Many genetic diseases first strike late in life, when an individual is past reproductive prime. This means that these late-onset diseases have little to no effect on evolutionary fitness, and therefore are experiencing no biological selection methods. Because of this, diseases such as Alzheimer's and Huntingdon's Disease, which are more of a threat than ever now due to increased human life spans, will not simply go away unless vast improvements are made in treatment of these illneses. Fortunately, the genetic information necessary for investigating new treatments is now being uncovered.

Alzheimer's disease results when the Beta-Amyloid precursor protein undergoes endoprotealysis to produce incomplete truncated forms. These truncated forms strongly self-associate into fibers and eventually form amyloid plaques, which are thought to be one of the earliest significan steops in the disease's progression. The mutations necessary for endoprotealysis can be of two types which produce two forms of the disease. The mutations may be a sngle locus autosomal dominant, leading to the early onset (less than sixty years of age) form of the disease, or they may involve the ApoE allele, which results in the late onset form.

The interesting characterisitcs of the mutations are that the early onset form is strongly seen in families. However, the ApoE instance does not segregate in families but is based on heterozygosity and modifiers. If an individual possesses two versions of ApoE4, a specific genotype, then that person is at high risk to develop Alzheimer's at a young age. If a person is heterozygous with one E4 allele and one E3, or, better still, E1 (which appears to protect against the E4 allele), the disease will see in later if at all. Two E2s, E3s, or one of each produces a relatively low risk of a very late onset. This situation, with E2 protecting against E4, is an example of the modifier effect. Thinally then, other genes and gene products, such as presenilin, can affect the path of the illness.

In the above example then, the genetic information determines not only the likelihood of a disease to occur but also the timing of the disease in terms of onset and severity. This couold be medicinally important for properly attempting treatment, and, as it turns out, Alzheimer's is not unusual in this respect. Huntingdon's disease, for example, is also genetic, and from the genetic information a definite diagnosis can be made, as well as an approximate age of onset. However, the specific type of mutation in Huntingdon's disease, triplet repeats, also contains information as to the fate of the offspring in terms of the severity of the disease and the age of onset.

Triplet repeat diseases are those caused by high numbers of polymorphic triplets in a gene. This means that a normal individual may have twenty repeated CAG triplets, a person at risk's parent may have sixty and a person with the disease may have a hundred or a thousand more. In Huntingdon's people with more than thirty-five repeats are affectded, while in Fragile X Syndrome people with between sixty and two hundred have offspring at risk and individuals with over two-hundred and thirty are affected. Aside from showing this pattern, triplet repeats generally involve GC rich triplets such as CAG and CGC, which has lead to theories regarding alternative DNA structures and CpG methylation as risk or timing factors. Also, triplet repeat mutations are generally dominant, found in exons, and demonstrate anticipation. However, there are exceptions to all of these generalizations.

Anticipation is a genetic phenomenon that results in an increase in the severity of a disease with an earlier age of onset in successive generations. In anticipation, having a number of triplet repeats larger than the norm but not enough to cause the disease (called a premutation) increases the odds of a triplet expansion. A triplet expansion is the addition of more triplet repeats, possible through a tetraplex intermediate. With this larger number of triplet repeasts it is more likely for a tetraplex to form, which produces even more repeats. This is due to somatic instability. This is an instance where normal numbers of repeats are stable, premutation amounts are unstable in pedigree (some sexes/individuals show and some do not), and full mutation numbers are unstable in all individuals. Eventually through this process a full mutation results, and approximately at which time the odds of expansion approach one, meaning each succeeding generation will have more repeats than the previous. This then leasds to an earlier age of onset and increased severity of the disease.

However, not every individual in the succeeding generation will suffer a larger number of repeats. A large effect on triplet expansion appears to be made through genetic imprinting. In imprinting, the sex of the parent who passed a specific gene has a strong influence on the mechanisms of that gene. With triplet repeats, it appears that a CAG triplet will be expanded if passed down from the father while a CGG will be expanded if passed down from the mother. Fragile X Syndrome shows this feature. If the affected X chromosome is inherited maternally, both sons and daughters are likely to suffer an expansion. However, any expansions in the offspring they have depends on their sex. The affected son will have offspring without any further lengthening of the triplet repeats. The affected daughter, unfortunately, will have childeren with more repeats and thus again an earlier age of onset and increased severity of the disease.

With this new information, then, new routes of treatment become possible. Perhaps preventing the tetraplex intermediate could serve as preventative medicine, or perhaps DNA binding medicines could hamper methylation and inactivation of genes. Or perhaps entirely new ideas will develop as still more is learned. Regardless, a whole genome of new medical opportunities exists.

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