Tay-Sachs Disease: A Short Causative Review

Introduction:
Tay-Sachs Disease is a genetic disorder that is inherited. It affects the central nervous system and may ultimately prove fatal within a short period from onset. There is no known cure for the disease. The more severe form of the disease becomes manifest in very young babies. The disease is initiated by mutative forms of the HEXA gene (HEXA, U.S. National Library of Medicine, 2006) that is normally autosomally recessive in the parents but is subsequently dominantly expressed in the baby. These genetic implications will be expanded on subsequently.

At first, the affected baby appears healthy enough and develops normally for the first few months of its life. Then, development slows and the symptoms of the disease begin to show.

Symptoms: In affected babies, as the nerves distend with fatty substances, mental and physical abilities, even in their rudimentary states in such early childhood babies, deteriorate (Tay-Sachs disease, NINDS, 2007). The baby loses sight, hearing and is unable to swallow and its muscles gradually atrophy till paralysis sets in ((Tay-Sachs disease, NINDS, 2007). Neurological symptoms include dementia, seizures and a propensity to get startled at noise (Tay-Sachs disease, NINDS, 2007).
When the disease becomes manifest in older persons, as it may do when the genetic implications are partial and the disease is pathologically less severe, there is gradual neural degradation with unsteady characteristic movement patterns (Tay-Sachs disease, NINDS, 2007). Persons with Tay-Sachs also have 'cherry-red' spots on their eyes (Tay-Sachs disease, NINDS, 2007).

Pathological Characteristics:
Affected babies lack an essential enzyme -hexosaminidase A (hex A) that is required to break down fatty substances in the brain and nerve cells. The lack of this essential enzyme allows fatty substances to accumulate on the brain and nerve cells until, ultimately, they stop working properly and the entire central nervous system is severely implicated functionally. The baby dies, usually by the age of five (March of Dimes, 2006).

The disease is named after Warren Tay, British ophthalmologist, and Bernhard Sachs, American neurologist, who diagnosed symptomatic patterns of the disease in the late 19th century (Tay-Sachs disease, Wikipedia, 2007).

Tay-Sachs: A Genetic Disorder
There are some genetic disorders like Tay-Sachs disease and sickle-cell anemia that are most likely to occur among common descendents of ancestors who have originated from a particular geographical region as well as current residents there. Tay-Sachs disease is most likely to become manifest in descendents of Ashkenazi Jews, who originate from the Eastern and Central European regions. It is also found prevalent among French Canadian descendents as well as the Cajuns of the East Coast of the USA, both groups having a fairly common ancestry. It is important to note, though, that such an ethnically prone genetic disorder is also likely to occur among people who may belong to any ethnic group other the disorder prone group (Why are some genetic conditions common in some ethnic groups, U.S. National Library of Medicine, 2006).

Genetic Implications
Tay-Sachs disease is initiated when a certain gene on chromosome 15, on the long arm 'q' of the chromosome between the 23 and 24 positions, is in mutative form. There may be up to 100 possible mutations for the gene and any one of these mutative forms will be responsible for the disorder. The official name of the gene is hexosaminidase A (alpha polypeptide). The official symbol is 'HEXA' (HEXA, U.S. National Library of Medicine, 2006). The HEXA gene carries instructions for making one part, the alpha ( ) subunit, of the enzyme -hexosaminidase A. Another gene, a counterpart of the HEXA gene but not associated with Tay-Sachs disease, called HEXB gene, makes the other subunit, the beta ( ) part, that unites with the alpha part to form the normally functioning -hexosaminidase A enzyme. -hexosaminidase A is found in lysosomes, also called suicide bodies, which are found inside body cells. These special cell organelles break down toxic substances, including fatty substances in nerve cells of the central nervous system that may be considered detrimental when they tend to accumulate beyond normal levels, inside cells and act as the cell's recycling centers breaking down potential toxins into lesser harmful substances (HEXA, U.S. National Library of Medicine, 2006).

