symptoms and extend life by reducing the chance of contracting infections. infants are given feeding tubes when they can no longer swallow. in late-onset tay–sachs, medication (e.g., lithium for depression) can sometimes control psychiatric symptoms and seizures, although some medications (e.g., tricyclic antidepressants, phenothiazines, haloperidol, and risperidone) are associated with significant adverse effects. outcomes as of 2010, even with the best care, children with infantile tay–sachs disease usually die by the age of 4. children with the juvenile form are likely to die between the ages 5–15, while the lifespans of those with the adult form will probably not be affected. epidemiology founder effects occur when a small number of individuals from a larger population establish a new population. 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 3,500 newborn among ashkenazi jews. french canadians and the cajun community of louisiana have an occurrence similar to the ashkenazi jews. irish americans have a 1 in 50 chance of being a carrier. in the general population, the incidence of carriers as heterozygotes is about 1 in 300. the incidence is approximately 1 in 320,000 newborns in the general population in the united states. three general classes of theories have been proposed to explain the high frequency of tay–sachs carriers in the ashkenazi jewish population: heterozygote advantage. when applied to a particular allele, this theory posits that mutation carriers have a selective advantage, perhaps in a particular environment. reproductive compensation. parents who lose a child because of disease tend to "compensate" by having additional children following the loss. this phenomenon may maintain and possibly even increase the incidence of autosomal recessive disease. founder effect. this hypothesis states that the high incidence of the 1278instatc chromosomes is the result of an elevated allele frequency that existed by chance in an early founder population. tay–sachs disease was one of the first genetic disorders for which epidemiology was studied using molecular data. 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. history main article: history of tay–sachs disease waren tay and bernard sachs were two physicians. they described the disease's progression and provided differential diagnostic criteria to distinguish it from other neurological disorders with similar symptoms. both tay and sachs reported their first cases among ashkenazi jewish families. tay reported his observations in 1881 in the first volume of the proceedings of the british ophthalmological society, of which he was a founding member. by 1884, he had seen three cases in a single family. 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. sachs, who recognized that the disease had a familial basis, proposed that the disease should be called amaurotic familial idiocy. however, its genetic basis was still poorly understood. although gregor mendel had published his article on the genetics of peas in 1865, mendel's paper was largely forgotten for more than a generation – not rediscovered by other scientists until 1899. 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 1901 and 1906, 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 1880–1924, 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. in 1969, shintaro okada and john s. o'brien showed that tay–sachs disease was caused by an enzyme defect; they also proved that tay–sachs patients could be diagnosed by an assay of hexosaminidase a activity. the further development of enzyme assays demonstrated that levels of hexosaminidases a and b could be measured in patients and carriers, allowing the reliable detection of heterozygotes. during the early 1970s, researchers developed protocols for newborn testing, carrier screening, and pre-natal diagnosis. by the end of 1979, researchers had identified three variant forms of gm2 gangliosidosis, including sandhoff disease and the ab variant of gm2-gangliosidosis, accounting for false negatives in carrier testing. society and culture main article: societal and cultural aspects of tay–sachs disease since carrier testing for tay–sachs began in 1971, millions of ashkenazi jews have been screened as carriers. jewish communities embraced the cause of genetic screening from the 1970s 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. because tay–sachs disease was one of the first autosomal recessive genetic disorders for which there was an enzyme assay test (prior to polymerase chain reaction testing methods), it was intensely studied as a model for all such diseases, and researchers sought evidence of a selective process. 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." this controversy among researchers has reflected various debates among geneticists at large: dominance versus overdominance. 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/balance controversy. 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. in theoretical population genetics, selectionists emphasize the primacy of natural selection as a determinant of evolution and of variation within a population, while neutralists favor a form of motoo kimura's neutral theory of molecular evolution, which emphasizes the role of genetic drift. research directions enzyme replacement therapy enzyme replacement therapy techniques have been investigated for lysosomal storage disorders, and could potentially be used to treat tay–sachs as well. 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. researchers have also tried directly instilling the deficient enzyme hexosaminidase a into the cerebrospinal fluid (csf) which bathes the brain. 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. jacob sheep model tay–sachs disease exists in jacob sheep. the biochemical mechanism for this disease in the jacob sheep is virtually identical to that in humans, wherein diminished activity of hexosaminidase a results in increased concentrations of gm2 ganglioside in the affected animal. sequencing of the hexa gene cdna of affected jacobs sheep reveal an identical number of nucleotides and exons as in the human hexa gene, and 86% nucleotide sequence identity. a missense mutation (g444r) was found in the hexa cdna of the affected sheep. this mutation is a single nucleotide change at the end of exon 11, resulting in that exon's deletion (before translation) via splicing. 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. substrate reduction therapy other experimental methods being researched involve substrate reduction therapy, which attempts to use alternative enzymes to increase the brain's catabolism of gm2 gangliosides to a point where residual degradative activity is sufficient to prevent substrate accumulation. one experiment has demonstrated that using the enzyme sialidase allows the genetic defect to be effectively bypassed, and as a consequence, gm2 gangliosides are metabolized so that their levels become almost inconsequential. if a safe pharmacological treatment can be developed – one that increases expression of lysosomal sialidase in neurons without other toxicity – then this new form of therapy could essentially cure the disease. another metabolic therapy under investigation for tay–sachs disease uses miglustat. this drug is a reversible inhibitor of the enzyme glucosylceramide synthase, which catalyzes the first step in synthesizing glucose-based glycosphingolipids like gm2 ganglioside. increasing β-hexosaminidase a activity as tay–sachs disease is a deficiency of β-hexosaminidase a, deterioration of affected individuals could be slowed or stopped through the use of a substance that increases its activity. however, since in infantile tay–sachs disease there is no β-hexosaminidase a, the treatment would be ineffective, but for people affected by late-onset tay–sachs disease, β-hexosaminidase a is present, so the treatment may be effective. the drug pyrimethamine has been shown to increase activity of β-hexosaminidase a. however, the increased levels of β-hexosaminidase a still fall far short of the desired "10% of normal hexa", above which the phenotypic symptoms begin to disappear. cord blood transplant this is a highly invasive procedure which involves destroying the patient's blood system with chemotherapy and administering cord blood. of five people who had received the treatment as of 2008, two were still alive after five years and they still had a great deal of health problems. critics point to the procedure's harsh nature—and the fact that it is unapproved. other significant issues involve the difficulty in crossing the blood–brain barrier, as well as the great expense, as each unit of cord blood costs $25,000, and adult recipients need many units. gene therapy on 10 february 2022, the first ever gene therapy was announced, it uses an adeno-associated virus (aav) to deliver the correct instruction for the hexa gene on brain cells which causes the disease. only two children were part of a compassionate trial presenting improvements over the natural course of the disease and no vector-related adverse events.