Course:MEDG550/Student Activities/Tay-Sachs

Tay-Sachs Disease

Tay-Sachs disease is a rare genetic condition that causes progressive loss of brain and spinal cord function which leads to reduced mental and physical abilities. Tay-Sachs disease is caused by the absence of an important compound, hexosaminidase-A (Hex-A) enzyme, that normally breaks down the part of nerve cells called gangliosides, in the brain. Without Hex-A enzyme, gangliosides build up in nerve cells causing death of these cells and damage to the brain. Most often this damage leads to symptoms by the age of 6 months and death by age 4. However, there is a more rare form of Tay-Sachs that presents in adulthood.

Clinical Features

In the most common type of Tay-Sachs disease, the muscles begin to weaken around 6 months of age and there is a progressive loss of skills such as turning over, sitting, and crawling. Affected babies also display an exaggerated startle reaction to loud noises. Over time, vision and hearing loss occur as well as seizures. Typically, progression of the disease leads to paralysis and death by age 5.

In a much rarer form of Tay-Sachs, symptoms appear later in life. The symptoms onset anytime from adolescence to 30s and include clumsiness, mood alterations, and muscle weakness. The late-onset form is extremely variable and extremely rare.

Diagnosis

The diagnosis of Tay-Sachs can be made based on a combination of the clinical features, including characteristic features of the eye and enzyme levels of Hex-A.

There is a characteristic cherry-red spot in the retina of the eye that is identified upon eye examination of someone with Tay-Sachs. The spot appears red due to the white appearance of the surrounding cells, the neurons. The cherry-red spot is shown on the right.

Tay-Sachs Cherry Red Spot

Hex-A levels in the blood can be used to make a diagnosis of Tay-Sachs as well as identify carriers of Tay-Sachs disease. In individuals affected with Tay-Sachs, there is no Hex-A present. In individuals who are carriers of Tay-Sachs, the Hex-A enzyme level is lower when compared to individuals who are not carriers for Tay-Sachs.

Genetic testing, which looks for specific mutations in the DNA, is also diagnostic for Tay-Sachs disease and can also identify mutation carriers. Because not all mutations in HEXA are known, the genetic test may miss some carriers. The test detects 95% of carriers who are of Ashkenazi Jewish descent and around 60% of carriers in the general population.

Prevalence

Tay-Sachs is rare in the general population, with approximately 1/112,000 live births per year. However, the prevalence is much higher in the Ashkenazi Jewish population where 1/3600 live births are affected. A higher incidence is also observed in French Canadian and Louisiana Cajun populations. These high frequencies of Tay-Sachs disease in certain populations is thought to be due to the “founder effect,” where a new population is founded by a small number of individuals leading to loss of genetic diversity. The certain HEXA mutations in these founder populations are known as “founder mutations.”

Genetics

The HEXA gene is responsible for providing instructions for the enzyme Hex-A to form and function correctly, but when changes, called mutations, happen in the HEXA gene Tay-Sachs disease can occur. More than 120 different mutations in the HEXA gene have been identified to cause. Tay-Sachs disease.

Inheritance

Autosomal Recessive Inheritance

Tay-Sachs disease is inherited in an autosomal recessive pattern. Autosomal means that it is not inherited in a sex-specific manner, that is, males and females are affected equally. Recessive means that two copies of the mutation are required for the disease to occur in an individual. Each parent of a child with Tay-Sachs carries one copy of the mutation, and when each parent passes down their copy, the child is affected with Tay-Sachs. The risk of two mutations being passed down (one from mom and one from dad) is 25%, so in each pregnancy there is a 25% chance Tay-Sachs will develop when both parents carry a mutation. There is a 50% chance the child will inherit one mutation, or a be a carrier, like the parents. Lastly, there is a 25% chance the child will not inherit either of the mutations for Tay-Sachs. The diagram on the right shows an autosomal recessive inheritance pattern.

Carrier Screening

The carrier frequency for the general population is 1/250 In the Ashkenazi Jewish population, however, the carrier frequency is thought to be much higher, about 1/27, and is estimated to be of similar high prevalence in some French-Canadian populations, the Pennsylvania Amish, and the Louisiana Cajuns.

Due to the high carrier frequency in some populations, carrier screening (also referred to as carrier testing) can be done to see if individuals are at risk of having a child with Tay-Sachs disease. Testing criteria and details may depend on where you live, but generally, if one partner is or may be of Ashkenazi Jewish, French Canadian or Louisiana Cajun descent carrier testing is available. Ashkenazi Jewish individuals will likely be screened by a blood test that which looks specifically at the mutations in the HEXA gene that are common in the Ashkenazi Jewish population for causing Tay-Sachs. This test may also include screeening for other genetic conditions found at a high rate within Ashkenazi Jews. French Canadian, Louisiana Cajun or someone with a family history of Tay-Sachs disease will receive a blood test that looks at the level of HEX-A enzyme present in the blood. Tay-Sachs disease carriers will ahve lower levels of HEX-A enzyme compared to non-carriers. Population-based carrier screening has lowered the risk of having a child affected by Tay-Sachs by 90%.

