Tay-Sachs disease

Tay-Sachs disease (abbreviated TSD) is a fatal genetic disorder, inherited in an autosomal recessive pattern, in which harmful quantities of a fatty substance called ganglioside GM2 accumulate in the nerve cells in 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 population of 1887.

Signs and symptoms

Infants with Tay-Sachs disease appear to develop normally for the first few months of life. Then, as nerve cells become distended with fatty material, 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.

A much rarer form of the disorder which occurs in patients in their twenties and early thirties is characterized by unsteadiness of gait and progressive neurological deterioration. Patients with Tay-Sachs have a "cherry-red" spot in the back of their eyes (the retina).

Pathogenesis

The condition is caused by insufficient activity of an enzyme called hexosaminidase A that catalyzes the biodegradation of acidic fatty materials 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. Both parents must be carriers in order to have an affected child. Prenatal monitoring of pregnancies is available if desired.

To expand on the genetic basis, Tay-Sachs is an autosomal recessive genetic condition: if both parents are carriers, there is a 25% risk with each pregnancy for an affected child.

The disease results from mutations on chromosome 15 of the HEXA gene encoding the alpha-subunit of the lysosomal enzyme alpha-N-acetylhexosaminidase. This enzyme is necessary for breaking down N-galactosamine from GM2 gangliosides in brain and nerve cells. More than ninety mutations have been identified in the HEXA gene. These consist of base pair insertions, base pair deletions, splice site mutations, and point mutations. All of these mutations alter the protein product. For example, a four base pair insertion in exon 11 results in an altered reading frame for the HEXA gene while a three base pair deletion eliminates the amino acid phenylalinine from the protein product at position 304. A G to C point mutation at amino acid 180 changes the codon UAC to UAG causing termination of the polypeptide. A G to A point mutation at amino acid 170 changes the codon CGA to CAA and CGG to CAG which produces glutamine instead of arginine. A G to C mutation in the splice site of intron 12 has also been identified. This mutation creates a recognition site for the restriction enzyme Ddel resulting in abnormal splicing and the production of aberrant mRNA species.

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.[1] (http://www.haaretz.com/hasen/spages/528417.html)

Therapy

There is currently no way to effectively cure or treat TSD. Even with the best care TSD children will die by the age of five. However, research is ongoing and several methods of treatment are being investigated, although significant hurdles remain before any of them will be functional. 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 cerebral spinal 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.

Epidemiology

Ashkenazi Jews have a high incidence of Tay-Sachs and other lipid storage diseases. In the United States, 1 in 27 Ashkenazi Jews is a recessive carrier, compared to 1 in 200 in the general population [2] (http://www.jewishsf.com/bk030613/1b.shtml). French Canadians and the Cajun community of Louisiana have the same carrier rate as Ashkenazi Jews, one in 27, and among Irish Americans the carrier rate is about one in 50. [3] (http://www.tay-sachs.org/taysachs.php)

In 1991, Jared Diamond theorized that Jews who are heterozygous for Tay-Sachs are resistant to tuberculosis, which was common in the Eastern European ghettos where they lived. Puzzlingly, it has been estimated that it would take more than 300 generations to reach the observed frequency of TSD heterozygosity, yet Ashkenazi Jews have only been a separate group for 70 generations (Shaw and Smith, 1969). Also, one would expect a higher frequency of TSD in other ethnic groups living in the same conditions, which is not the case. More research is needed to answer these questions.

References

• Based in part on the 'Tay-Sachs Disease Information Page' of the National Institute of Neurological Disorders and Stroke (see http://www.ninds.nih.gov/disorders/taysachs/taysachs.htm ).

External links

• Tay-Sachs.org (http://www.tay-sachs.org)
• National Society of Genetic Counselors (http://www.nscg.org)
• YGYH.org (http://www.ygyh.org/tay/)