Tay–Sachs disease

Tay–Sachs disease
Specialty	Pediatrics, neurology, medical genetics

Tay-Sachs disease (abbreviated TSD, also known as "GM2 gangliosidosis") is a genetic disorder, fatal in the most common variant known as Infantile Tay-Sachs disease. TSD is 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 (Ashkenazi) population of 1887. Studies of this same population demonstrated that Tay-Sachs provides resistance to tuberculosis.

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 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. Death usually occurs between 2-5 years.

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.^[1]

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 twenties and early thirties. LOTS is frequently misdiagnosed (by appromiximately eight years), is usually non-fatal, and is characterized by unsteadiness of gait and progressive neurological deterioration. Symptoms present in adolescence or adulthood with 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 accomodated. Psychiatric symptoms and seizures can be controlled with medications. ^[2][3]

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. 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.

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

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 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 phenylalanine 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.[4]

Therapy

There is currently no way to effectively cure or treat TSD. Even with the best care Infantile 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 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).^[5]

Epidemiology

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

The carrier form of this disease serves as a form of protection against tuberculosis (TB). TB's prevalence in the Jewish populations of the time was very high, due in part to religious persecution and exclusion of the Jewish population from the mainstream. Jews were forced to live in slums, where poor living conditions spread of TB, and increased the benefit provided by carrier form of this disease. This is cited by many as the reason for the observed prevalence.

In the United States, about 1 in 27 to 1 in 30 Ashkenazi Jews is a recessive carrier.[6]. French Canadians and the Cajun community of Louisiana have an occurrence similar to the Ashkenazi Jews. It has been found that Irish Americans have a 1 in 50 chance of a person being a recessive carrier. The general population has an incidence of about 1 in 300. [7]

References

• Chavany C, Jendoubi M (1998). "Biology and potential strategies for the treatment of GM2 gangliosidoses". Mol Med Today. 4 (4): 158–65. PMID 9572057.
• Fernandes Filho JA, Shapiro BE (2004). "Tay-Sachs disease". Arch Neurol. 61 (9): 1466–8. PMID 15364698.
• ^ Kolodny, E. H.; Neudorfer, O.; Gianutsos, J.; Zaroff, C.; Barnett, N.; Zeng, B.; Raghavan, S.; Torres, P.; Pastores, G. (2004). "Late-onset Tay-Sachs disease: natural history and treatment with OGT 918 (Zavesca[TM])". Source Journal of Neurochemistry. 90 (54). ISSN 0022-3042. {{cite journal}}: horizontal tab character in |journal= at position 7 (help)CS1 maint: multiple names: authors list (link)
• Lewis, Rick. quoted in Evolution: Human Genetics: Concepts and Application January 29, 2006.
• Mahuran DJ (1999). "Biochemical consequences of mutations causing the GM2 gangliosidoses". Biochim Biophys Acta. 1455 (2–3): 105–38. PMID 10571007.
• ^ Moe, MD, Paul G. & Tim A. Benke, MD, PhD (2005). "Neurologic & Muscular Disorders". Current Pediatric Diagnosis & Treatment (17th ed.).{{cite book}}: CS1 maint: multiple names: authors list (link)
• ^ Neudorfer O, Pastores GM, Zeng BJ, Gianutsos J, Zaroff CM, Kolodny EH (2005). "Late-onset Tay-Sachs disease: phenotypic characterization and genotypic correlations in 21 affected patients". Genet Med. 7 (2): 119–23. PMID 15714079.{{cite journal}}: CS1 maint: multiple names: authors list (link)
• ^ Rosebush PI, MacQueen GM, Clarke JT, Callahan JW, Strasberg PM, Mazurek MF. (1995). "Late-onset Tay-Sachs disease presenting as catatonic schizophrenia: diagnostic and treatment issues". J Clin Psychiatry. 56 (8): 347–53. PMID 7635850.{{cite journal}}: CS1 maint: multiple names: authors list (link)

Related Articles,Links Based in part on the 'Tay-Sachs Disease Information Page' of the National Institute of Neurological Disorders and Stroke

External links

• Online Mendelian Inheritance in Man (OMIM): 272800 (describing Tay-Sachs) and Online Mendelian Inheritance in Man (OMIM): 606869 (describing the HEXA gene)
• HEXA gene
• Tay-Sachs and Tuberculosis
• National Tay-Sachs and Allied Diseases
• National Tay-Sachs and Allied Diseases of Delaware Valley
• Your Genes, Your Health, on Tay-Sachs