February 23, 2011 | 3:56 pm
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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