Dr, Stephen Cederbaum has recently retired from his position as Professor of Psychiatry, Pediatrics and Human Genetics at UCLA. He is former Chief of the Division of Genetics in the Pediatrics Department at UCLA and Associate Director of the Mental Retardation Research Center. He is a founding member and past-president of the Society for Inherited Metabolic Disorders, and founder and first chair of the California Newborn Screening Advisory Committee. Dr. Cederbaum specializes in the diagnosis, treatment and study of human biochemical disorders.
Dr. L. What is Tay Sachs Disease?
Dr. C. Tay sachs disease is a disorder in which an enzyme called hexosaminidase A is deficient in the body of affected individuals resulting in the accumulation of a fatty substance in the brain which leads to neurological deterioration and eventually death. An enzyme is a protein that catalyzes (i.e. increases or decreases) the rate of a chemical reaction. Almost all metabolic processes in a biological cell need enzymes to regulate the rate of metabolism
The children appear normal at birth, but by 4-6 months of age, normal developmental progress ceases and a steady deterioration and loss of abilities evolve. The patients are usually blind and immobile by 1 year of age, are hypersensitive to sound and develop seizures. Death often occurs by age 2 although modern support programs can prolong life for several years longer. A characteristic finding on physical examination is a “cherry red spot” in the eye. This is due to a general atrophy and pallor in most of the eye, but the retention of function and the blood supply in one round area distinguishes it from the pale appearance around it.
Dr. L. Explain the Genetics.
Dr. C. Tay-Sachs Disease is inherited in what geneticists describe as an autosomal recessive manner. This means that both parents are carriers of one abnormal gene, which is balanced by one normal one. In these circumstances, when the egg and sperm combine to form the new individual there is a 25% chance that the offspring will inherit both non-functional (abnormal) genes. In this form of inheritance, the normally functioning genes prevent the carriers from showing any symptoms. The carrier frequency for Tay Sachs disease amongst Jews of Ashkenazi origin is as high as 1 in 27 and the disease frequency is one in 2500 to 1 in 3000. It is about 100 times less frequent in a non-Jewish population.
Dr. L. Are other groups affected and why?
Dr. C. As I mentioned in response to the previous question, the frequency of Tay Sachs disease is highest amongst Ashkenazi Jews, but also amongst the French Canadian population that migrated to what is now Quebec from Brittany in the 17th and 18th centuries. Although a number of different explanations have been proposed, it appears most likely that the condition in both of these groups arose when a small founder population happened to carry a gene for a defective form of the enzyme hexosaminidase A. It is also possible that there was some evolutionary pressure that caused this gene to be favored and therefore increased in the population, but that has not been demonstrated.
In both instances, the gene defects are complete enough so that the disorder invariably occurs in infancy with little variation in the time of onset.
Dr. L. What are the different types and what is the late onset type?
Dr. C. The name Tay-Sachs disease refers to the specific and typical presentation in infancy. It was only many years later that the defect was demonstrated in Hexosaminidase A. Other forms of the disorder have a later onset. They are due to a less complete block of the enzyme and consequently progress at a slower rate. Because the brain has already developed by this time, the symptoms are those of a degenerative neurological disorder but does not resemble the infantile disease. While the name “late-onset Tay-Sachs disease” is often used, it should more properly be called late-onset hexosaminidase A deficiency.
Dr. L. What is the mechanism that causes the disease?
Dr. C. The disorder is due to the failure of the enzyme to degrade a complex lipid, found in the brain that must be synthesized and degraded on a regular basis. Consequently, this complex lipid accumulates in the brain and destroys the nerve cells in a manner that is incompletely understood. The nerve cells become bloated with the fatty material and the head becomes larger than normal.
Dr. L. How is the diagnosis made?
Dr. C. Until 40 years ago, the diagnosis was made based on ethnicity, typical clinical symptoms, and the presence of the cherry red spot in the eye - and in some instances with confirmatory microscopic study of a biopsy. With the discovery of the enzyme defect, determination of the enzyme activity level in the white blood cells replaced this approach and enabled the diagnosis to be made more easily. More recently still, DNA analysis of the genes has replaced enzyme analysis as the method of choice.
Dr. L. Please discuss the screening program.
