Tay - Sachs Disease: Clinical Summary - Term Paper Example

Tay - Sachs disease: Clinical Summary A number of diseases are inheritable in nature either due to inherent genetic defects or mutations in genes, which may exist or occur in either of the parents. Tay-Sachs is one such inheritable disorder which manifests as a nervous anomaly in which there is progressive destruction of neurons in the brain and spinal cord, invariably and ultimately resulting in death of the victim. It is inherited as an autosomal recessive trait (Hill & Schorr, 2001). The disease occurs in persons with a defective gene on chromosome 15, and has usually been more common in specific ethnic communities which include the east European Ashkenazi Jews, French Canadians and the Cajun community from Louisiana State in the United States (www.genome.gov). However the likelihood of its occurrence in other communities cannot be denied. This particular genetic defect results in non production of an essential enzyme, hexosaminidase-A (Hex-A), which is responsible for the metabolism of a fatty substance called GM2 ganglioside. GM2 ganglioside which belongs to the lipid family accumulates to an abnormal extent in the neurons resulting in their gradual and progressive destruction (www.genome.gov). A child inheriting the gene for this disorder, may or may not suffer from the disease and may just be a carrier, but once the genetic defect expresses in such a child, the chances of survival are virtually negligible as yet there is no cure for this disease. In its most common form, the disease expresses in infancy itself and the child who may appear normal until 3 to 6 months of age, starts deteriorating rapidly and does not survive for long (http://ghr.nlm.nih.gov). The symptoms in an affected child start appearing at around six months of age manifested usually as muscle weakness, movement disability and abnormal righting reflexes. The child starts missing the normal developmental milestones associated with this age (Merck.com). There is continuous deterioration of motor activities and cognitive ability. Initially there are exaggerated responses to sensory stimuli which slowly progresses to complete loss of visual and auditory sensory functions. An eye abnormality is a pathognomic lesion of this disease and is known as the ‘Cherry Red Macular Spot’ (http://ghr.nlm.nih.gov)). In the later stages complete loss of intellectual ability, seizures and paralysis occur, invariably resulting in death. In another rare form this genetic defect expresses in some persons as late as in the 20s and 30s age groups, manifested by an unsteady gait and progressive neurological deterioration (NINDS). Biochemical Basis of Disease Technically the disease condition is described as sphingolipidosis due to hexosaminidase deficiency that produces severe neurologic symptoms leading to early death (Merck.com). Sphingolipids are complex fatty molecules and one of their complex forms known as Gangliosides increases in Tay-Sachs disease. Gangliosides are acidic form of fatty material. They are usually synthesized and metabolized rapidly during the early stages of brain development (NINDS). The two major forms of Gangliosides are GM1 and GM2. In Tay-Sachs disease, the concentration of GM2 in particular increases manifold (Merck.com). Diagnosis Diagnosis of the disease is based on the basis of parental history and typical symptoms of the disease. A complete and confirmatory diagnosis can be established on the basis of an enzyme assay (Merck.com). The beta-hexosaminidase-A activity can be measured from a simple blood test from the victim’s or the carrier (either or both parents’) sample. Another modern technique for diagnosis is the PCR (Polymerase Chain Reaction) which is not used frequently although it is more accurate. PCR involves the isolation and amplification of DNA from the carrier or affected individual and then employing modern molecular biology techniques to identify mutations in the genes. The enzyme assay is however, relatively simpler and more cost effective way and therefore the standard method of diagnosis. In a comparative analysis it was discovered that the specificity and predictive value of the DNA-based test makes it more useful as an adjunct to the enzyme based diagnostic test (Raine-Triggs, et al, 1990). According to the authors, the DNA test allows precise definition of the carrier state for the known mutations. When both parents carry the defective gene, there are 25% chances of each baby being born with the Tay-Sachs disorder. Therefore, pre marriage screening for the defective gene can be used to advise such individuals against marriage. Advances in prenatal testing can predict whether the gene is present in the embryo or not making room for abortion as a suggested means of avoiding the disease, but there are ethical issues involved. Treatment is futile and as a consolation only symptomatic treatment can be administered in the form of anticonvulsant drugs to control the seizures, supported by