One of the greatest rewards of scientific research is the “Eureka!” moment—that sudden gleeful breakthrough that can occur after much effort and many months of work. When a scientist experiences this lightning flash of insight, all the smaller discoveries of years past come together in a meaningful way, like the pieces of a puzzle, forming a much larger discovery. Indeed, HD can be compared to an enormous puzzle, the outlines of which are known, and the rest of which is still a mystery.
The genetic nature of the disease provides a kind of framework for discoveries about the changes that take place in the body on the cellular and molecular levels during the course of the disease. The macro-level changes observed in people with HD also provide guidelines about the micro-level changes occurring within their brains and bodies as the disease progresses.
With a rough outline to use as a guide, scientists can begin finding new pieces of the puzzle and fitting the puzzle pieces together to form recognizable pieces of the bigger picture. By putting the newly discovered pieces in place, scientists can make strides toward finding effective treatments not just for the symptoms of HD but also for the root genetic defect, or mutation, that causes the disease.
In 1993, an international team of researchers, which included Dr. MacDonald and her colleague, Dr. James Gusella, identified the responsible mutation. They found a CAG triplet repeat expansion in a region of human chromosome 4. Found in the nucleus (the information center) of cells, chromosome 4 is, like other chromosomes (we have 23 pairs of them), comprised of the DNA and associated proteins. Lengths of DNA in a chromosome make up genes, which are the functional units of heredity in humans and other organisms.
Each person inherits two copies (called alleles) of each gene, one from mother and one from father (the only exception being genes on sex chromosomes). Because HD is inherited as a genetically dominant character, a person needs only one mutated copy of the gene, called the expanded HD CAG allele, to inherit the disease. (For more information on genes and chromosomes, please click here
Genes are often compared to blueprints for making proteins. If the blueprint is defective, a defective protein will be made. Unlike the non-HD allele, which makes huntingtin protein with fewer than about 37 glutamines (one of the building blocks of the protein), the expanded HD allele makes an abnormal version of huntingtin, with an excess of glutamines (more than 37 or so of them in a row). Due to this mutation, the expanded glutamine version of the huntingtin protein does something—or is a byproduct of another process that does something—that contributes to the slow destruction of nerve cells in the brain. While the onset of symptoms can vary widely, the onset typically occurs between the ages of 30 and 50, after a substantial percentage of the nerve cells have died. There is also a juvenile form of the disease whose symptoms commonly appear before the age of 20. For more information on juvenile HD, please click here.
Physicians typically group the symptoms into three categories: movement, cognitive, and psychiatric. Movement symptoms include uncontrollable movements such as twisting and turning (known as "chorea"), rigidity, falling down, difficulty physically producing speech, and, in the later stages of the disease, difficulty swallowing, which can lead to significant weight loss. Cognitive symptoms include the altered organization and generally slowed processing of information in the brain. The most common psychiatric symptom of HD is depression; other symptoms include personality changes, anxiety, obsession, delirium, and mania. Denial of having HD is also a common symptom of the disease.
Presymptomatic genetic testing is available for those at risk for HD (i.e. people whose mother and/or father were diagnosed with the disease). While there is currently no cure for HD, there are drugs available to treat some of the symptoms, particularly chorea and depression. Some HD researchers, however, are beginning to develop and test drugs that target the presymptomatic effects of the genetic mutation that causes the disease.
Dr. MacDonald is one such researcher who works at the beginning of the disease pathway. She and Dr. Gusella, now director of the Center for Human Genetic Research, believe that the most effective treatments will be those that are specifically designed to reverse the first effects of the genetic mutation. These effects may impart altered physiology that is intrinsic to being born with and living with the HD mutation from birth. Scientists are still a long way from fully understanding the biology of the disease and the underlying mechanisms of nerve cell degeneration.
Last Modified: 05/22/2009
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