Huntington's Disease

 

 

From: Oxsan
Date: 26 Apr 2001
Time: 09:58:06

I feel that I should tell you that I have been reading a book called Genome by Matt Ridley and that I, a graduate zoologist, realize only now that my profession has long ago left me behind and that what I took as cellular biology at the University of Texas was as kindergarten is to Oxford. The modern cellular biologist knows more about what is going on in that cell than I ever dreamed of. So what I have to say below comes mostly from reading Ridley's book (and a TV show I once saw on Huntington's disease) and I probably got some of it wrong---and even if I didn't his book was published in 1999 and is probably now totally obsolete. Anyway----

Huntington's disease (HD) is an always fatal, totally untreatable inherited disease caused by a defect on the short arm of one of the chromosomes in pair 4. In the final one million "genetish" words (genetish words are always three character groups composed of the four characters C, G, A, T) on this chromosome in the people who have the disease there is a repetition of the "word" CAG an unusual number of times. This series may be 200 repetitions or two thousand or even more. The greater the number of repetitions the earlier in life the person will experience the active disease symptoms and the more rapid will be the progress of the disease.

The disease when it does appear starts with a slight decline in intellectual ability (uh-oh), followed by arm and leg jerking, deep depression, hallucinations and death. There is no treatment. The disease is incurable .

Folk singer Woody Guthrie died of this disease in 1967 and his widow endowed a fund to attempt to locate the gene responsible for the disease. Medical researchers knew then that the disease was inherited, that the gene which carried it was dominant but they did not know which chromosome carried the gene or the nature of the genetic defect.

The "genetish" word CAG is (as all genetish words are) a recipe for an amino acid. RNA ,present in every cell , operating with the word CAG produces the amino acid glutamine. It is believed today that the presence of excess glutamine in brain cells and the formation of a protein called "huntingtin" from the glutamines in the brain cells causes the symptoms of the disease and finally death.

Monk Mendel taught us long ago that since the trait is dominant if a man carrying the defective gene for HD mates with a woman who has no history of HD then the probability of the offspring ever developing HD is exactly 2 out of 4 or 50%.

Working through Woody Guthrie's fund a woman named Nancy Wexler (whose mother had active HD) administered a study in Venezuela in three villages near Lake Maracaibo where there is a large isolated pocket of people with HD caused by the union of a deserting sailor and a woman appropriately named Maria Concepcion in the late 18th Century. There were nine thousand descendants alive and identifiable in 1981 and of those 371 had the disease actively and 3600 were of an age that they could still develop the disease. Wexler conceived the idea of taking blood samples from these 371 and 3600 Venezuelans and sending it back to a man named Jim Gusella in Boston who would devote his life to looking for the anomaly that caused HD. In 1993 after twelve years of searching Gusella found the strange accumulation of CAG words on the short arm of the 4th chromosome. We now knew what caused Huntington's Disease. We could look at a tissue sample of anyone and tell them if they had incipient HD. But if they did there is absolutely nothing we could do to prevent or retard the onset of the disease. What could we ever do to keep those millions of brain cells from producing glutamines and prevent the RNA from stitching it into cell-indigestible protein like Huntington? All we could tell anyone is that in their brain was a time bomb which one day would go boom.

But when the blood was being collected on the shores of Lake Maracaibo we did not know any of that although Wexler admits that there were some signs and symptoms that a trained researcher with a lot of experience could see if the disease was near onset before the patient was even aware of them. And when she was collecting the blood she was invariably asked by each volunteer donor "Can you tell me please, do I have the disease?". Wexler said that the invariable answer was always "I must know you much better before I could possibly answer such a question."

Would you say that Wexler was right in not telling the patient that HD was approaching? Is it right now with what we know to tell teenagers or persons considering marriage that in twenty or thirty years they will develop HD? What do you think?

Love

dad,granpa,ami