tay–sachs disease tay–sachs disease tay–sachs disease is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord. the most common form is infantile tay–sachs disease, which becomes apparent around the age of three to six months of age, with the baby losing the ability to turn over, sit, or crawl. this is then followed by seizures, hearing loss, and inability to move, with death usually occurring by the age of three to five. less commonly, the disease may occur in later childhood or adulthood (juvenile or late-onset). these forms tend to be less severe, but the juvenile form typically results in death by age 15. tay–sachs diseaseother namesgm2 gangliosidosis, hexosaminidase a deficiencycherry-red spot as seen in the retina in tay–sachs disease. the fovea's center appears bright red because it is surrounded by a whiter than usual area.specialtymedical geneticssymptomsinitially: decreased ability to turn over, sit, or crawllater: seizures, hearing loss, inability to moveusual onsetthree to six months of agedurationlong termtypesinfantile, juvenile, late-onsetcausesgenetic (autosomal recessive)diagnostic methodtesting blood hexosaminidase a levels, genetic testingdifferential diagnosissandhoff disease, leigh syndrome, neuronal ceroid lipofuscinosestreatmentsupportive care, psychosocial supportprognosisdeath often occurs in early childhoodfrequencyrare in the general population tay–sachs disease is caused by a genetic mutation in the hexa gene on chromosome 15, which codes a subunit of the hexosaminidase enzyme known as hexosaminidase a. it is inherited in an autosomal recessive manner. the mutation disrupts the activity of the enzyme, which results in the build-up of the molecule gm2 ganglioside within cells, leading to toxicity. diagnosis may be supported by measuring the blood hexosaminidase a level or genetic testing. tay–sachs disease is a type of gm2 gangliosidosis and sphingolipidosis. the treatment of tay–sachs disease is supportive in nature. this may involve multiple specialities as well as psychosocial support for the family. the disease is rare in the general population. in ashkenazi jews, french canadians of southeastern quebec, the old order amish of pennsylvania, and the cajuns of southern louisiana, the condition is more common. approximately 1 in 3,600 ashkenazi jews at birth are affected. the disease 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 disease in ashkenazi jews. carriers of a single tay–sachs allele are typically normal. it has been hypothesized that being a carrier may confer protection from tuberculosis, explaining the persistence of the allele in certain populations. researchers are looking at gene therapy or enzyme replacement therapy as possible treatments. signs and symptoms tay–sachs disease is typically first noticed in infants around 6 months old displaying an abnormally strong response to sudden noises or other stimuli, known as the "startle response". 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. infantile infants with tay–sachs disease appear to develop normally for the first six months after birth. 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. juvenile juvenile tay–sachs disease is rarer than other forms of tay–sachs, and usually is initially seen in children between two and ten years old. people with tay–sachs disease experience cognitive and motor skill deterioration, dysarthria, dysphagia, ataxia, and spasticity. death usually occurs between the ages of five and fifteen years. late-onset a rare form of this disease, known as adult-onset or late-onset tay–sachs disease, usually has its first symptoms during the 30s or 40s. 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. 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, cognitive decline, and psychiatric illness, particularly a schizophrenia-like psychosis. late-onset tay–sachs patients may become fully wheelchair-bound. until the 1970s and 1980s, when the disease's molecular genetics became known, the juvenile and adult forms of the disease were not always recognized as variants of tay–sachs disease. post-infantile tay–sachs was often misdiagnosed as another neurological disorder, such as friedreich's ataxia. genetics tay–sachs disease is inherited in an autosomal recessive pattern. 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, meaning that when both parents are carriers, there is a 25% risk of giving birth to an affected child with each pregnancy. the affected child would have received a mutated copy of the gene from each parent. if a child received a normal copy from one parent and a mutated copy from the other, it is a carrier. tay–sachs results from mutations in the hexa gene on chromosome 15, which encodes the alpha-subunit of beta-n-acetylhexosaminidase a, a lysosomal enzyme. by 2000, more than 100 different mutations had been identified in the human hexa gene. these mutations have included single base insertions and deletions, splice phase mutations, missense mutations, and other more complex patterns. each of these mutations alters the gene's protein product (i.e., the enzyme), sometimes severely inhibiting its function. in recent years, population studies and pedigree analysis have shown how such mutations arise and spread within small founder populations. initial research