ABSTRACT:

Tay–Sachs disease is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord..also known as GM2 gangliosidosis or Hexosaminidase A deficiency) is an autosomal recessive genetic disorder. In its most common variant known as infantile Tay-Sachs disease it presents with a relentless deterioration of mental and physical abilities which commences at 6 months of age and usually results in death by the age of four.It is caused by a genetic defect in a single gene with one defective copy of that gene inherited from each parent. The disease occurs when harmful quantities of gangliosides accumulate in the nerve cells of the brain, eventually leading to the premature death of those cells. There is currently no cure or treatment. Tay- Sachs disease is a rare disease. Other autosomal disorders such as cystic fibrosis and sickle cell anemia are far more common. TSD is an autosomal recessive genetic disorder, meaning that when both parents are carriers, there is a 25% risk of giving birth to an affected child.

KEYWORDS: Tay-sachs disease (TSD), Infantile, Pregnant mother, Genetic Disorders.

INTRODUCTION:

Tay–Sachs disease is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord.¹ The most common form is infantile Tay–Sachs disease which becomes apparent around three to six months of age, with the baby losing the ability to turn over, sit, or crawl.¹ This is then followed by seizures, hearing loss, and inability to move, with death usually occurring by the age of three to five.^3,1 Less commonly, the disease may occur in later childhood or adulthood (juvenile or late-onset).¹ These forms tend to be less severe,¹ but the juvenile form typically results in death by age 15.⁴ There’s no cure for the disease, but scientists have a good idea of what causes it, how it worsens, and how to use genetic testing to screen for it early in pregnancy.

Researchers are working to make advances in gene therapy or bone marrow transplants that they hope will allow treatment of Tay-Sachs in the future 2 Tay–Sachs disease is caused by a genetic mutation in the HEXA gene on chromosome 15, which codes for a subunit of the hexosaminidase enzyme known as hexosaminidase A.¹ It is inherited from a person's parents in an autosomal recessive manner.¹ The treatment of Tay–Sachs disease is supportive in nature.² This may involve multiple specialities as well as psychosocial support for the family.² The disease is rare in the general population.¹ In Ashkenazi Jews, French Canadians of southeastern Quebec, the Old Order Amish of Pennsylvania, and the Cajuns of southern Louisiana, the condition is more common.^2,1 Approximately 1 in 3,600 Ashkenazi Jews at birth are affected.²

SYMPTOMS:

A baby born with Tay-Sachs grows like they should until 3 to 6 months of age. Around this time, parents might notice that their baby’s development starts to slow and their muscles weaken. Over time, the disease causes more symptoms in babies, including Past age 3, there are few visible changes in children with Tay-Sachs, but their nervous system continues to get worse, often leading to death by age.

· A loss of motor skills such as turning over, sitting, and crawling

· A very strong reaction to loud noises

· Trouble focusing on objects or following them with their eyes

· Cherry-red spots, which can be identified with an eye

exam, in the eyes

· By age 2, most children with Tay-Sachs have started getting more serious problems. They can include:

· Swallowing and breathing issues that keep getting worse

· Seizures

· Loss of mental function, hearing, and sight

· Paralysis

PATHOPHYSIOLOGY:

Tay–Sachs disease is caused by insufficient activity of the enzyme hexosaminidase A. Hexosaminidase A is a vital hydrolytic enzyme, found in the lysosomes, that breaks down sphingolipids. When hexosaminidase A is no longer functioning properly, the lipids accumulate in the brain and interfere with normal biological processes. Hexosaminidase A specifically breaks down fatty acid derivatives called gangliosides; these are made and biodegraded rapidly in early life as the brain develops. Patients with and carriers of Tay–Sachs can be identified by a simple blood test that measures hexosaminidase A activity.⁵

The hydrolysis of GM2-ganglioside requires three proteins. Two of them are subunits of hexosaminidase A; 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 ganglioside storage, primarily in the lysosomes of neurons. Tay–Sachs disease (along with AB-variant GM2-gangliosidosis and Sandhoff disease) occurs because a mutation inherited from both parents deactivates or inhibits this process. Most Tay– Sachs mutations probably do not directly affect protein functional elements (e.g., the active site). Instead, they cause incorrect folding (disrupting function) or disable intracellular transport.¹⁹

CAUSES AND RISK FACTORS:

· Defects in a gene called HEXA cause Tay-Sachs. (You can think of genes as “coding” that your parents pass along to you. Genes are in your cells, and they set your body’s traits -- everything from your eye color and blood type to your sex.2

