Huntingtons disease genetics

Today’s New York Times (Sunday, March 18, 2007) has a fascinating front-page article by Amy Harmon, titled: “Facing Life With a Lethal Gene“. It describes the dilemma of a young woman whose family history is positive for Huntington disease—a devastating genetic disorder that affects the patient’s ability to walk, talk, swallow, and eventually causes loss of cognitive faculties. The nature of her dilemma: Should she undergo genetic testing to find out if she carries this awful gene?


The genetic basis of Huntington’s disease

The gene involved in Huntington Disease is called the HD gene. The wild-type (normal) gene includes a stretch of the trinucleotide CAG (cytosine, adenine, guanine) repeats of between 6 and 36. If the number of repeats exceeds 40, Huntington disease ensues. CAG is the genetic code for the amino acid glutamine, and this kind of CAG repeat of glutamine (whose letter symbol is Q) actually occurs in several other genes, and the proteins they code for. The interesting thing is that increase in Q repeats occurs in many of the genes that contain the poly CAG sequence, causing diseases that are grouped together as polyQ diseases.

When the increased number of CAG occurs in the mother, the number of repeats tends to stay the same in the offspring. But if the disease is inherited from the paternal line, the number tends to increase with every successive generation. This is called Q expansion, and the larger the number of repeats, the earlier the disease shows up, and the more severe it is. Thus, in general, the disease manifests itself in the 30’s to 40’s, but with a large number of repeats, it can declare itself in the 20’s or even in early childhood.

To add insult to injury, the mutation is autosomal dominant, meaning that both males and females are affected equally—and that all that is needed to exhibit the disease is inheritance of only one gene, either from the father or the mother. Thus, if either parent has the disease, the chances are 50% that any one of the offspring will inherit it. If the first generation of offspring escapes the disease, the following generation has a 25% chance of inheritance, and so on.


How could evolution “tolerate” this mutation?

The disease was described only at the end of the 19th century by a physician in Ohio called George Huntington, who wrote the paper when he was one year out of medical school (!). As I mentioned before, the disease strikes mostly in the 30’s and 40’s. By then, most people already have their first or second child—completely unaware of the deadly gene they are carrying. Furthermore, for unknown reasons, some of the patients actually don’t show the full spectrum of physical manifestations, but do manifest the psychological ones: loss of facial recognition, aggressive behavior, loss of executive functions (cognitive flexibility, abstract thinking, initiation of appropriate actions and inhibition of inappropriate ones, planning). Many other psychiatric diseases manifest a similar behavioral pattern, making the specific diagnosis of Huntington’s disease very difficult in these people.


Fortunately, there is a genetic test

And it isn’t very expensive—a few hundred dollars.

Fortunately, you might ask? What about all the psychological and ethical issues such a diagnosis raises? Let’s consider a few of them.

  • You get a positive test—what now? Do you just curl up and wait for the first symptoms to strike? Do you get married? Tell your spouse? Have children? Almost invariably people, who receive the diagnosis, go through the stages of denial, rage, and depression. Some “graduate” to acceptance and go about living their lives; others are just stuck in the rage and depression stage.
  • Many people don’t want to know for either fatalistic reasons (“if I have it, I’ll know soon enough” or “if this is the will of God, so be it”) or for more practical reasons, like insurability. Our healthcare system (if you can call it that) is designed to care for the well and worried well. But if you are really sick, or you carry the genes for a heritable disease, you and your family are a poor risk, and every insurance company will try to unearth some kind of clause to drop you at the first opportunity.


The bottom line

What about your family members who are undiagnosed? By receiving your own diagnosis, you are basically telling your parents that one of them is going to get the disease, and your siblings have a 50% chance of getting it as well. Such situations cause much strife, with families falling apart under this incredibly emotional and practical stress.


What to do?

Plato, quoting Socrates, famously said that “the unexamined life is not worth living”. In those days, the meaning was philosophical: Life without introspection, without honest examination of one’s values, without asking the “what” and the “why” of our lives on earth, such a life is mere existence, is vacuous, and is worthless. But the age of DNA has given “examined life” a wholly new and unexpected meaning. The examination is no longer solely on the philosophical level, it is also on the level of what makes us what and who we are. Is the wildly gesturing, drooling, incoherently grunting, the same person we identify today as “I”? What are we going to do about it?

These are tough questions that are left to each individual to grapple with.



So what happened to the young woman featured in the NYT article? You should go and read it; it’s worth it. But if you can’t wait, here is the story. She went ahead and took the test. She was positive. And after going through anger and depression, she arrived at the acceptance stage, immersed herself in preparing physically and psychologically for the inevitable, and plunged into work supporting research into this dread disease.

Hooray for the indomitable human spirit! Eventually, it will prevail.

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.