Tay-Sachs Disease: Causes and Treatments
1. Introduction
Phonetic disorders, including apraxia (the inability to coordinate the movements of lips, tongue, and other parts of the speech mechanism), roughness, grunting, or other breath difficulties, and/or loss of prior speech and language skills (usually within the first 1-3 years), are also common features of late-infantile TSD. After having a physically, intellectually, and emotionally challenged child for 3 years, affected families are familiar with the fact that sensory and cognitive milestones are being missed. The humane act of parenting this special child to his or her full ability becomes laborious and unfulfilling as lost functions are painfully observed rather than celebrated. For all patients with catastrophic diseases, management aims to give the patient an optimized life, avoiding difficult procedures or treatments, and thus prolonging the quality of the patient’s life.
Tay-Sachs disease (TSD), also known as GM2 gangliosidosis, type 1, is a lysosomal storage disorder caused by a complete deficiency of hexosaminidase A. It affects both the brain and the spinal cord. The disease is named after Warren Tay, a British ophthalmologist, who first described the disease in 1881, and Bernard Sachs of the United States, who described the cellular changes in the brain as well as the genetic nature of TSD. TSD occurs because of the inability of an enzyme called hexosaminidase A to fully function because it is missing. The enzyme delivers the necessary instructions for the natural biological breakdown of fatty substances called gangliosides in the body. In the case of Tay-Sachs, the accumulated gangliosides inside the brain’s nerve cells lead to their destruction. Children typically present normally at birth, then fail to develop regular growth and begin to regress. Within two to five months, the infant can present with initial symptoms. TSD has an autosomal recessive inheritance pattern.
2. Causes of Tay-Sachs Disease
Tay-Sachs disease is caused by mutations in the HEXA gene. The HEXA gene occurs as a dimer (dry soap) in a variety of combinations: two α chains, two β chains, and α or α and β chains. A mutation may occur in the HEXA α subunit or within two α subunits or within the β subunit of the enzyme. The most common HEXA mutation, present in over 80% of patients as a single allele, is c.1278insTATC in exon 11. All HEXA mutations lead to an accumulation of GM2 ganglioside, mainly in neurons. The degree of enzyme impairment is the highest when the first nucleotide of codon 178 of the HEXA gene is affected. The second highest degree is encountered when the 5′ splice junction sequence IVS9-6 is affected. The least detrimental mutations do not produce any residual enzyme amylolysis at all. The degree of the enzyme impairment is an important determinant of the severity of the disease, with the highest degree causing the infantile form.
Tay-Sachs disease is a fatal genetic disorder in children that causes progressive destruction of the nervous system. Its symptoms include a cherry-red spot visible in the back of the eye, muscle weakness, loss of motor skills, and seizures. The condition is caused by mutations in the HEXA gene and it is inherited in an autosomal recessive pattern. Because carriers of the defective gene may not know they are carriers and since the disease has devastating consequences for children, some Ashkenazi Jewish organizations, including Dor Yeshorim and JScreen, now provide screening programs to prevent matches between carriers.
3. Symptoms and Diagnosis
While the vision can remain intact, children begin to show a persistent lack of visual attention by 6-8 months. Along with hypotonia and social interaction, this often precipitates a visit to an ophthalmologist, movement specialist, or pediatric specialist. The evaluation of a deteriorating child should include a complete metabolic screen that can be obtained on a dried blood sample. A neurometabolic disease such as Tay-Sachs disease is a possible diagnosis. Affected children usually have a cherry-red macula and a dull retina, in addition to their optic atrophy and macular pallor. The eye exam is not appreciated when the macular cherry-red spot is missed on a slit-lamp examination. The goal of the complete metabolic screen is to find updated methods that can facilitate more rapid and directed evaluation of the possible causes of the specific onset or worsening of the infant’s condition. The evaluation for possible disorders can help prevent months of evaluation for non-specific illnesses, such as nonspecific seizures or irritability. Family and social stress can be reduced.
Infants who develop Tay-Sachs on average have symptoms by the age of 3 to 6 months. Symptoms commonly include a gradual, but relentless, loss of vision and an increase in irritability and startle reactions. Most affected infants sit up by 8 months but lie flat by 10 months. Parents often describe their infant as not managing to achieve a fully normal social smile by 6-8 months, adding to the parents’ concerns. Children with Tay-Sachs usually have chronic tonic episodes but they remain hypotonic even as they become increasingly weak. The child eventually becomes completely flaccid. Seizure activity is common and may be difficult to control. Eventually, the child is incapacitated and dies, usually before 5 years of life. Children may die by 2 years, and some children live as long as 5 years. Adolescents and adults do not develop Tay-Sachs disease.
4. Treatment Options
The more detailed the TSD symptoms are, the earlier the treatment with synthetic compounds has to begin – ideally as soon as the baby is born. Otherwise, the brain might already have been damaged too severely – even if the active substance crosses the blood-brain barrier to reach the nerve cells. This is one reason why a successful treatment is more likely with gall die, who develop rapidly in the first one and a half years of their life. That is when the largest amounts of the TSD-causing genes are being translated into the Hex A proteins. Meanwhile, however, tests of the previously described drugs for TSD treatment have shown that they turned out toxic for nerves. Therefore, a large part of the German research and development of such drugs is focusing on one specific non-toxic compound that can inhibit the formation of the TSD gene products as well as the enzyme Hex A.
While drugs have already been tested and approved for other diseases, they usually have to be further developed in order to be used in treating Tay-Sachs disease. An ideal treatment would be a drug that curbs the activity of the TSD-causing genes: the alpha and beta subunits of the lysosomal enzyme HexA. In earlier tests, such drugs reduced the synthesis of hexosaminidase A in the liver, heart, and brain of mice by more than 90 percent. Mice that were given the drugs in the formative stage exhibited an 80 percent drop in the fat storage levels in their brains typical of Tay-Sachs disease, while 17-month-old mice showed a 50 percent reduction. Such drugs could be administered as tablets, intravenously, or into the cerebrospinal fluid.
5. Conclusion
Carriers will find it relevant to their life planning decisions to have their Tay-Sachs predisposition identified. study concluded that, despite the possibility of negative outcomes, those whose genetic predisposition is known in advance are less distressed by both decision making and their decisions than carriers who remain ignorant about their risk probabilities. Finally, challenges of adults and children stricken by Tay-Sachs, as well as the ongoing needs of their families, must be addressed by development of multidisciplinary services which respect the unique mixture of medical, psychosocial, and spiritual needs of those in distress. Only then can the interdisciplinary model of intervention effectively eliminate the negative assumptions about genetic disorders and people facing them.
The cornerstone for treatment of disorders such as Tay-Sachs disease includes the interdisciplinary model, with genetic counseling being a primary treatment tool. Fears and misconceptions are less likely to perpetuate when family members gain clear understanding of the genetic disorder predisposition of their children. They will also become part of the scientists’ efforts to identify environmental factors which may trigger a predisposition to, or actually cause, the disorder. Additionally, they will help decide on reasonable preventative measures, as well as actively participate in the development of new intervention strategies. For families of children already stricken by Tay-Sachs disease, genetic counseling provides information about the chance of the infant’s siblings inheriting the disease, as well as about the availability of prenatal and pre-marital testing which may be brought about by the discovery of genetic predisposition.