· Most people have two healthy versions of this HEXA

gene, which gives instructions to your body to make an enzyme (a type of protein) known as Hex-A. This enzyme prevents the buildup of a fatty substance called GM2 ganglioside in your brain and spinal cord.²

· Some people have just one healthy copy of the gene, and they still make enough Hex-A protein to keep the brain and spinal cord healthy. But babies born with Tay-Sachs disease got a changed copy of the gene from both parents, so they don’t make any Hex-A protein. This is what makes them so sick²

INHERITANCE:

Tay-Sachs disease is inherited in an autosomal recessive manner.⁶ This means that to have the disease, a person must have a mutation in both copies of the responsible gene in each cell. There is nothing either parent can do, before or during a pregnancy, to cause a child to have Tay-Sachs disease. People with Tay-Sachs disease inherit one mutation from each of their parents. The parents, who each have one mutation, are known as carriers. Carriers of an autosomal recessive disease typically do not have any signs or symptoms (they are "unaffected"). When 2 carriers of an autosomal recessive disease have children, each child has a:

· 1 in 4 chance to have the disease

· 1 in 2 chance to be an unaffected carrier like each parent

· 1 in 4 chance to be unaffected and not a carrier.

DIAGNOSIS:

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

TESTING RESOURCES:

The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional. Pregnant women can have a test to find out whether their unborn babies have the problem that causes Tay-Sachs. If the tests don’t find any Hex-A protein, the baby has Tay-Sachs. If the tests find Hex-A, the baby doesn’t have the disease.

THESE TESTS INCLUDE:

· Chorionic villus sampling (CVS). Your doctor takes a small sample of the placenta with a needle or small tube

and analyzes it. They can do this between the 10th and 12th weeks of pregnancy.

· Amniocentesis. The doctor uses a needle to take a sample of the amniotic fluid that surrounds the baby and tests it.

TREATMENT:

Currently, there is no cure for Tay-Sachs disease, and there is no treatment that stops or slows the progression of the disease. Treatment aims to relieve some of the symptoms, manage infections, prevent complications, and increase quality of life as much as possible. Treatment for symptoms may include anticonvulsants to control seizures in children, and antipsychotic medications for psychiatric disorders in adults. Of note, tricyclic antidepressants are thought to be ineffective, and they may actually inhibit the little enzyme activity that may be present in some people with the disease. Preventing complications involves getting adequate nutrition and hydration, preventing airway obstruction, and avoiding severe constipation with food additives, stool softeners, or laxatives.^4,5,7 Research into potential treatments for Tay-Sachs disease is ongoing.

Some of the specialists, treatments, and programs you might consider include:

· Speech-language pathologists. They can provide ways to help your baby keep the suck-swallow reflex going as well as help you figure out when it is time to consider a feeding tube for your little one.

· Neurologists. These specialists can help you manage your baby’s seizures with medication.

· Respiratory health. Specialists such as pediatricians and pulmonologists (doctors who treat lung and breathing problems) can recommend ways for parents to lower their child’s chance of lung infections.

· Chest physiotherapy (CPT). Therapy to tap on the chest wall can help break up mucus in the lungs so your child can cough it up.

· Feeding tubes. Your child may have trouble swallowing or may have breathing problems that include inhaling food or liquid into their lungs while eating. You can insert a feeding tube through your child’s nose into their stomach each time. Or a doctor may put in a tube during surgery.

· Play and stimulation. You can help your child interact with the world through music, scents, and textures.

· Massages. These can relax your baby.

· Palliative and hospice care. These programs help manage quality of life for children with Tay-Sachs and their families.

Prevention:

You can have a blood test that analyzes your genes or the levels of the Hex-A protein in your blood to tell you whether you are a Tay-Sachs carrier.

If two people planning to have children find out that they’re both carriers, a genetic counselor can help them review the options for lowering the chances of having a baby with Tay-Sachs.

OUTCOME:

As of 2010, even with the best care, children with infantile Tay–Sachs disease usually die by the age of 4. Children with the juvenile form are likely to die from the ages 5–15, while those with the adult form will probably not be affected^.8, ⁹

EPIDEMIOLOGY:

Aahkenazi jews have a high incidence of Tay–Sachs and other lipid storage diseases. In the United States, about 1 in 27 to 1 in 30 Ashkenazi Jews is a recessive carrier. The disease incidence is about 1 in every 3,500 newborn among Ashkenazi Jews.¹⁰ 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 being a carrier.¹¹ In the general population, the incidence of carriers as heterozygotes is about 1 in 300.⁹ The incidence is approximately 1 in 320,000 newborns in the general population in United States.^13.