Dr. C. Shortly after the discovery of the deficiency of the enzyme hexosaminidase A as the cause of the disease, it was shown that carriers of the disease, especially in the higher risk communities could be detected with high efficiency. This paved the way for a then revolutionary strategy of detecting carriers in these communities, and allowing couples planning marriage or already married to plan their futures with the knowledge of the 25% risk to each of their children. Options included ignoring this knowledge, deciding to choose another mate who was not a carrier, or performing amniocentesis and prenatal diagnosis with the option of terminating affected pregnancies. Intensive publicity and outreach programs in houses of worship and schools have resulted in the virtual elimination of Tay-Sachs disease in these higher risk communities. In populations at lower risk, such screening would be extremely inefficient and ineffective. Because only a small number of mutations causes Tay-Sachs disease in these higher risk communities, screening is now accomplished using DNA, rather than enzymatic techniques.
Dr. L. Discuss prevention.
Dr. C. Screening programs were first carried out on a population basis, but were always reenforced in obstetrical practice. It is now customary for obstetricians to ascertain the ethnicity of a couple who come to them with a pregnancy. If both members of the couple are of Ashkenazi Jewish background, they are asked to present evidence that they have had screening for Tay-Sachs disease carrier status (and that of other disorders known to be more frequent in this population group) or at least one member of the couple is advised to have such screening. In case only one member of the couple is of Ashkenazi Jewish origin and no testing has been done previously, it is often recommended that the non-Jewish member have Tay-Sachs screening by enzymatic testing. Other strategies are of course possible.
Dr. L. What is the management and is there a treatment?
Dr. C. There is no generally recognized treatment for Tay-Sachs disease or the later onset form of hexosaminidase deficiency. There have been some patients treated with bone marrow transplantation. This approach may prolong life but has generally been disappointing. The management is limited to treating specific symptoms such as seizures, ensuring that the patients receive adequate nutrition, usually through a tube in the stomach as the disease progresses, and keeping the patients comfortable. The disorder can be very distressing to families and support for them is important.
Dr. L. What is the impact on Jewish communities?
Dr. C. Jewish communities are, in the main, well educated and medically sophisticated. They accepted this higher risk of Tay-Sachs disease as a challenge and a problem with a solution and embraced screening. In very Orthodox communities in which pregnancy termination was frowned upon and arranged marriages common, the results of testing became part of the basis for arranging a marriage. There was no perception in this community that carrying these disorders was a black mark and one of which to be ashamed
Dr. L. Discuss the future for this disease focusing on research, such as enzyme replacement therapy, gene therapy, and substrate reduction therapy.
Dr. C. Much research is going on in Tay-Sachs disease and in other allied disorders. Nothing resembling a breakthrough seems to be on the horizon. Enzyme replacement is an unpromising approach (although is used in Gaucher Disease – see upcoming blog). The enzymes would not cross from the blood into the brain because nature has provided a barrier between the two compartments. In unaffected individuals, this is a protective mechanism. Unfortunately, in those with brain disorders it also serves as a barrier to effective enzyme therapy. In principle, the enzyme could be injected repeatedly into the spinal fluid, but this too would be inefficient and likely to be ineffective in the long run. The enzyme would have to reach all the brain cells and would have to be re-injected at intervals to account for its normal degradation and the reaccumulation of the complex lipid. Gene (and stem cell) therapy have been associated with great hype and hope, but so far the manipulation and delivery of these therapies has posed a challenge and the solution to these issues is unlikely to arrive in the near or intermediate-term future.
Another approach in active study is substrate reduction therapy. By inhibiting the synthesis of the complex lipid accumulating in this disorder, and, incidentally, other complex compounds needed by the body and brain, the progress of the disease may be slowed. This approach cannot prevent the progression - only slow it. Stopping the synthesis, even if it were possible would have serious consequences for the body. This form of therapy is approved for another, more mild, complex-lipid storage disorder, but is only in research trials for Tay-Sachs.
Dr. L. Thank you Dr. Cederbaum for sharing your expertise and for your many years of caring for thousands of special needs kids.
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February 14, 2011 | 1:04 pm
Dr. Lavin: There are several methods to prevent genetic diseases generally and in Jewish people specifically. (See my previous blog on Jewish Genetic Diseases.) I have the distinct pleasure of interviewing an expert in Infertility and Reproductive Endocrinology who will discuss various options for prevention. Before we delve into preimplantation diagnosis, Dr. Ben-Ozer, can you explain amniocentesis and CVS sampling?
