected individuals. Babies born with Tay-Sachs disease appear normal at birth, and symptoms of the disease do not appear until the infants are approximately four-to-six months of age. It is at this time that these children begin to lose previously attained skills, such as sitting up or rolling over. They gradually lose their sight, hearing and swallowing abilities. There is severe developmental delay. These children usually die by the age of four.
Individuals with Tay-Sachs disease lack a substance in their body called hexosaminidase A (Hex A). Hex A is responsible for breaking down a certain type of fat called GM2-ganglioside. When Hex A is missing from the body, it cannot break down this fat. The fatty substance accumulates to toxic levels in the body, mainly in the brain and nervous system. There is no cure for Tay-Sachs, although research is on-going regarding possible treatment options.
An estimated one in every 25 Ashkenazi Jews is a carrier for Tay-Sachs disease. The gene is located on chromosome 15.
Usher Syndrome Type 1F
Usher Syndrome Type 1F is characterized by profound hearing loss which is present at birth, and adolescent-onset retinitis pigmentosa, a disorder that significantly impairs vision. Affected individuals usually require cochlear implants to help with speech development. Balance is often impaired, and visual acuity typically begins to decline around age 10.
A mutation in the PCDH15 gene, located on chromosome 10, has a carrier frequency of 1 in 141 in the Ashkenazi Jewish population. Currently, there is no treatment for Usher Syndrome Type 1F.
Usher Syndrome Type III
Usher Syndrome Type III is milder than type 1, but still causes progressive hearing loss and vision loss. Hearing is often normal at birth with progressive hearing loss typically beginning during childhood or early adolescence. Vision loss due to retinitis pigmentosa begins to develop in adolescence, and is also progressive, often leading to blindness by adulthood. The rate of decline of hearing and vision can vary from person to person.
A mutation in the CLRN1 gene, located on chromosome #3 has a carrier frequency of 1 in 107 in the Ashkenazi Jewish population. Currently, there is no treatment for Usher Syndrome Type III but hearing loss can be managed with hearing aids and possible cochlear implant.
Walker-Warburg syndrome is a severe muscle, eye, brain syndrome. It presents with muscle weakness, feeding difficulties, seizures, blindness with eye and brain anomalies and delayed development. Life expectancy is below 3 years. The carrier frequency in the Ashkenazi population for one Ashkenazi founder mutation is approximately 1 in 149 and the detection rate is >95%.