{{Infobox_Disease |
  Name           = Tay-Sachs disease |
  Image          = |
  Caption        = |
  DiseasesDB     = 12916 |
  ICD10          = |
  ICD9           =  |
  ICDO           = |
  OMIM           = 272800 |
  OMIM_mult      =  |
  MedlinePlus    = 001417 |
  eMedicineSubj  = ped |
  eMedicineTopic = 3016 |
  MeshID         = D013661 |
}}
'''Tay-Sachs disease''' (abbreviated '''TSD''', also known as '''GM2 gangliosidosis''', '''Hexosaminidase A deficiency''' or '''Sphingolipidosis''') is a genetic disorder, fatal in its most common variant known as '''Infantile Tay-Sachs disease'''.  TSD is inherited in an autosomal recessive pattern. The disease occurs when harmful quantities of a fatty acid derivative called a ganglioside accumulate in the nerve cells of the brain. Gangliosides are lipids, components of cellular membranes, and the ganglioside GM2, implicated in Tay-Sachs disease, is especially common in the nervous tissue of the brain. 

The British Enersen, Ole Daniel. [http://www.whonamedit.com/doctor.cfm/474.html Warren Tay.] WhoNamedIt.com.  Retrieved on American cellular changes of Tay-Sachs and noted an increased prevalence in the Eastern European Jewish (Ashkenazi) population in 1887.  

Research in the late 20th century demonstrated that Tay-Sachs disease is caused by a genetic mutation on the HEXA gene on chromosome 15. A large number of HEXA mutations have been discovered, and new ones are still being reported. These mutations reach significant frequencies in several populations. French Canadians of southeastern Quebec have a carrier frequency similar to Ashkenazi Jews, but they carry a different mutation. Many Cajuns of southern Louisiana carry the same mutation that is most common in Ashkenazi Jews. Most HEXA mutations are rare, and do not occur in genetically isolated populations. The disease can potentially occur from the inheritance of two unrelated mutations in the HEXA gene, one from each parent.<ref name="Genedis"></ref>

Tay-Sachs disease is a rare disease. Other autosomal disorders such as cystic fibrosis and sickle cell anemia are far more common. The importance of Tay-Sachs lies in the fact that an inexpensive enzyme assay test was discovered and subsequently automated, providing one of the first "mass screening" tools in medical genetics.<ref>O'Brine JS, Okada S, Chen A, Fillerup DL (1970). "Tay-Sachs disease. Detection of heterozygotes and homozygotes by serum hexaminidase assay." ''New England Journal of Medicine'' '''283''', pp 15-20.}}</ref><ref name="KabackAdvances"></ref> In this way, it became a research and public health model for understanding and preventing all autosomal genetic disorders. 

== Symptoms ==
thumb|right|200px|Fundus photograph showing retina changes associated with Tay-Sachs disease.

Tay-Sachs disease is classified in variant forms, based on the time of onset of neurological symptoms.<ref name = "NINDS">{{cite web |url= http://www.ninds.nih.gov/disorders/taysachs/taysachs.htm |
title= Tay-Sachs Disease Information Page |publisher=  date = [[February 14 2007 | accessdate = 2007-05-10}}</ref> The variant forms reflect diversity in the mutation base.  

All patients with Tay-Sachs disease have a "cherry-red" spot, easily observable by a physician using an ophthalmoscope, in the back of their eyes (the retina).<ref name="NINDS"/> This red spot is the area of the retina which is accentuated because of gangliosides in the surrounding retinal ganglion cells (which are neurons of the central nervous system). The choroidal circulation is showing through "red" in this region of the fovea where all of the retinal ganglion cells are normally pushed aside to increase visual acuity. Thus, the cherry-red spot is the only normal part of the retina seen.  Microscopic analysis of neurons shows that they are distended from excess storage of gangliosides. 

*'''Infantile TSD.''' Infants with Tay-Sachs disease appear to develop normally for the first six months of life. Then, as nerve cells become distended with gangliosides, a relentless deterioration of mental and physical abilities occurs. The child becomes blind, deaf, and unable to swallow. Muscles begin to atrophy and paralysis sets in. Death usually occurs before the age of 4 or 5.<ref name="NINDS"/>   
 
*'''Juvenile TSD.''' Extremely rare, Juvenile Tay-Sachs disease usually presents itself in children between 2 and 10 years of age. They develop cognitive, motor, speech difficulties (dysarthria), swallowing difficulties (dysphagia), unsteadiness of gait (ataxia), and spasticity. Patients with Juvenile TSD usually die between 5–15 years.<ref></ref>   
  
