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Explain How 2 Normal Appearing Parents Can Have a Baby With Tay-sachs Disease.

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Medical status

Tay–Sachs disease
Other names GM2 gangliosidosis, hexosaminidase A deficiency[1]
Tay-sachsUMich.jpg
Reddish spot as seen in the retina in Tay–Sachs disease. The fovea's eye appears bright red because it is surrounded past a whiter than usual surface area.
Specialty Medical genetics
Symptoms Initially: Decreased ability to turn over, sit, or crawl[1]
After: Seizures, hearing loss, disability to motion[1]
Usual onset 3 to six months of age[one]
Duration Long term[ii]
Types Infantile, juvenile, tardily-onset[ii]
Causes Genetic (autosomal recessive)[1]
Diagnostic method Testing claret hexosaminidase A levels, genetic testing[2]
Differential diagnosis Sandhoff disease, Leigh syndrome, neuronal ceroid lipofuscinoses[ii]
Treatment Supportive intendance, psychosocial support[2]
Prognosis Decease oft occurs in early babyhood[1]
Frequency Rare in the general population[1]

Tay–Sachs disease is a genetic disorder that results in the devastation of nerve cells in the brain and spinal cord.[1] The most common class is infantile Tay–Sachs disease which becomes apparent around iii to six months of age, with the infant losing the ability to plow over, sit down, or clamber.[one] This is so followed past seizures, hearing loss, and inability to move, with death usually occurring by the age of three to five.[3] [1] Less commonly, the disease may occur in later on childhood or adulthood (juvenile or late-onset).[1] These forms tend to exist less astringent,[ane] simply the juvenile form typically results in death by historic period 15.[4]

Tay–Sachs illness is caused past a genetic mutation in the HEXA factor on chromosome 15, which codes for a subunit of the hexosaminidase enzyme known as hexosaminidase A.[1] Information technology is inherited from a person'southward parents in an autosomal recessive manner.[1] The mutation disrupts the activity of the enzyme, which results in the build-upwards of the molecule GM2 ganglioside within cells, leading to toxicity.[1] Diagnosis may be supported past measuring the blood hexosaminidase A level or genetic testing.[2] Tay–Sachs disease is a type of GM2 gangliosidosis and sphingolipidosis.[5]

The treatment of Tay–Sachs disease is supportive in nature.[2] This may involve multiple specialities too equally psychosocial support for the family unit.[two] The disease is rare in the general population.[i] In Ashkenazi Jews, French Canadians of southeastern Quebec, the Old Lodge Amish of Pennsylvania, and the Cajuns of southern Louisiana, the status is more than common.[2] [i] Approximately 1 in 3,600 Ashkenazi Jews at nativity are affected.[ii]

The illness is named after British ophthalmologist Waren Tay, who in 1881 first described a symptomatic red spot on the retina of the eye; and American neurologist Bernard Sachs, who described in 1887 the cellular changes and noted an increased rate of illness in Ashkenazi Jews.[6] Carriers of a single Tay–Sachs allele are typically normal.[2] It has been hypothesized that being a carrier may confer protection from tuberculosis, explaining the persistence of the allele in certain populations.[7] Researchers are looking at gene therapy or enzyme replacement therapy as possible treatments.[2]

Signs and symptoms [edit]

Tay–Sachs illness is typically kickoff noticed in infants around 6 months onetime displaying an abnormally stiff response to sudden noises or other stimuli, known equally the "startle response". At that place may as well exist listlessness or muscle stiffness (hypertonia). The disease is classified into several forms, which are differentiated based on the onset historic period of neurological symptoms.[8] [9]

Infantile [edit]

Infants with Tay–Sachs illness appear to develop normally for the first half-dozen months after birth. Then, as neurons go distended with GM2 gangliosides, a relentless deterioration of mental and physical abilities begins. The child may get blind, deaf, unable to consume, atrophied, and paralytic. Death usually occurs before the historic period of four.[8]

Juvenile [edit]

Juvenile Tay–Sachs disease is rarer than other forms of Tay–Sachs, and normally is initially seen in children between two and x years sometime. People with Tay–Sachs affliction feel cerebral and motor skill deterioration, dysarthria, dysphagia, clutter, and spasticity.[10] Decease unremarkably occurs between the ages of five and fifteen years.[4]

Late-onset [edit]

