There may also be listlessness or muscle stiffness hypertonia. The disease is classified into several forms, which are differentiated based on the onset age of neurological symptoms. Then, as neurons become distended with GM2 gangliosides, a relentless deterioration of mental and physical abilities begins. The child may become blind , deaf , unable to swallow , atrophied , and paralytic.
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There may also be listlessness or muscle stiffness hypertonia. The disease is classified into several forms, which are differentiated based on the onset age of neurological symptoms. Then, as neurons become distended with GM2 gangliosides, a relentless deterioration of mental and physical abilities begins. The child may become blind , deaf , unable to swallow , atrophied , and paralytic. Death usually occurs before the age of four.
People with Tay—Sachs disease develop cognitive and motor skill deterioration, dysarthria , dysphagia , ataxia , and spasticity. In contrast to the other forms, late-onset Tay—Sachs disease is usually not fatal as the effects can stop progressing. It is frequently misdiagnosed. It is characterized by unsteadiness of gait and progressive neurological deterioration. The HEXA gene is located on the long q arm of human chromosome 15, between positions 23 and The affected child would have received a mutated copy of the gene from each parent.
By , more than different mutations had been identified in the human HEXA gene. Initial research focused on several such founder populations: Ashkenazi Jews. This mutation is the most prevalent mutation in the Ashkenazi Jewish population, and leads to the infantile form of Tay—Sachs disease. Pedigree analysis suggests the mutations were uncommon before the late 17th century. Researchers of that era did not yet know how common polymorphisms would prove to be.
The "Jewish Fur Trader Hypothesis," with its implication that a single mutation must have spread from one population into another, reflected the knowledge at the time. Because Tay—Sachs was one of the first genetic disorders for which widespread genetic screening was possible, it is one of the first genetic disorders in which the prevalence of compound heterozygosity has been demonstrated. The disease can potentially result from the inheritance of two unrelated mutations in the HEXA gene, one from each parent.
Classic infantile Tay—Sachs disease results when a child has inherited mutations from both parents that completely stop the biodegradation of gangliosides. When disease occurs because of two unrelated mutations, the patient is said to be a compound heterozygote.
Enzymes are protein catalysts for chemical reactions; as catalysts, they speed up reactions without being used up in the process, so only small enzyme quantities are required to carry out a reaction. Someone homozygous for a nonfunctional mutation in the enzyme-encoding gene has little or no enzyme activity, so will manifest the abnormal phenotype.
A heterozygote heterozygous individual has at least half of the normal enzyme activity level, due to expression of the wild-type allele. This level is normally enough to enable normal function and thus prevent phenotypic expression. Deficiency in any one of these proteins leads to ganglioside storage, primarily in the lysosomes of neurons.
Tay—Sachs disease along with AB-variant GM2-gangliosidosis and Sandhoff disease occurs because a mutation inherited from both parents deactivates or inhibits this process.
Most Tay—Sachs mutations probably do not directly affect protein functional elements e. Instead, they cause incorrect folding disrupting function or disable intracellular transport. Total hexosaminidase enzyme activity is decreased in individuals with Tay—Sachs as is the percentage of hexosaminidase A.
After confirmation of decreased enzyme activity in an individual, confirmation by molecular analysis can be pursued. The choroidal circulation is showing through "red" in this foveal region where all retinal ganglion cells are pushed aside to increase visual acuity.
Thus, this cherry-red spot is the only normal part of the retina; it shows up in contrast to the rest of the retina. Microscopic analysis of the retinal neurons shows they are distended from excess ganglioside storage. If both parents are identified as carriers, prenatal genetic testing can determine whether the fetus has inherited a defective gene copy from both parents. Amniocentesis is usually performed at 15—18 weeks.
In addition to Tay—Sachs disease, preimplantation genetic diagnosis has been used to prevent cystic fibrosis and sickle cell anemia among other genetic disorders.
In Orthodox Jewish circles, the organization Dor Yeshorim carries out an anonymous screening program so that carriers for Tay—Sachs and other genetic disorders can avoid marrying each other. Children with the juvenile form are likely to die from the ages 5—15, while those with the adult form will probably not be affected. In this illustration, the original population is on the left with three possible founder populations on the right.