*'''Adult/Late Onset TSD.''' A rare form of the disorder, known as Adult Onset Tay-Sachs disease or Late Onset Tay-Sachs disease (LOTS), occurs in patients in their 20s and early 30s. LOTS is frequently misdiagnosed, and is usually non-fatal. It is characterized by unsteadiness of gait and progressive neurological deterioration. Symptoms of LOTS, which present in adolescence or early adulthood, include speech and swallowing difficulties, unsteadiness of gait, spasticity, cognitive decline, and psychiatric illness, particularly schizophrenic-like psychosis. Patients with LOTS frequently become full-time wheelchair users in adulthood, but many live full adult lives if psychiatric and physical difficulties are accommodated. Psychiatric symptoms and seizures can be controlled with medications.<ref></ref><ref></ref>

The development of improved testing methods has allowed neurologists to diagnose Tay-Sachs and other neurological diseases with greater precision. Until the 1970s and 80s, when the molecular genetics of the disease became known, the juvenile and adult forms of the disease were not recognized as variants of Tay-Sachs. Post-infantile Tay-Sachs was often mis-diagnosed as another neurological disorder, such as Friedreich ataxia.<ref></ref>

==Etiology and pathogenesis ==
thumb|right|300px|Tay-Sachs disease is inherited in the [[autosomal recessive pattern, depicted above.]]
The condition is caused by insufficient activity of an enzyme called recessive genetic disorder, meaning that both parents must be carriers in order to give birth to an affected child. Then, there is a 25% chance with each pregnancy of having a child with TSD. Prenatal monitoring of pregnancies is available.<ref name="NINDS"/>

cofactor for the enzyme. Deficiency in any one of these proteins leads to storage of the ganglioside, primarily in the neuronal cells. Tay-Sachs disease (along with GM2-gangliosidosis and Sandhoff disease) occurs because a genetic mutation inherited from both parents deactivates or inhibits this process. Most Tay-Sachs mutations appear not to affect functional elements of the protein. Instead, they cause incorrect folding or assembly of the enzyme, so that intracellular transport is disabled.<ref></ref>

== Mutations and polymorphism ==

The disease results from mutations on chromosome 15 in the ''HEXA'' gene encoding the alpha-subunit of the lysosomal enzyme beta-N-acetylhexosaminidase A. More than 90 mutations have been identified to date in the HEXA gene, and new mutations are still being reported. These mutations have included base pair insertions and deletions, splice site mutations, point mutations, and other more complex patterns. Each of these mutations alters the protein product, and thus inhibits the function of the enzyme in some manner. In recent years, population studies and pedigree analysis have shown how such mutations arise and spread within small founder populations.<ref name="Genedis"/> 

For example, a four base pair insertion in Ashkenazi Jewish population, and leads to the infantile form of Tay-Sachs disease.<ref name="Genedis"/> The same mutation occurs in the Cajun population of southern Louisiana, an American ethnic group that has been isolated for several hundred years because of linguistic differences. Researchers have traced carriers from several Louisiana families to a single founder couple, not known to be Jewish, that lived in France in the 18th century.<ref>{{cite journal
  | author = McDowell GA, Mulest EH, Fabacher P, Shapira JE, Blitzer MG
  |title = The presence of two different infantile Tay-Sachs disease mutations in a Cajun population 
  | journal = American Journal of Human Geneticcs 
  | date=1992 
  | volume=51 
  | issue=5 
  | pages=1071–1077 
  | pmid = 1307230
  | url= http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1682822&blobtype=pdf |format = PDF |accessdate = 2007-05-10}}</ref>

An unrelated mutation, a long sequence deletion, occurs with similar frequency in families with French Canadian ancestry, and has the same pathological effects. Like the Ashkenazi Jewish population, the French Canadian population grew rapidly from a small founder group, and remained isolated from surrounding populations because of geographic, cultural, and language barriers. In the early days of Tay-Sachs research, the mutations in these two populations were believed to be identical. Some researchers claimed that a prolific Jewish ancestor must have introduced the mutation into the French Canadian population. This theory became known as the "Jewish Fur Trader Hypothesis" among researchers in population genetics.  However, subsequent research has demonstrated that the two mutations are unrelated, and pedigree analysis has traced the French Canadian mutation to a founding family that lived in southern Quebec in the late 17th century.<ref></ref><ref></ref>

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 any genetic diseases. Researchers of that era did not yet know how common polymorphism 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 of the time. Subsequent research has proven that a large number of HEXA mutations can cause some form of the disease. Because Tay-Sachs disease 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 was demonstrated.<ref></ref> 