The History of Screening in the Jewish Community
In 1983, an organization called Dor Yeshorim was formed with the goal of preventing Tay Sachs disease in the Ashkenazi Jewish population. After losing four children to Tay Sachs disease, a Jewish Rabbi named Josef Ekstein founded Dor Yeshorim and began to offer genetic testing to the Jewish community. Through Dor Yeshorim, confidential genetic testing can be done and entered in to a database with an ID number. A Jewish couple contemplating marriage can check their genetic compatibility using their ID numbers without details of their genetic information being revealed. Since its inception in 1983, Dor Yeshorim has expanded testing to several disorders that are prevalent in the Jewish population. The organization has received both praise and criticism from the international community.

Treatment

Tay-Sachs currently has no cure or effective treatment. The symptoms associated with the disease are managed, such as making the child as comfortable as possible and controlling seizures.

Ongoing Research

Someday gene therapy or enzyme replacement therapy may be successful in slowing the disease progression. Gene therapy is applicable to Tay-Sachs because the cause of the disease is due to an abnormal gene, HEXA. Gene therapy is a technology that works to add in the functional gene to compensate for the abnormal gene. Enzyme replacement therapy is a similar idea, however it refers to adding in the gene product, the enzyme in this case, to help alleviate symptoms and manifestation of disease.

Genetic Counselling

Health professional who specialize in genetic testing, called genetic counsellors, can help you arrange carrier or prenatal testing for Tay-Sachs. Please contact your family physician for a referral. Aspects of conversation may include any or all the topics outlined on this page, depending the specific needs of the patient.

Prenatal diagnosis

When both parents are carriers of Tay-Sachs, prenatal diagnostic testing is offered in every pregnancy because there is a 25% chance of having an affected baby. There are two types of prenatal diagnostic tests, a chorionic villus sample (CVS) or an amniocentesis. CVS is an invasive procedure offered 10-12 weeks of pregnancy, and involves removing a small sample of the placenta. This procedure comes with a risk of miscarriage, which is quoted to be 1%. Amniocentesis is an invasive procedure offered starting at 16 weeks of pregnancy, and involves a small amount of amniotic fluid, the fluid surrounding the baby, to be sampled. This procedure has .5% risk of miscarriage associated with it.

See images of CVS and amniocentesis:

Amniocentesis

Chorionic Villus Sampling

Assisted Reproductive Technologies

Genetic counsellors would also discuss assisted reproductive technologies because some couples may not want to have to face the decision of terminating an affected pregnancy. Either egg or sperm donation, or preimplantation genetic diagnosis can be used to prevent passing on Tay-Sachs. In egg or sperm donation, one member of the couple would be a biological parent to the child, and the donated egg or sperm would be tested to ensure carrier status of Tay-Sachs. In preimplantation genetic diagnosis, both members of the couple can be biological parents to the child, but only an unaffected embryo or embryos are implanted into the woman’s uterus. The latter procedure is more expensive and more time consuming, but remains an option for families who want to be biological parents and not worry about passing on Tay-Sachs.

Adoptions is another option available to families.

Patient Resources

Genetic counsellors also serve patients by connecting them with useful resources. A number of resources for Tay-Sachs exist and some are listed below.

[1] National Tay Sachs and Allied Disease of Canada; provides educational information, group and peer support.

[2] National Tay-Sachs & Allied Diseases Association; US based, fighting to treat and cure Tay-Sachs, Canavan, Sandhoff, GM1 and related diseases, support for families, information, volunteer opportunities, events.

[3] March of Dimes, support organization with connections to support resources and an online support community.

[4] US specific, rare diseases organization, events and online support community.

[5] The Cure & Action for Tay-Sachs Foundation; support for families, raising awareness, funding for research for potential treatment; located in England and Wales.

References

<references>

1. National Human Genome Research Institute. “Learning About Tay-Sachs Disease.” 2011. NIH. 10 Mar. 2016<https://www.genome.gov/10001220>.
2. Gravel, Roy A. "Tay-Sachs Disease." Genetics. 2003. Encyclopedia.com. 9 Mar. 2016<http://www.encyclopedia.com>.
3. Genetics Home Reference. “Tay-Sachs disease.” 2012. National Library of Medicine. 09 Mar. 2016<https://ghr.nlm.nih.gov/condition/tay-sachs-disease>.
4. National Organization for Rare Disorders. “Tay Sachs Disease.” 2002. 08 Mar. 2016<http://rarediseases.org/rare-diseases/tay-sachs-disease/>.
5. March of Dimes. “Amniocentesis.” 2012. 10 Mar. 2016< http://www.marchofdimes.org/pregnancy/amniocentesis.aspx#>.