Tay-Sachs disease

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 in 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 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
All patients with Tay-Sachs have a "cherry-red" spot in the back of their eyes (the retina).

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 five.

Juvenile TSD
Extremely rare, Juvenile Tay-Sachs disease usually presents itself in children between two and ten years. 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.

Pathogenesis
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. The allele for TSD is recessive, meaning that both parents must be carriers in order to create an affected child; even then, there is only a 25% chance of having a child with TSD. Prenatal monitoring of pregnancies is available if desired.

The disease results from mutations on chromosome 15 in the HEXA gene encoding the alpha-subunit of the lysosomal enzyme beta-N-acetylhexosaminidase A. This enzyme is necessary for breaking down N-galactosamine from GM2 gangliosides in brain and nerve cells.

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.

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. An unrelated mutation in exon 11, a single point transposition of C to G, occurs with similar frequency in families with French Canadian and Cajun ancestry, and has the same effect. 

Disease can potentially occur 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
In populations with a high carrier frequency for TSD, genetic counseling is recommended so genetic testing can be done to detect carriership. Preimplantation genetic diagnosis can be considered in couples where both are carriers. In countries where selective abortion is legal, this method can be contemplated.

In Orthodox Jewish circles, the organisation Dor Yeshorim carries out an anonymous screening program, preventing the stigma of carriership while decreasing the rate of homozygosity in this population.

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 Jews. In Israel, only one child was born with Tay-Sachs in 2003, and preliminary results from early 2005 indicated that none were born with it in 2004.

Therapy
There is currently no way to cure or treat TSD. Even with the best care children with Infantile TSD will die by the age of five, and the progress of Late-Onset TSD can only be slowed, not reversed. However, research is ongoing and several methods of treatment are being investigated, although significant hurdles remain before any of them will be past the experimental stages.

The first treatment method that was investigated by scientists was enzyme replacement therapy, whereby functional Hex A would be injected into the patient to replace the missing enzyme, a process similar to insulin injections. However, the enzyme was found to be too large to be able to pass from the blood into the brain through the blood-brain barrier, where the blood vessels in the brain develop junctions so small that many toxic (or large) molecules cannot enter into nerve cells and cause damage.

Researchers also tried instilling Hex A into the cerebrospinal fluid, which bathes the brain. However, neurons are not able to take up the large enzyme efficiently even when it is placed next to the cell, so the treatment is still ineffective.

The most recent option explored by scientists has been gene therapy. However, scientists still believe that they are years away from the technology to transport the genes into neurons, which they say would be just as hard as transporting the enzyme. Currently, most research involving gene therapy involves developing a method of using a viral vector to transfer new DNA into neurons. If the defective genes were to be replaced throughout the brain Tay Sachs could theoretically be cured.

Other highly experimental methods being researched involve the manipulation of the brain's metabolism of GM2 gangliosides. One experiment has shown that, using the enzyme sialidase, the genetic defect can be effectively bypassed and GM2 gangliosides metabolized to be almost inconsequential. If a safe pharmacological treatment causing the increased expression of lysosomal sialidase in neurons can be developed, a new form of therapy, essentially curing the disease, could be on the horizon.

Therapies being investigated for Late-Onset TSD include treatment with the drug OGT 918 (Zavesca).

Epidemiology
Historically, Eastern European people of Jewish descent (Ashkenazi Jews) have a high incidence of Tay-Sachs and other lipid storage diseases. Documentation of Tay-Sachs in this Jewish population reaches back to 15th century Europe.

A continuing controversy is whether heterozygotes, individuals who are carriers of one copy of the gene but do not actually develop the disease, have some selective advantage. The classic case of heterozygote advantage is sickle cell anemia, and some researchers have argued that there must be some evolutionary benefit to being a heterozygote for Tay-Sachs as well.

One theory is that being a Tay-Sachs carrier serves as a form of protection against tuberculosis. TB's prevalence in the European Jewish population was very high, in part because Jews were forced to live in crowded conditions. Another theory (Gregory Cochran) is that Tay-Sachs and the other lipid storage diseases that are prevalent in Ashkenazi Jews may enhance dendrite growth and promote higher intelligence when present in carrier form, thus providing a selective advantage at a time when Ashkenazi Jews were restricted to intellectual occupations. (See Ashkenazi intelligence.) Neither of these theories has been proven. Other studies have suggested that the high prevalance of Tay-Sachs in the Jewish population is due to genetic drift and founder effects.

In the United States, about 1 in 27 to 1 in 30 Ashkenazi Jews is a recessive carrier.. 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 a person being a carrier. In the general population, the incidence of carriers (heterozygotes) is about 1 in 300. 

Related Articles,Links Based in part on the 'Tay-Sachs Disease Information Page' of the National Institute of Neurological Disorders and Stroke
 * Lewis, Rick. quoted in Evolution: Human Genetics: Concepts and Application January 29, 2006.