Compound heterozygosity ultimately explains some of the variability of the disease, including 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 TSD results when a child has inherited mutations from both parents that completely inactivate the heterozygotes, but with two different HEXA mutations that both inactivate, alter, or inhibit enzyme activity in some way. When a patient has at least one copy of the HEXA gene that still enables some hexosaminidase A activity, a later onset form of the disease occurs. When disease occurs because of two unrelated mutations, the patient is said to be a compound heterozygote.<ref name="genereviews"></ref>

== Testing ==
Screening for Tay-Sachs disease was one of the first great successes of the emerging field of genetic counseling and diagnosis. Jewish communities, both inside and outside of Israel, embraced the cause of genetic screening from the 1970s on. Success with Tay-Sachs disease led Israel to become the first country to offer free genetic screening and counseling for all couples.  Israel has become a leading center for research on genetic disease. Both the Jewish and Arab/Palestinian populations in Israel contain many ethnic and religious minority groups, and Israel's initial success with Tay-Sachs disease has led to the development of screening programs for other diseases. Israel's success with Tay-Sachs disease has also opened several discussions and debates about the proper scope of genetic testing for other disorders.<ref></ref>

Genetic screening for carriers of Tay-Sachs disease is possible because an inexpensive enzyme assay test is available. It detects lower levels of the enzyme hexosaminidase A in serum. Developed and then automated during the 1970s, the enzyme assay test is not as precise as genetic testing based on polymerase chain reaction (PCR) techniques; however, it is cost effective for much broader use and allows screening for a disease that is rare in most populations. Couples with positive or ambiguous test results on the enzyme assay test may be referred for more precise screening. Current testing methods screen a panel of the most common mutations, although this leaves open a small probability of both false positive and false negative results. PCR testing is more effective when the ancestry of both parents is known, allowing for proper selection of genetic markers. Genetic counselors, working with couples that plan to conceive a child, assess risk factors based on ancestry to determine which testing methods are appropriate.<ref name="genereviews"> As the cost of PCR techniques declines and knowledge about mutations increases, it may become possible to screen for all mutations.<ref></ref>

Proactive testing has been quite effective in eliminating Tay-Sachs occurrence among Ashkenazi Jews, both in diaspora. On January 18, 2005, the Israeli English language daily Haaretz reported that as a "Jewish disease" Tay-Sachs had almost been eradicated. Of the 10 babies born with Tay-Sachs in North America in 2003, none had been born to Jewish families. In Israel, only one child was born with Tay-Sachs in 2003, and preliminary results from early 2005 indicated that none were born with the disease in 2004.<ref></ref>

== Prevention ==
Three approaches have been used to prevent or reduce the incidence of Tay-Sachs disease in the Ashkenazi Jewish population:

* '''Prenatal diagnosis'''. If both parents are identified as carriers, prenatal genetic testing can determine whether the fetus has inherited a defective copy of the gene from both parents. For couples who are willing to terminate the pregnancy, this eliminates the risk of Tay-Sachs, but abortion raises ethical issues for many families.<ref> </ref> 

{{Infobox Malattia
|RaraIT=RFG030
|ICD9=
|Eponimo1=Warren Tay
|Eponimo2=Bernard Sachs
|Eponimo3=Alfred Washington Adson
}}
La '''malattia di Tay-Sachs''' è una cerebrosidosi genetica ereditaria rara, dovuta ad un deficit dell'enzima esosaminidasi A, che provoca l'accumulo del ganglioside GM2 nel cervello. Il gene che causa la malattia si trova sul quindicesimo cromosoma (15q23).
Esistono tre forme della malattia:
*'''Forma infantile''' che si manifesta nei primi mesi di vita che causa nel bambino ritardo psicomotorio, ipotonia, amaurosi, e in alcuni casi megalencefalia e sussulti associati a forti rumori. Nella forma infantile della malattia è visibile una macchia rosso ciliegia nel fondo degli occhi. La morte subentra in concomitanza di decerebrazione.
*'''Forma giovanile''' che insorge tra i 2 e gli 8 anni. I sintomi sono disturbi del comportamento, atassia e regressione mentale, che anche in questo caso portano a decerebrazione.
*'''Forma dell'adulto''' o '''cronica''' può comparire dai 10 anni, ma la diagnosi è possibile solo in età adulta. Questa si manifesta in due forme: la prima simile alla malattia di Friedreich, attraverso atassia spinocerebellare, la seconda invece è simile alla sindrome di Wohlfart-Kugelberg-Welander con una amiotrofia spinale giovanile.

La diagnosi della malattia comporta l’analisi enzimatica e la biopsia. Ancora non si conosce alcuna terapia efficace.