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Tay-Sachs disease

2007 Schools Wikipedia Selection. Related subjects: Health and medicine

   CAPTION: Tay-Sachs disease
   Classifications and external resources

     ICD- 10   E 75.0
     ICD- 9    330.1
      OMIM     272800 272750
   MedlinePlus 001417
    eMedicine  ped/3016

   Tay-Sachs disease (abbreviated TSD, also known as "GM2 gangliosidosis")
   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 present in lipids, which are components of
   cellular membranes, and the ganglioside GM2, implicated in Tay-Sachs
   disease, is especially common in the nervous tissue of the brain.

   The disease is named after the British ophthalmologist Warren Tay who
   first described the red spot on the retina of the eye in 1881, and the
   American neurologist Bernard Sachs who described the cellular changes
   of Tay-Sachs and noted an increased prevalence in the Eastern European
   Jewish ( Ashkenazi) population in 1887. It has been suggested that
   asymptomatic carriers of Tay-Sachs (those with one defective version of
   HEXA and one normal gene) may have a selective advantage, but this has
   never been proven.

   Research in the late 20th century demonstrated that Tay-Sachs disease
   is caused by mutations 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 and Cajuns
   of southern Louisiana have a carrier frequency similar to Ashkenazi
   Jews, but they carry a different mutation. 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.

Symptoms

   Tay-Sachs is classified in variant forms, based on the time of onset of
   neurological symptoms. The variant forms reflect diversity in the
   mutation base. All patients with Tay-Sachs have a "cherry-red" spot in
   the back of their eyes (the retina). This red spot is the area of the
   retina which is accentuated because of the 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 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 3.

     * 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, and swallowing difficulties;
       unsteadiness of gait ( ataxia), and spasticity. Patients with
       Juvenile TSD usually die between 5-15 years.

     * 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 difficulties (dysarthria), swallowing difficulties
       (dysphagia), unsteadiness of gait (ataxia), spasticity, cognitive
       decline, and psychiatric illness, particularly schizophrenic-like
       psychosis. Patients with LOTS frequently become wheelchair-bound in
       adulthood, but many live full adult lives if psychiatric and
       physical difficulties are accommodated. Psychiatric symptoms and
       seizures can be controlled with medications.

Etiology and pathogenesis

   Tay-Sachs disease is inherited in the autosomal recessive pattern,
   depicted above.

   The condition is caused by insufficient activity of an enzyme called
   hexosaminidase A that catalyzes the biodegradation of fatty acid
   derivatives known as gangliosides. Gangliosides are made and
   biodegraded rapidly in early life as the brain develops. Patients and
   carriers of Tay-Sachs disease can be identified by a simple blood test
   that measures hexosaminidase A activity. TSD is a recessive genetic
   disorder, meaning that both parents must be carriers in order to give
   birth to an affected child. Even then, there is only a 25% chance with
   each pregnancy of having a child with TSD. Prenatal monitoring of
   pregnancies is available.

   Hydrolysis of GM2-ganglioside requires three proteins. Two of them are
   subunits of hexosaminidase A, and 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 storage of the ganglioside, primarily in the
   lysosomes of neuronal cells. Tay-Sachs disease (along with
   GM2-gangliosidosis and Sandhoff disease) occurs because a genetic
   mutation inherited from both parents inactivates 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.

   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 alter the protein product,
   and thus inhibit 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.

   For example, 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. The same mutation
   occurs in the Cajun population of southern Louisana, an American ethnic
   group that has been isolated for several hundred years because of
   linguistic differences. Researchers have speculated that it may have
   entered this population because a Jewish merchant family assimilated
   into Cajun society.

   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.

   Tay-Sachs 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 biodegradation of gangliosides.
   Late onset forms of the disease occur because of the diverse mutation
   base. Patients may technically be 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.

Testing and prevention

   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
   lead Israel to become the first country to offer free genetic screening
   and counseling for all couples. Israel has become a leading centre 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 lead to
   the development of screening programs for other diseases.

   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 during the 1970s,
   the enzyme assay test is not as accurate 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. 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.

   Proactive testing has been quite effective in eliminating Tays-Sachs
   occurrence amongst Ashkenazi Jews. Of the 10 babies born with Tay-Sachs
   in North America in 2003, none were 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.
   Three approaches have been used to prevent or reduce the incidence of
   Tay-Sachs disease in the Ashkenazi Jewish population:
     * Prenatal diagnosis and selective abortion. 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 selective
       abortion raises ethical issues for many families.

     * Mate selection. In Orthodox Jewish circles, the organization Dor
       Yeshorim carries out an anonymous screening program so that couples
       who are likely to conceive a child with Tay-Sachs or another
       genetic disorder can avoid marriage. Nomi Stone of Dartmouth
       College describes this approach. "Orthodox Jewish high school
       students are given blood tests to determine if they have the
       Tay-Sachs gene. Instead of receiving direct results as to their
       carrier status, each person is given a six-digit identification
       number. Couples can call a hotline, if both are carriers, they will
       be deemed 'incompatible.' Individuals are not told they are
       carriers directly to avoid any possibility of stigmatization or
       discrimination. If the information were released, carriers could
       potentially become unmarriageable within the community." Anonymous
       testing eliminates the stigma of carriership while decreasing the
       rate of homozygosity in this population. Stone notes that this
       approach, while effective within a confined population such as
       Chassidic or Orthodox Jews, may not be effective in the general
       population.

     * Preimplantation genetic diagnosis. By retrieving the mother's eggs
       for in vitro fertilization and conceiving a child outside the womb,
       it is possible to test the embryo prior to implantation. Only
       healthy embryos are selected for transfer into the mother's womb.
       In addition to Tay-Sachs disease, PGD has been used to prevent
       cystic fibrosis, sickle cell anaemia, Huntington disease, and other
       genetic disorders. However this method is expensive. It requires
       invasive medical technologies, and is beyond the financial means of
       many couples.

Therapy

   There is currently no cure or treatment for TSD. Even with the best
   care, children with Infantile TSD die by the age of 4, and the progress
   of Late-Onset TSD can only be slowed, not treated.
   Retrieved from " http://en.wikipedia.org/wiki/Tay-Sachs_disease"
   This reference article is mainly selected from the English Wikipedia
   with only minor checks and changes (see www.wikipedia.org for details
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