proper nutrition and hydration measures. Fluorescence-based assays for β-hexosaminidase activity can be used to determine the carrier frequencies for Tay - Sachs disease in susceptible individuals (Martin et al, 2007). The only way to avoid the disease is by avoiding pregnancy in parents with defective genes or pre-natal screening during pregnancy to evaluate the inheritance in the embryonic stage of life itself. Molecular Mechanisms The increase in the concentration of GM2 gangliosides, the acidic fatty material which is specifically rich in content in the neuronal cell membranes leads to neuronal cell death as the deficiency of Hexosaminidase-A enzyme fails to check its production (Merck.com). Hexosaminidase enzyme is made up of two subunits, α and β, encoded by the HEXA and the HEXB gene respectively (themedicalbiochemistrypage.org). Tay-Sachs disease is caused by mutation in the alpha subunit of the hexosaminidase-A gene (HEXA). The various combinations of α and β subunits are responsible for the various isoforms of β- Hexosaminidase. The cleavage of the GM2 gangliosides is catalyzed only by the HEXA form of β- Hexosaminidase (themedicalbiochemistrypage.org). The process is initiated by the GM2 activator protein which then allows for the action of hexosaminidase in digesting the GM2 ganglioside, as shown in the figure below. In the absence of these enzymes, the degradation of sphingolipids doe not take place and the cellular lysosomes become engorged ultimately choking all cellular functions within the neurons. The HEXA gene is present on chromosome 15q23–q24 spanning 35 kb and composed of 14 exons (themedicalbiochemistrypage.org). The number of mutations occurring in the HEXA gene responsible for Tay-Sachs disease is 92. 65 mutations result in single nucleotide changes while the rest include deletions or insertions only. Mutations in the HEXA gene result in defective synthesis of the α-subunit of β-hexosaminidases and subsequent defective formation of the HEXA and HEXS forms of the enzyme (themedicalbiochemistrypage.org). Figure: HEXA and GM2 Activator Action on GM2 Gangliosides (Picture courtesy: the medicalbiochemistrypage.org) In susceptible individuals, the HEXA is absent in many tissues including leukocytes and plasma (www.humpath.com). This results in the accumulation of GM2 ganglioside in such tissues including heart, liver and spleen, but the maximum impact is in the neurons in the central and autonomic nervous systems. Microscopic examination reveals ballooning of neurons with cytoplasmic vacuoles which harbor distended lysosome filled with gangliosides. When stained with oil red O and Sudan black B the cells stain positive for fat (www.humpath.com). Electron microscopy reveals cytoplasmic inclusion bodies with whorled configurations within lysosomes (www.humpath.com). Within the brain substance, there is characteristic destruction of neurons, proliferation of microglia, and accumulation of complex lipids in phagocytes (www.humpath.com). Such changes are observed in the cerebellum, basal ganglia, medulla oblongata, spinal cord, and dorsal root ganglia and in the neurons of the autonomic nervous system. Implications Couples carrying the mutated gene need to explore the options available to them for raising a healthy family. As there is no cure for the disease, it is wiser to consult a genetic counselor before going in for pregnancy. Prenatal diagnosis early in pregnancy can reveal the presence of Tay-Sachs and a therapeutic abortion is the only remedy. Works Cited Genetic Conditions - Tay-Sachs disease, online article available at: http://ghr.nlm.nih.gov/condition=taysachsdisease, Assessed April 13, 2009 Hill L.W. & Schorr S.J. 2001. Prenatal Screening for Tay - Sachs disease by Louisiana Obstetricians: A Survey Study, Southern Medical Journal, Vol.94, No.9. Introduction to Tay - Sachs disease, online article available at: http://themedicalbiochemistrypage.org/taysachsdisease.html, Assessed April 14, 2009. Learning About Tay - Sachs disease, Online article available at: http://www.genome.gov/10001220, Assessed April 14, 2009. Martin D.C., Mark B.L., Triggs-Raine B.L. & Natowicz M.R. 2007. Evaluation of the Risk for Tay-Sachs Disease in Individuals of French Canadian Ancestry Living in New England, Clinical Chemistry 53:3, 392–398. NINDS Tay-Sachs Disease Information Page, Available online at: http://www.ninds.nih.gov/disorders/taysachs/taysachs.htm, Assessed April 10, 2009 Tay - Sachs disease and Sandhoffs Disease, Online topic available at: http://www.merck.com/mmpe/sec19/ch296/ch296f.html, Assessed April 14, 2009. Tay-Sachs disease, Informative article available online at: http://www.humpath.com/Tay-Sachs-disease, Assessed, April 14, 2009. Triggs-Raine B.L. , Feigenbaum A.S. , Natowicz M. , Skomorowski M.A. , Schuster S.M. ,Clarke J.T. , MahuranD.J., Kolodny E.H. & Gravel R.A. 1990. Screening for carriers of Tay-Sachs disease among Ashkenazi Jews. A comparison of DNA-based and enzyme-based tests, NEJM, Vol. 323:6-12, No. 1 Read More