A rare form of this disease, known every bit Developed-Onset or Late-Onset Tay–Sachs disease, usually has its commencement symptoms during the 30s or 40s. In contrast to the other forms, tardily-onset Tay–Sachs affliction is usually not fatal as the effects tin stop progressing. It is frequently misdiagnosed. It is characterized by unsteadiness of gait and progressive neurological deterioration. Symptoms of late-onset Tay–Sachs – which typically begin to be seen in adolescence or early adulthood – include speech and swallowing difficulties, unsteadiness of gait, spasticity, cerebral decline, and psychiatric illness, especially a schizophrenia-like psychosis.[xi] People with late-onset Tay–Sachs may become full-time wheelchair users in adulthood.[ commendation needed ]

Until the 1970s and 1980s, when the affliction'south molecular genetics became known, the juvenile and developed forms of the illness were not e'er recognized as variants of Tay–Sachs affliction. Post-infantile Tay–Sachs was often misdiagnosed as another neurological disorder, such every bit Friedreich's ataxia.[12]

Genetics [edit]

The HEXA gene is located on the long (q) arm of human chromosome 15, between positions 23 and 24.

Tay–Sachs disease is an autosomal recessive genetic disorder, pregnant that when both parents are carriers, in that location is a 25% risk of giving birth to an afflicted child with each pregnancy. The afflicted child would accept received a mutated re-create of the gene from each parent.[8] If one parent has this Genetic disorder and is passed down to the child, then the kid becomes a carrier.[xiii]

Tay–Sachs results from mutations in the HEXA factor on chromosome 15, which encodes the blastoff-subunit of beta-N-acetylhexosaminidase A, a lysosomal enzyme. Past 2000, more than 100 different mutations had been identified in the homo HEXA gene.[14] These mutations have included single base of operations insertions and deletions, splice stage mutations, missense mutations, and other more circuitous patterns. Each of these mutations alters the gene'southward protein product (i.e., the enzyme), sometimes severely inhibiting its function.[fifteen] In contempo years, population studies and pedigree assay have shown how such mutations arise and spread within pocket-sized founder populations.[ citation needed ] Initial research focused on several such founder populations:

  • Ashkenazi Jews. A four base pair insertion in exon xi (1278insTATC) results in an altered reading frame for the HEXA factor. This mutation is the most prevalent mutation in the Ashkenazi Jewish population, and leads to the infantile form of Tay–Sachs affliction.[16]
  • Cajuns. The same 1278insTATC mutation found amidst Ashkenazi Jews occurs in the Cajun population of southern Louisiana. Researchers have traced the ancestry of carriers from Louisiana families back to a single founder couple – not known to exist Jewish – who lived in France in the 18th century.[17]
  • French Canadians. Two mutations, unrelated to the Ashkenazi/Cajun mutation, are absent in France but mutual among certain French-Canadian communities living in southeastern Quebec and Acadians from the Province of New Brunswick. Full-blooded analysis suggests the mutations were uncommon before the late 17th century.[18] [19]

In the 1960s and early 1970s, when the biochemical basis of Tay–Sachs disease was first becoming known, no mutations had been sequenced straight for genetic diseases. Researchers of that era did not however know how common polymorphisms would show to be. The "Jewish Fur Trader Hypothesis," with its implication that a single mutation must have spread from one population into another, reflected the noesis at the time.[20] Subsequent inquiry, even so, has proven that a large diverseness of different HEXA mutations can cause the disease. Because Tay–Sachs was one of the offset genetic disorders for which widespread genetic screening was possible, it is one of the commencement genetic disorders in which the prevalence of compound heterozygosity has been demonstrated.[21]

Compound heterozygosity ultimately explains the disease's variability, including the late-onset forms. 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. Tardily onset forms occur due to the diverse mutation base – people with Tay–Sachs disease may technically exist heterozygotes, with ii differing HEXA mutations that both inactivate, modify, or inhibit enzyme action. When a patient has at least one HEXA re-create that still enables some level of hexosaminidase A activity, a later onset affliction form occurs. When disease occurs because of 2 unrelated mutations, the patient is said to be a chemical compound heterozygote.[22]

Heterozygous carriers (individuals who inherit one mutant allele) show abnormal enzyme activity just manifest no affliction symptoms. This phenomenon is called authority; the biochemical reason for wild-type alleles' authorisation over nonfunctional mutant alleles in inborn errors of metabolism comes from how enzymes function. Enzymes are protein catalysts for chemic reactions; as catalysts, they speed upward reactions without beingness used up in the process, so only small enzyme quantities are required to conduct out a reaction. Someone homozygous for a nonfunctional mutation in the enzyme-encoding gene has little or no enzyme activity, so volition manifest the abnormal phenotype. A heterozygote (heterozygous private) has at to the lowest degree one-half of the normal enzyme activeness level, due to the expression of the wild-type allele. This level is unremarkably enough to enable normal role and thus preclude phenotypic expression.[23]