The lysosomes use the beta-hexosaminidase A enzyme as part of a complex of substances to break down the fatty substance GM2 ganglioside (other fatty substances may also be implicated) that tends to accumulate in parts of the central nervous system like the brain, spinal cord and other associated nerve cells. When there is a mutated form of the gene HEXA the enzyme beta-hexosaminidase A is either totally non-functional or with reduced functional capabilities implying total or partial elimination of GM2 on the neural pathways. Severe psychophysical dysfunctions become pathologically evident. More than 90 mutations of the gene are responsible for the non-functional enzyme signifying the most severe form of the disorder that begins at infancy, as stated earlier, and progresses to fatality within a very short period of time, usually within four or five years of birth. The other mutative forms are responsible for the reduced functionality of the enzyme when activity is possible at a lower efficiency level (HEXA, U.S. National Library of Medicine, 2006). These last mutative forms are responsible for the less severe form of the disorder that appears later on in life - childhood, adolescence or even adulthood. Symptoms, as stated earlier, are also less severe than in the absolutely fatal infantile form (Tay-Sachs, U.S. National Library of Medicine, 2006).

Evolutionary Probabilities:
It is probable that initial mutations of the HEXA gene, during the temporal course of human history, became evident in small pockets of the global population. Since the mutated gene lies dormant as an autosomally recessive trait - only one of the pair of autosomal chromosome is affected - very few individuals with the trait became initiators of the disease. This is so because marriage of one individual with the recessive trait (the potential disease carrier) and the other without it (the non-carrier) ensures that the baby does not ever receive two copies of the recessive pattern (to become dominantly affected) as one parent is not a carrier. It may be, thus, that such babies become carriers when one copy of the mutated gene is passed down from the carrier parent while the other chromosome has the unaffected HEXA gene. This is possible in communities still residing in or immigrant from the relevant geographical regions where such mutations were historically initiated by some yet undiscovered factor/factors with extended relationships. When individuals from such communities come together in marriage with others from other communities that are not Tay-Sachs prone the probability is very low that two individuals with the same Tay-Sachs recessive trait become aligned through marital ties to produce a Tay-Sachs baby with both chromosomes affected by the mutated form of the HEXA gene. There is a tendency in such communities where there is a Tay-Sachs proneness but there is also healthy intercommunal marriage habits for mutated forms of the HEXA gene to disperse harmlessly among individuals till the threat of production of Tay-Sachs babies is much reduced.

Conversely, in close communities like the Ashkenazi Jews of Eastern and Central Europe and possibly the French Canadians and Cajuns of North America, marriage is often between closely related individuals (with intracommunal connotations) with high probability of both being carriers of the mutated gene. Such marriages are highly prone to production of Tay-Sachs babies. These close communities with possible intracommunal marital habits residing in or immigrant from pathologically sensitive geographical regions provide concentrated populations of carriers where high probabilities of the disease manifestation exist.

One way to preempt birth of Tay-Sachs babies is to conduct genetic tests (genetic screening) on marriageable individuals in such disease-prone communities and warn against nuptial ties between two carriers. This may not only dilute concentrated carrier populations but also, maybe in the near future, allow the mutated gene to recede into oblivion as multiple fractionation of carrier populations (dispersal) ultimately preempts all possibilities of Tay-Sachs births. Thus, optimal dispersal among the world population can be achieved only when there is no probability existing of two carriers in any community anywhere globally coming together in marriage.

Conclusion
Tay-Sachs disease is an autosomally recessive genetic disorder. Autosomal chromosomes are those associated with body cells only. Each parent of a Tay-Sachs baby will have only one copy of the recessive pattern on one of the allotted pair of autosomal chromosomes and will not be affected by the disorder but, when the baby is born, it will have two copies, one copy from each parent, and these two copies, evident on both of the allotted pair of the baby's autosomal chromosomes, will pathologically imply that the potential recessive trait is converted into a pathologically active dominant trait that may affect the baby very early in life. The parents are not affected because each of them have only one copy of the mutated form on one chromosome while the other chromosome that belongs to the chromosome pair, chromosomes occur in pairs, has a normal HEXA gene that allows synthesis of normally functioning beta-hexosaminidase A enzyme. Thus, the parents, possessing the recessive trait, have relatively normal secretion of beta-hexosaminidase A while the baby, possessing the dominant trait with both autosomal chromosomes implied, will have no secretion of the enzyme. It is assumed here that a Tay-Sachs baby implies inheritance of the more severe form of the genetic mutations. Babies that inherit the less severe form may develop Tay-Sachs later on in life and are here not termed as 'Tay Sachs' babies.

It is sad to say that, to date, there is no cure for this deadly disease that proves fatal to babies as young as five years.

Link to be added:
Tay-Sachs disease, National Institute of Neurological Disorders and Strokes, 2007. Extracted on 20th November, 2007, from: http://www.ninds.nih.gov/disorders/taysachs/taysachs.htm