Discovery of Huntington's gene launches search for a cure

On the shores of a lake in Venezuela, hundreds of people suffered from a mysterious affliction. They stumbled along the street, weaving like drunkards. Violent outbursts were common.

Practically every household near Lake Maracaibo had at least one member with the disease, a result of inbreeding, isolation and an inclination toward large families. They traced the symptoms in ancestors dating to the 1800s.

They knew the disease as el mal.

Psychologist Nancy Wexler knew it as Huntington's, a disease first described in 1872 by the American physician Dr. George Huntington. The disease killed three of Wexler's uncles and finally her mother in 1978. By that time, Wexler was already on the hunt for a cure, and a gene.

The presence of the Lake Maracaibo community was a revelation to Wexler. It came at a time when scientists were entranced by the promise of the human genome and its potential to map a cure for disease.

In the 1980s, Wexler made dozens of trips to Venezuela to track the disease's progression through more than 13,000 individuals, mapping a complex genealogy across pieces of paper taped to the walls of her office building.

The blood samples she collected would help molecular biologists finally locate the gene for Huntington's in 1993.

They found it on the short arm of chromosome 4. In a normal gene, a trio of nucleotide bases -- cytosine, adenine and guanine -- drive the production of an amino acid called glutamine. In someone with Huntington's disease, the gene contains too many repeats of this nucleotide triplet. Instead of 17 or 20 repeats, it will repeat 42 or more times.

The protein that results is too large. Brain cells have a hard time removing it, so it accumulates and slowly kills off brain cells.

"Certain parts of the brain are more vulnerable," said Dr. Kathleen Shannon, a movement disorders specialist at Rush University Medical Center in Chicago. "These parts control speed and coordination of movements, controlling emotion, behavior and mood."

That's why people with Huntington's disease lack coordination and have jerky movements. After 10 years with the disease, they often need wheelchairs. The lack of muscle control includes the throat, so swallowing becomes difficult.

They have trouble maintaining emotional equilibrium. Some people become irritable, aggressive, even violent. Or they become very passive and unmotivated.

The disease also erodes their cognitive skills. Unlike Alzheimer's, which primarily affects memory, Huntington's affects a person's executive function -- the ability to organize, plan and learn.

"They lose their jobs pretty early because these are things that are pretty important," Shannon said.

Scientists are still trying to figure out the normal function of the protein associated with Huntington's, which might help explain why the altered form causes harm.

The length of the genetic stammer is important; people with longer repeats often develop symptoms at younger ages. And the gene can alter from one generation to the next. A father with Huntington's stands a chance of passing on a gene with an even higher number of repeats.

In some cases, a parent with a borderline-high number of repeats never develops symptoms of the disease. But he or she could produce a sperm or egg with a few extra repeats. These extra repeats might be just enough to cause the child to have an abnormal gene.

Search for a cure

If you have multiple sclerosis, Alzheimer's or Parkinson's disease, the medical world has a way to treat you.

If you have Huntington's disease, you're out of luck. While doctors can prescribe medications to manage some symptoms, not a single drug has been approved by the FDA to treat the disease itself.

Scientists are looking. The discovery of the Huntington's gene in 1993 launched an explosion of research as scientists sought to identify drugs that could slow the progression of the illness.

Now, some of the drugs that worked in animals are being tested in humans.

An international group of researchers have formed the Huntington Study Group to better understand the disease and research potential treatments. Investigators at Massachusetts General Hospital in Boston and John Hopkins University in Baltimore, as well as Rush University Medical Center in Chicago, are part of this group.

Some lines of research hold promise. But it's hard to predict when doctors will find something that works, Shannon said.

"People often want to say gene therapy or stem cells are the answer," she said. "Well, we don't know. It's really difficult to know. Any study we do takes several years."

The long, slow progression of the disease is good for patients, but bad for scientists in a hurry to find an effective treatment. Rather than wait years to see if a potential treatment works, researchers are trying to find "biomarkers," or biological signs that the disease has progressed or slowed, Shannon said.

Brain scans can show whether certain drugs slow the deterioration of affected areas of the brain. Other studies are tracking early symptoms of the disease so scientists will have a baseline of the disease's progression.

Huntington's also faces a hurdle common to other rare diseases. It's too expensive to develop a drug from scratch to treat the relatively small population of people with Huntington's; a pharmaceutical company would never recoup its investment.

So rather than testing new compounds, Huntington's researchers are testing drugs already used to treat other diseases.

Here are a few of the current treatments being tested:

• One drug, tetrabenazine, has been shown to help calm the involuntary, writhing movement of the limbs associated with Huntington's and is being considered for FDA approval. While not a wonder drug -- it doesn't address cognitive or emotional decline -- it would be the first treatment expressly approved for Huntington's in the U.S.

• Researchers are testing high doses of coenzyme Q10, which has neuroprotective properties and might slow the decline of people with Huntington's.

• They're also looking at minocycline -- a drug used to treat infections. In mice, minocycline slowed the onset of Huntington's symptoms.

• Two observational studies, called PHAROS and PREDICT-HD follow people who are at risk of Huntington's. Researchers hope to learn more about the earliest signs of the disease, which could eventually lead to treatments to delay the onset of symptoms. Another observational study called COHORT will track both people who have been diagnosed with Huntington's and those who are at risk of the disease.