Dr. Ben-Ozer: Amniocentesis (Amnio), Chorionic Villous Sampling (CVS) and Preimplantation Genetic Diagnosis (PGD) are all procedures that detect chromosomal (genetic) abnormalities in the fetus. Amnio, in which amniotic fluid from around the baby is collected by passing a needle through the mother‘s abdomen and the uterus, is generally performed around 14-16 weeks of gestation. CVS is a placental biopsy obtained through the vagina, usually at 10-12 weeks of gestation, but may be of higher risk than the Amnio.
Dr. Lavin: Very simply, what is fertilization and what is an embryo? What is in vitro fertilization and what is preimplantation diagnosis?
Dr. Ben-Ozer: In vitro fertilization is a process by which oocytes (eggs) are retrieved from a woman, combined with sperm in a specialized laboratory, and the resulting fertilized eggs, called embryos, are grown for several days until they are either transferred back into the womb (uterus) or frozen for future use. PGD is a process by which a chromosome analysis is performed on embryos prior to transferring them into the uterus, in order to select normal embryos. This is performed by a highly skilled embryologist who under the microscope makes an opening in the shell surrounding the embryo, removes a single cell (sometimes a few) from each embryo, and fixes it on a slide in preparation for a DNA analysis.
Dr. Lavin: In PGD, how do you tell a good cell from a bad cell?
Dr. Ben-Ozer: Two days following the biopsy, we receive a detailed report of the chromosome analysis of each embryo, so we can select a normal embryo to transfer into the uterus.
Dr. Lavin: How successful is this procedure and are there risks?
Dr. Ben-Ozer: When done properly, the embryo at the early stages of development does not appear to be harmed by the absence of a single or several cells. This is a highly technical procedure and should only be performed in specialized IVF laboratories by specially trained embryologists. The DNA analysis is also very complex, and the DNA biopsy slides are sent to specialized laboratories around the country, depending on the specific genetic analysis needed. The accuracy of the testing is close to 100%.
Dr. Lavin: What is your role in these procedures?
Dr. Ben-Ozer: My role is to review the appropriate genetic options available to the couple, stimulate the woman to produce multiple eggs, perform the egg retrieval procedure, review the chromosome analysis, and perform the embryo transfer procedure, in which the embryo(s) are placed back into the uterus by passing a special catheter through the vagina, usually under ultrasound guidance.
Dr. Lavin: Let’s discuss the religious, ethical and moral aspects. Do we need a Rabbi’s opinion at this point?
Dr. Ben-Ozer: Many IVF cycles are done with Halachic blessing and supervision. Because In vitro Fertilization was obviously not available in Biblical times, certain Rabbis evaluate the couple’s specific needs and history in relation to the intent of the Halachic laws, and decide if the couple is religiously supported in proceeding with IVF, surrogacy, and even egg donation. Thus, Jewish couples are encouraged to speak with their local Rabbi if they are having fertility issues.
Snunit Ben-Ozer, M.D. is board certified in both Reproductive Endocrinology, Infertility and Ob/Gyn and is Founder of the Tree of Life Center for Fertility in Tarzana, and Beverly Hills. She is also Associate Clinical Professor at the University of California Los Angeles, Dept Ob/Gyn and has a special interest in fertility in advanced maternal age, PCOS, and recurrent pregnancy losses.
For Further Information Contact:
Snunit Ben-Ozer, M.D.
18370 Burbank Blvd., Suite 514
Tarzana, CA 91356
Phone #: 818-344-8522
February 3, 2011 | 1:05 am
In Part 1 on Jewish Genetic Diseases, I described concepts of genetic testing, the Genome Project, preimplantation diagnosis, genetic engineering and gene therapy. The following questions and answers explain in more detail how these programs are implemented.
1. What is genetic testing?
These tests are examinations of an individual’s DNA found in chromosomes which are the chemical alphabets that spell out genes just as letters spell out words. But, what are genes? Genes are the blueprints or instructions used to make the body’s building blocks or cells. Genetic testing enables physicians to check for defects in the DNA that may cause a disease.
2. How do genes cause disease?
Most genes determine critical components that must function correctly in order for your body to be healthy. Genes that spell out a defective component can cause a disease, which can be handed down through generations just like eye color.
3. How are genetic diseases passed from one generation to the other?
Everyone has two copies of each gene. Therefore, when a man and woman have a child, each contributes one copy of their genes to that child. As a general rule, a disease is expressed only if the child has two copies of the defective gene, although there are exceptions. A normal copy of the gene tells the body how to correctly build the product that is controlled by that gene, and this type of gene is called an autosomal recessive gene. Autosomal means that it is not associated with the sex of the offspring, which implies that the risks are equal for boy and girl babies. Recessive means that if one copy of the gene is normal, the damaged gene recedes (does not appear) into the background and cannot cause the disease.