Three general classes of theories have been proposed to explain the high frequency of Tay–Sachs carriers in the Ashkenazi Jewish population:

· Heterozygote advantage.¹⁴ When applied to a particular allele, this theory posits that mutation carriers have a selective advantage, perhaps in a particular environment.¹⁵

· Reproductive compensation. Parents who lose a child because of disease tend to "compensate" by having additional children following the loss. This phenomenon may maintain and possibly even increase the incidence of autosomal recessive disease.¹⁶

· Founder effect. This hypothesis states that the high incidence of the 1278insTATC chromosomes¹⁵ is the result of an elevated allele frequency¹⁵ that existed by chance in an early founder population.^15, ¹⁸

Tay–Sachs disease was one of the first genetic disorders for which epidemiology was studied using molecular data. Studies of Tay–Sachs mutations using new molecular techniques such as linkage disequilibrium and coalescence analysis have brought an emerging consensus among researchers supporting the founder effect theory.^15, ^17, ¹⁹

CONCLUSION:

Late-onset Tay-Sachs disease is an infrequent disorder and the diagnosis is often missed or delayed (by approximately 8 years). Early on, the majority of patients develop signs of either cerebellar or anterior motor neuron involvement. Affected individuals may also develop psychotic episodes. In most cases, the later- onset of expression results from the presence of at least one allele (usually the G269S mutation), associated with residual enzyme (beta-hexosaminidase A) activity. A positive family history is a valuable clue, enabling early diagnosis. Nonspecific cerebellar atrophy on brain imaging is another important finding. This entity should be considered among patients presenting with speech, gait, and balance problems, and those with psychiatric disorders even when focal neurologic deficits may be initially absent. Accurate diagnosis will permit appropriate genetic counseling regarding disease prognosis and reproductive risks.

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7. Kaback MM, Desnick RJ. Hexosaminidase A Deficiency. GeneReviews. August 11, 2011; https://www.ncbi.nlm.nih.gov/books/NBK1218/.

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10. Rozenberg R, Pereira Lda V (2001). "The frequency of Tay–Sachs disease causing mutations in the Brazilian Jewish population justifies a carrier screening program". Sao Paulo medical journal [Revista paulista de medicina]. 119 (4): 146–149. doi:10.1590/s1516-31802001000400007. PMID 11500789.

11. "1,000 New York Irish to get tested for Tay Sachs disease gene". Irish Central. Retrieved 13 February 2020.

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14. Jump up to:a b Chakravarti A, Chakraborty R (1978). "Elevated frequency of Tay–Sachs disease among Ashkenazic Jews unlikely by genetic drift alone". American Journal of Human Genetics. 30 (3): 256–261. PMC 1685578. PMID 677122.

15. Jump up to:a b c d Frisch A, Colombo R, Michaelovsky E, Karpati M, Goldman B, Peleg L (March 2004). "Origin and spread of the 1278insTATC mutation causing Tay–Sachs disease in Ashkenazi Jews: Genetic drift as a robust and parsimonious hypothesis". Human Genetics. 114 (4):366–376. doi:10.1007/s00439-003- 10728. PMID 14727180. S2CID 10768286.

16. Koeslag JH, Schach SR (1984). "Tay–Sachs disease and the role of reproductive compensation in the maintenance of ethnic variations in the incidence of autosomal recessive disease". Annals of Human Genetics. 48 (3): 275–281. doi:10.1111/j.1469- 1809.1984.tb01025.x. PMID 6465844. S2CID 23470984.

17. Jump up to:a b Risch N, Tang H, Katzenstein H, Ekstein J (2003). "Geographic Distribution of Disease Mutations in the Ashkenazi Jewish Population Supports Genetic Drift over Selection". American Journal of Human Genetics. 72 (4): 812–822. doi:10.1086/373882. PMC 1180346. PMID 12612865.

18. Slatkin M (2004). "A Population-Genetic Test of Founder Effects and Implications for Ashkenazi Jewish Diseases". American Journal of Human Genetics. 75 (2): 282–293. doi:10.1086/423146. PMC 1216062. PMID 15208782.

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Received on 17.05.2021 Modified on 14.07.2021

Int. J. Nur. Edu. and Research. 2021; 9(4):475-478.

DOI: 10.52711/2454-2660.2021.00110

Bhawana. B. Bhende