Pathophysiology [edit]

Tay–Sachs affliction is caused past bereft activity of the enzyme hexosaminidase A. Hexosaminidase A is a vital hydrolytic enzyme, plant in the lysosomes, that breaks down sphingolipids. When hexosaminidase A is no longer functioning properly, the lipids accrue in the encephalon and interfere with normal biological processes. Hexosaminidase A specifically breaks down fat acid derivatives called gangliosides; these are made and biodegraded rapidly in early life as the encephalon develops. Patients with and carriers of Tay–Sachs tin can be identified by a unproblematic blood test that measures hexosaminidase A activity.[8]

The hydrolysis of GM2-ganglioside requires 3 proteins. Two of them are subunits of hexosaminidase A; the third is a pocket-size glycolipid send poly peptide, the GM2 activator protein (GM2A), which acts equally a substrate-specific cofactor for the enzyme. Deficiency in any 1 of these proteins leads to ganglioside storage, primarily in the lysosomes of neurons. Tay–Sachs disease (forth with AB-variant GM2-gangliosidosis and Sandhoff disease) occurs because a mutation inherited from both parents deactivates or inhibits this process. Nearly Tay–Sachs mutations probably do not directly bear on protein functional elements (due east.g., the active site). Instead, they cause wrong folding (disrupting part) or disable intracellular transport.[24]

Diagnosis [edit]

In patients with a clinical suspicion for Tay–Sachs disease, with whatsoever age of onset, the initial testing involves an enzyme assay to mensurate the activeness of hexosaminidase in serum, fibroblasts, or leukocytes. Total hexosaminidase enzyme activity is decreased in individuals with Tay–Sachs as is the per centum of hexosaminidase A. Afterward confirmation of decreased enzyme activity in an individual, confirmation by molecular analysis tin can be pursued.[25] All patients with infantile onset Tay–Sachs affliction have a "cherry red" macula in the retina, easily appreciable by a medico using an ophthalmoscope.[eight] [26] This red spot is a retinal area that appears red considering of gangliosides in the surrounding retinal ganglion cells. The choroidal apportionment is showing through "red" in this foveal region where all retinal ganglion cells are pushed aside to increment visual acuity. Thus, this reddish-cherry spot is the only normal part of the retina; it shows up in contrast to the rest of the retina. Microscopic assay of the retinal neurons shows they are distended from excess ganglioside storage.[27] Unlike other lysosomal storage diseases (e.g., Gaucher illness, Niemann–Pick illness, and Sandhoff disease), hepatosplenomegaly (liver and spleen enlargement) is non seen in Tay–Sachs.[28]

Prevention [edit]

Three main approaches accept been used to prevent or reduce the incidence of Tay–Sachs:

  • Prenatal diagnosis. If both parents are identified as carriers, prenatal genetic testing can determine whether the fetus has inherited a defective gene copy from both parents.[29] Chorionic villus sampling (CVS), the near common form of prenatal diagnosis, can be performed between x and 14 weeks of gestation. Amniocentesis is usually performed at 15–18 weeks. These procedures accept risks of miscarriage of ane% or less.[xxx] [31]
  • Preimplantation genetic diagnosis. By retrieving the female parent'due south eggs for in vitro fertilization, it is possible to exam the embryo for the disorder prior to implantation. Good for you embryos are and then selected and transferred into the mother'due south womb, while unhealthy embryos are discarded. In add-on to Tay–Sachs disease, preimplantation genetic diagnosis has been used to prevent cystic fibrosis and sickle cell anemia among other genetic disorders.[32]
  • Mate selection. In Orthodox Jewish circles, the organisation Dor Yeshorim carries out an bearding screening plan so that carriers for Tay–Sachs and other genetic disorders tin avoid marrying each other.[33]

Management [edit]

As of 2010 at that place was no treatment that addressed the cause of Tay–Sachs illness or could wearisome its progression; people receive supportive care to ease the symptoms and extend life by reducing the chance of contracting infections.[34] Infants are given feeding tubes when they can no longer swallow.[35] In late-onset Tay–Sachs, medication (e.grand., 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.[22] [36]

Outcomes [edit]

As of 2010, fifty-fifty with the best care, children with infantile Tay–Sachs affliction commonly die by the age of 4. Children with the juvenile course are likely to dice between the ages five–xv, while the lifespans of those with the adult form will probably not be affected.[34]

Epidemiology [edit]

Founder effects occur when a small number of individuals from a larger population constitute a new population. In this illustration, the original population is on the left with 3 possible founder populations on the right. Two of the three founder populations are genetically singled-out from the original population.