focused on several such founder populations: ashkenazi jews. a four base pair insertion in exon 11 (1278instatc) results in an altered reading frame for the hexa gene. this mutation is the most prevalent mutation in the ashkenazi jewish population, and leads to the infantile form of tay–sachs disease. cajuns. the same 1278instatc mutation found among 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 be jewish – who lived in france in the 18th century. french canadians. two mutations, unrelated to the ashkenazi/cajun mutation, are absent in france but common among certain french-canadian communities living in southeastern quebec and acadians from the province of new brunswick. pedigree analysis suggests the mutations were uncommon before the late 17th century. in the 1960s and early 1970s, when the biochemical basis of tay–sachs disease was first becoming known, no mutations had been sequenced directly for genetic diseases. 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. subsequent research, however, has proven that a large variety of different hexa mutations can cause the disease. 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. 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. late onset forms occur due to the diverse mutation base – people with tay–sachs disease may technically be heterozygotes, with two differing hexa mutations that both inactivate, alter, or inhibit enzyme activity. when a patient has at least one hexa copy that still enables some level of hexosaminidase a activity, a later onset disease form occurs. when disease occurs because of two unrelated mutations, the patient is said to be a compound heterozygote. heterozygous carriers (individuals who inherit one mutant allele) show abnormal enzyme activity but manifest no disease symptoms. this phenomenon is called dominance; the biochemical reason for wild-type alleles' dominance over nonfunctional mutant alleles in inborn errors of metabolism comes from how enzymes function. 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 (i.e. will develop full-blown disease). a normal:mutated heterozygote (heterozygous individual, also known as a 'carrier') has at least half of the normal enzyme activity level, due to the expression of the wild-type allele. this level is normally enough to enable normal functioning and thus prevent phenotypic expression (i.e. a normal:mutated carrier will not become ill). pathophysiology tay–sachs disease is caused by insufficient activity of the enzyme hexosaminidase a. hexosaminidase a is a vital hydrolytic enzyme, found in the lysosomes, that breaks down sphingolipids. when hexosaminidase a is no longer functioning properly, the lipids accumulate in the brain and interfere with normal biological processes. hexosaminidase a specifically breaks down fatty acid derivatives called gangliosides; these are made and biodegraded rapidly in early life as the brain develops. patients with and carriers of tay–sachs can be identified by a simple blood test that measures hexosaminidase a activity. the hydrolysis of gm2-ganglioside requires three proteins. two of them are subunits of hexosaminidase a; the third is a small glycolipid transport protein, the gm2 activator protein (gm2a), which acts as a substrate-specific cofactor for the enzyme. 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.g., the active site). instead, they cause incorrect folding (disrupting function) or disable intracellular transport. diagnosis in patients with a clinical suspicion for tay–sachs disease, with any age of onset, the initial testing involves an enzyme assay to measure the activity of hexosaminidase in serum, fibroblasts, or leukocytes. 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. all patients with infantile onset tay–sachs disease have a "cherry red" macula in the retina, easily observable by a physician using an ophthalmoscope. this red spot is a retinal area that appears red because of gangliosides in the surrounding retinal ganglion cells. 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. unlike other lysosomal storage diseases (e.g., gaucher disease, niemann–pick disease, and sandhoff disease), hepatosplenomegaly (liver and spleen enlargement) is not seen in tay–sachs. prevention main article: prevention of tay–sachs disease three main approaches have 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. chorionic villus sampling (cvs), the most common form of prenatal diagnosis, can be performed between 10 and 14 weeks of gestation. amniocentesis is usually performed at 15–18 weeks. these procedures have risks of miscarriage of 1% or less. preimplantation genetic diagnosis. by retrieving the mother's eggs for in vitro fertilization, it is possible to test the embryo for the disorder prior to implantation. healthy embryos are then selected and transferred into the mother's womb, while unhealthy embryos are discarded. in addition to tay–sachs disease, preimplantation genetic diagnosis has been used to prevent cystic fibrosis and sickle cell anemia among other genetic disorders. mate selection. 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. management as of 2010 there was no treatment that addressed the cause of tay–sachs disease or could slow its progression; people receive supportive care to ease the