4. What is a carrier?
A carrier is an individual who has one copy of the defective gene and one of the normal gene because, as discussed above, having one normal copy of the gene is enough to prevent the disease. Therefore, the person would not have an autosomal recessive disease. However, if the carrier mates with another carrier who also has one copy of this same defective gene, there is a chance that the baby would have two copies of the defective gene and, therefore, be affected. That is the reason that couples who suspect they could be carriers may decide to undergo genetic testing.
5. What information can genetic testing provide?
Genetic testing can determine whether one or both partners carry a specific autosomal recessive gene defect. In other words, if neither is a carrier or if only one is a carrier, then there is no risk of having a baby with that disease. If, however, both people are carriers, then there is one chance in four (25%) that their baby would be affected by the disease. Therefore, testing before a couple decides to have a baby can determine what chance there is of the offspring having that specific genetic disease. Genetic testing can also be performed during pregnancy using two procedures: amniocentesis (obtaining a specimen of fluid from the vicinity of the fetus) or chorionic villus sampling (obtain actual cells from the fetus).
6. How is testing usually performed?
The test is most often performed on a sample of blood, which is sent to a specialty laboratory for the specific genetic diagnosis.
7. What if you are identified as a carrier?
If you are found to be a carrier, other members of your family could also be carriers, or they may even be at risk of having the disease. Genetic counseling, therefore, is available to determine these risks.
8. Which diseases can be detected?
There are several disorders that have been called “Jewish genetic diseases,” - not because they are specifically Jewish, but because they are much more common in the Jewish community. It is important to note that these diseases are not limited to Jewish individuals, but often occur in people who are or have been in areas from which Jews have emigrated.. Thus, they also occur in the non-Jewish community. Some examples are Gaucher disease, cystic fibrosis, Tay-Sachs disease, Canavan disease, Niemann-Pick disease, and Fanconi anemia. (A more complete list is found at the end of this article.)
9. Are there more genetic diseases that affect Jews?
Over the next several months, we will look at genetic diseases in several subgroups of Jewish people, which include the Samaritans, the Oriental Jews, Yemenite Jews, Karaites, African Jews, Sephardic Jews, and Ashkenazim.
Every resource that I have checked lists some, but not all disorders. I will list the majority of genetic diseases that I am familiar with in the following tables.
A). At the present time, there are at least 18 genetic diseases for which population screening is available for Ashkenazi Jews:
Familial Dysautonomia (Riley-Day Syndrome)
Gaucher Disease type 1
Mucolipoidosis type 4
Nieman-Pick Disease (type A:acute neuropathic form)
Glycogen Storage Disease type 1a
Maple Syrup Urine Disease
Spinal Muscular Atrophy
Usher Syndrome type 1
Usher Syndrome type 2
Lipoamide Dehydrogenase Deficiency (E3)
B). Additional Genetic Disorders Common Among Ashkenazim
A- beta lipoproteinemia
Primary torsion dystonia
PTA deficiency (plasma thromboplastin antecedent, or factor XI deficiency)
Spongy degeneration of the central nervous system
Congenital Adrenal Hyperplasia
C). At the present time, there are 4 genetic diseases that can be screened for in the Persian Jewish Community ( please refer to my article on the Persian Jewish Community in a previous Blog)
Autoimmune Polyendocrine Hormone Deficiency
Hereditary Inclusion Body Myopathy
D). Additional Genetic Disorders Among non-Ashkhenazi Jews including Sephardic and Oriental Jews
Familial Mediterranean fever
Glucose-6-phosphate dehydrogenase deficiency
Glycogen storage disease type 3 (deep branch or enzyme deficiency)
Selective vitamin B12 malabsorption
Acute hemolytic anemia
Aldolase A deficiency
Blue sclerae and keratoconus
Chronic airway disease
Combined factor V and factor VIII deficiency
Congenital hepatic fibrosis
Congenital ichthyosis with atrophy
Deaf-mutism with total albinism
Familial infantile renal tubular acidosis with congenital nerve deafness
Familial syndrome with a central nervous system and ocular malformations
Glycinuria associated with nephrolithiasis
Hidrotic ectodermal dysplasia