Ashkenazi Jews have a high incidence of Tay–Sachs and other lipid storage diseases. In the United States, near ane 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.[37] French Canadians and the Cajun customs of Louisiana take an occurrence like to the Ashkenazi Jews. Irish Americans have a 1 in 50 chance of beingness a carrier.[38] In the full general population, the incidence of carriers as heterozygotes is most one in 300.[9] The incidence is approximately i in 320,000 newborns in the full general population in the United States.[39]

3 full general classes of theories have been proposed to explain the high frequency of Tay–Sachs carriers in the Ashkenazi Jewish population:

  • Heterozygote advantage.[40] When practical to a detail allele, this theory posits that mutation carriers have a selective advantage, perhaps in a particular environment.[41]
  • Reproductive compensation. Parents who lose a kid considering of disease tend to "compensate" by having additional children following the loss. This miracle may maintain and peradventure fifty-fifty increase the incidence of autosomal recessive disease.[42]
  • Founder issue. This hypothesis states that the loftier incidence of the 1278insTATC chromosomes[41] is the consequence of an elevated allele frequency[xl] that existed by chance in an early founder population.[41]

Tay–Sachs disease was one of the start 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 accept brought an emerging consensus amidst researchers supporting the founder effect theory.[41] [43] [44]

History [edit]

Waren Tay and Bernard Sachs were two physicians. They described the affliction'southward progression and provided differential diagnostic criteria to distinguish information technology from other neurological disorders with similar symptoms.[ citation needed ]

Both Tay and Sachs reported their first cases amidst Ashkenazi Jewish families. Tay reported his observations in 1881 in the first volume of the proceedings of the British Ophthalmological Lodge, of which he was a founding member.[45] By 1884, he had seen iii cases in a single family unit. Years later, Bernard Sachs, an American neurologist, reported similar findings when he reported a example of "arrested cerebral development" to other New York Neurological Society members.[46] [47]

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 notwithstanding poorly understood. Although Gregor Mendel had published his article on the genetics of peas in 1865, Mendel'due south 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 starting time edition of the Jewish Encyclopedia, published in 12 volumes between 1901 and 1906, described what was then known almost the affliction:[48]

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 The states—over thirty in number. It was at start thought that this was an exclusively Jewish illness because well-nigh of the cases at first reported were between Russian and Polish Jews; but recently there take been reported cases occurring in not-Jewish children. The chief characteristics of the disease are progressive mental and concrete 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 unit 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 clearing to the United States peaked in the period 1880–1924, with the immigrants arriving from Russia and countries in Eastern Europe; this was likewise a menstruation of nativism (hostility to immigrants) in the United States. Opponents of immigration frequently questioned whether immigrants from southern and eastern Europe could be assimilated into American gild. Reports of Tay–Sachs illness contributed to a perception among nativists that Jews were an inferior race.[47]

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 past an assay of hexosaminidase A activity.[49] The further development of enzyme assays demonstrated that levels of hexosaminidases A and B could exist measured in patients and carriers, assuasive the reliable detection of heterozygotes. During the early 1970s, researchers developed protocols for newborn testing, carrier screening, and pre-natal diagnosis.[33] [50] 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.[51]

Society and culture [edit]

Since carrier testing for Tay–Sachs began in 1971, millions of Ashkenazi Jews have been screened every bit carriers. Jewish communities embraced the cause of genetic screening from the 1970s on. The success with Tay–Sachs illness has led Israel to become the showtime country that offers free genetic screening and counseling for all couples and opened discussions most the proper scope of genetic testing for other disorders in Israel.[52]

Because Tay–Sachs illness was one of the start autosomal recessive genetic disorders for which there was an enzyme assay examination (prior to polymerase chain reaction testing methods), information technology 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."[43]

This controversy amid researchers has reflected three debates among geneticists at big:[ citation needed ]

  • Dominance versus overdominance. In applied genetics (selective and agricultural breeding), this controversy has reflected the century-long debate over whether authorization or overdominance provides the best caption 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 option that operates to eliminate deleterious alleles. The balancing hypothesis, often associated with Theodosius Dobzhansky, states that heterozygosity will exist common at loci, and that it frequently reflects either directional selection or balancing choice.
  • Selectionists versus neutralists. In theoretical population genetics, selectionists emphasize the primacy of natural selection every bit a determinant of evolution and of variation within a population, while neutralists favor a form of Motoo Kimura'due south neutral theory of molecular evolution, which emphasizes the role of genetic migrate.[53]