Two of the three founder populations are genetically distinct from the original population. Ashkenazi Jews have a high incidence of Tay—Sachs and other lipid storage diseases. In the United States , about 1 in 27 to 1 in 30 Ashkenazi Jews is a recessive carrier. The disease incidence is about 1 in every 3, newborn among Ashkenazi Jews. Irish Americans have a 1 in 50 chance of being a carrier. Parents who lose a child because of disease tend to "compensate" by having additional children to replace them.
This phenomenon may maintain and possibly even increase the incidence of autosomal recessive disease. This hypothesis states that the high incidence of the insTATC chromosomes  is the result of an elevated allele frequency  that existed by chance in an early founder population.
Studies of Tay—Sachs mutations using new molecular techniques such as linkage disequilibrium and coalescence analysis have brought an emerging consensus among researchers supporting the founder effect theory. Both Tay and Sachs reported their first cases among Ashkenazi Jewish families.
Tay reported his observations in in the first volume of the proceedings of the British Ophthalmological Society, of which he was a founding member. Years later, Bernard Sachs, an American neurologist, reported similar findings when he reported a case of "arrested cerebral development" to other New York Neurological Society members. However, its genetic basis was still poorly understood. Thus, the Mendelian model for explaining Tay—Sachs was unavailable to scientists and doctors of the time.
The first edition of the Jewish Encyclopedia , published in 12 volumes between and , described what was then known about the disease:  It is a curious fact that amaurotic family idiocy, a rare and fatal disease of children, occurs mostly among Jews. The largest number of cases has been observed in the United States—over thirty in number.
It was at first thought that this was an exclusively Jewish disease because most of the cases at first reported were between Russian and Polish Jews; but recently there have been reported cases occurring in non-Jewish children.
The chief characteristics of the disease are progressive mental and physical enfeeblement; weakness and paralysis of all the extremities; and marasmus, associated with symmetrical changes in the macula lutea. On investigation of the reported cases, they found that neither consanguinity nor syphilitic, alcoholic, or nervous antecedents in the family history are factors in the etiology of the disease.
No preventive measures have as yet been discovered, and no treatment has been of benefit, all the cases having terminated fatally. Jewish immigration to the United States peaked in the period —, with the immigrants arriving from Russia and countries in Eastern Europe ; this was also a period of nativism hostility to immigrants in the United States. Opponents of immigration often questioned whether immigrants from southern and eastern Europe could be assimilated into American society.
Reports of Tay—Sachs disease contributed to a perception among nativists that Jews were an inferior race. During the early s, researchers developed protocols for newborn testing, carrier screening, and pre-natal diagnosis. Jewish communities embraced the cause of genetic screening from the s on. The success with Tay—Sachs disease has led Israel to become the first country that offers free genetic screening and counseling for all couples and opened discussions about the proper scope of genetic testing for other disorders in Israel.
A continuing controversy is whether heterozygotes carriers have or had a selective advantage. The presence of four different lysosomal storage disorders in the Ashkenazi Jewish population suggests a past selective advantage for heterozygous carriers of these conditions.
In applied genetics selective and agricultural breeding , this controversy has reflected the century-long debate over whether dominance or overdominance provides the best explanation for heterosis hybrid vigor.
The classical hypothesis of genetic variability, often associated with Hermann Muller , maintains that most genes are of a normal wild type , and that most individuals are homozygous for that wild type, while most selection is purifying selection that operates to eliminate deleterious alleles. The balancing hypothesis, often associated with Theodosius Dobzhansky , states that heterozygosity will be common at loci, and that it frequently reflects either directional selection or balancing selection.
Selectionists versus neutralists. The goal would be to replace the nonfunctional enzyme, a process similar to insulin injections for diabetes. However, in previous studies, the HEXA enzyme itself has been thought to be too large to pass through the specialized cell layer in the blood vessels that forms the blood—brain barrier in humans. However, intracerebral neurons seem unable to take up this physically large molecule efficiently even when it is directly by them. Therefore, this approach to treatment of Tay—Sachs disease has also been ineffective so far.
The Tay—Sachs model provided by the Jacob sheep is the first to offer promise as a means for gene therapy clinical trials , which may prove useful for disease treatment in humans. Of five people who had received the treatment as of , two were still alive after five years and they still had a great deal of health problems.
¿Qué es la enfermedad de Tay Sachs?
Enfermedad de Tay-Sachs