Huntington’s Disease

Though I fear all diseases, the ones I fear most are genetic diseases, diseases due to a defective gene (or genes) in a person’s genome. Reading James Watson’s book—DNA: The Secret of Life—over four years ago, I was enthralled with a disease I had never heard of before, that scared me out of my wits: Huntington’s disease. Watson opens chapter 11 with a middle-age woman, Leonore Wexler, who outside a courthouse in the early morning, appeared to be drunk—clumsily moving through a street as if she was intoxicated, eventually causing a cop to scold her for making a scene. Of course, she was not intoxicated at all, she was succumbing to one of the most horrible diseases on the planet—a neurological disorder which leads to progressive deterioration in brain function. Eventually, those affected lose all knowledge of themselves and others, lose control of their motor movement, and death always awaits.

The problem is due to a person’s genetic make-up. Huntington’s disease (HD) is an autosomal dominant illness, meaning that only one copy of the abnormal gene is enough to cause it and an affected parent has a 50% chance of passing it to their child. A faulty gene (due to an original mutation) on the short arm of chromosome 4 is the cause of HD. The gene codes for the production of the huntingtin protein, HTT. HD is a tri-nucleotide repeat disorder, cytosine-adenine-guanine (CAG) repeats more than the normal range. According to the genetic code, CAG codes for the amino acid glutamine. Usually, a person who has fewer than 36 CAG repeats produces the normal huntingtin protein, while a person with over 36 CAG repeats produces mutant HTT. This mutant HTT, through a mechanism not clearly understood, increases the decay of medium spiny neurons, the latter representing approximately 90% of the neurons within the striatum of the basal ganglia (other areas like the substantia nigra and layers 3, 5, and 6 of the cerebral cortex are affected as well). This, as you know, plays a crucial role in the movement of body, limbs and even eyes. The repeat of CAG is directly proportional to the age of onset and rate of progression. A person with a high number of repeats will experience HD sooner and go through progression to the terminal phase more rapidly than a person with say, 39 CAG repeats.

In 1968, Alice and Nancy—Leonore Wexler’s daughters— were informed by their father, Milton Wexler about their mother’s illness and that they, too, had a 50-50 chance of succumbing to the ravaging disease. Milton set up the Hereditary Disease Foundation (HDF) to raise money and press the government for funding HD research. In the 1970’s Nancy Wexler molded herself as a geneticist and, like Optimus Prime taking on the decepticons, she took it upon herself to take on Huntington’s. In Watson’s book, he points out that Lake Maracaibo, Venezuela is a hotspot for HD, as there is a high incidence of the illness there, and the population is isolated. Back then, HD was not known beyond its symptoms, the hunt for the gene responsible for the disease was on. Nancy became one with the people of Lake Maracaibo since 1979. If you want, you can read about her team’s progress and triumph with the use of RFLP linkage; with the help of 150 scientists around the world, the gene was isolated in 1993. The technological advancement required to home in on the faulty gene was very important, it set up the stage for the human genome project.

Though we know the gene responsible for the disease, we are still a long way from a cure. Treatment is not available; we only have medicine which “alleviates” some of the symptoms. The illness is found in 1 of 20,000 persons of European descent, and in America, it is estimated that 1 in 10,000 people have HD. The symptoms typically begin when a person is between 30–50 years of age and progresses over a 10–25 year period. This is a scary aspect; one can lead a normal life and have children, only to find you are doomed to die relatively young and that you have likely condemned your children to the same fate. The earliest symptoms of HD are uncontrollable muscle movements, clumsiness, mood changes, and memory lapses. Later, difficulty in walking, talking, and of course, death. HD does not cause death directly but rather leaves the body compromised with complications and susceptible to things such as pneumonia and heart attack. High suicide rate is also not uncommon for this disease. The only answer I can think of to cure this disease is nanotechnology- nanobots checking DNA strands in cells, base by base, and cleaving the extra CAG repetitions in an HD patient’s chromosome 4. Unfortunately, that is well into the future. I have read that gene silencing may be more practical right now, silencing the mutant HTT, thus, thwarting the protein from gluing molecules in the brain and killing the medium spiny neurons. Finally, Stem cell therapy may also be a revolutionary way to counteract the illness by transplanting stem cells into affected regions of the brain, replenishing the lost neurons. Sadly, none of these options are easy things to do yet.

Tags: Diseases