Enquiry directions [edit]

Enzyme replacement therapy [edit]

Enzyme replacement therapy techniques have been investigated for lysosomal storage disorders, and could potentially be used to treat Tay–Sachs also. The goal would exist to replace the nonfunctional enzyme, a procedure similar to insulin injections for diabetes. All the same, in previous studies, the HEXA enzyme itself has been thought to be too large to laissez passer through the specialized cell layer in the blood vessels that forms the blood–brain barrier in humans.[ commendation needed ]

Researchers have too tried directly instilling the deficient enzyme hexosaminidase A into the cerebrospinal fluid (CSF) which bathes the brain. However, intracerebral neurons seem unable to have up this physically large molecule efficiently even when it is direct by them. Therefore, this approach to treatment of Tay–Sachs disease has also been ineffective and then far.[54]

Jacob sheep model [edit]

Tay–Sachs disease exists in Jacob sheep.[55] The biochemical mechanism for this affliction in the Jacob sheep is near identical to that in humans, wherein diminished activity of hexosaminidase A results in increased concentrations of GM2 ganglioside in the afflicted animal.[56] Sequencing of the HEXA gene cDNA of affected Jacobs sheep reveal an identical number of nucleotides and exons as in the homo HEXA gene, and 86% nucleotide sequence identity.[55] A missense mutation (G444R)[57] was found in the HEXA cDNA of the affected sheep. This mutation is a single nucleotide alter at the end of exon xi, resulting in that exon'south deletion (before translation) via splicing. The Tay–Sachs model provided by the Jacob sheep is the showtime to offering promise equally a means for gene therapy clinical trials, which may prove useful for illness treatment in humans.[55]

Substrate reduction therapy [edit]

Other experimental methods beingness researched involve substrate reduction therapy, which attempts to use alternative enzymes to increase the brain's catabolism of GM2 gangliosides to a indicate where balance degradative action is sufficient to prevent substrate accumulation.[58] [59] 1 experiment has demonstrated that using the enzyme sialidase allows the genetic defect to be effectively bypassed, and every bit a event, GM2 gangliosides are metabolized so that their levels become near inconsequential. If a safe pharmacological treatment tin can be developed – one that increases expression of lysosomal sialidase in neurons without other toxicity – so this new form of therapy could essentially cure the illness.[60]

Another metabolic therapy nether investigation for Tay–Sachs illness uses miglustat.[61] This drug is a reversible inhibitor of the enzyme glucosylceramide synthase, which catalyzes the commencement stride in synthesizing glucose-based glycosphingolipids like GM2 ganglioside.[62]

Increasing β-hexosaminidase A action [edit]

As Tay–Sachs disease is a deficiency of β-hexosaminidase A, deterioration of affected individuals could exist slowed or stopped through the use of a substance that increases its activity. However, since in infantile Tay–Sachs affliction there is no β-hexosaminidase A, the treatment would be ineffective, but for people affected past Late-Onset Tay–Sachs disease, β-hexosaminidase A is present, and so the treatment may be effective. The drug pyrimethamine has been shown to increase action of β-hexosaminidase A.[63] However, the increased levels of β-hexosaminidase A still autumn far short of the desired "10% of normal HEXA", above which the phenotypic symptoms begin to disappear.[63]

Cord blood transplant [edit]

This is a highly invasive process which involves destroying the patient's blood organization with chemotherapy and administering cord claret. Of five people who had received the handling equally of 2008, 2 were still live after five years and they nonetheless had a great deal of health problems.[64]

Critics point to the procedure'due south harsh nature—and the fact that that it is unapproved. Other significant issues involve the difficulty in crossing the blood–brain bulwark, equally well every bit the smashing expense, as each unit of measurement of cord blood costs $25,000, and adult recipients need many units.[65]

Cistron therapy [edit]

On ten February 2022, the first ever factor 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 child were office of a compassionate trial presenting improvements over the natural course of the disease and no vector-related agin events.[66] [67] [68]

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External links [edit]

  • GeneReviews/NCBI/NIH/UW entry on hexosaminidase A deficiency, Tay–Sachs disease
  • NINDS Tay–Sachs Disease Data Folio
  • Tay–Sachs disease at NLM Genetics Home Reference
  • Tay–Sachs on NCBI
  • "National Tay-Sachs & Allied Diseases Clan (NTSAD)". www.ntsad.org.
  • "Cure Tay-Sachs Foundation". www.curetay-sachs.org.

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Source: https://en.wikipedia.org/wiki/Tay%E2%80%93Sachs_disease

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