The cups fell to the floor with a crash. Was this the alarm signal? Or was it forgetting his sister's phone number the other day, even though he calls her often? Was the telling event last weekend, when he burst into a string of curse words and tailgated the driver who had just cut him off?
Incidents that to other people may seem like simple clumsiness, forgetfulness or an overreaction brought on by stress could mean disaster for Martin, a 48-year-old shipping agent. For years, he had been observing himself and his siblings with a sharp eye. Any little slip could constitute a somber omen. But after this latest string of mishaps, he could not bear the uncertainty any longer. He went in for the blood test. Three days later what Martin had feared since childhood was confirmed as the terrible truth: he was suffering from the genetic mutation that had killed his mother, his uncle and his grandfather.
Huntington's disease was recognized as an inherited disorder more than 100 years ago, yet the mutation that causes it was not discovered until 1993. A DNA test on a blood sample was quickly devised to reveal whether a person carried the abnormal form of the gene, which leads to progressive destruction of the brain, crippling muscles and mental function. Since then, every man or woman who has had a parent or other relative with the disease has faced a vexing choice: Should he or she take the test? A positive verdict is a damnation--the disease leads to certain death, given that there is no cure. Not knowing can be easier; most people do not begin to exhibit symptoms until they are middle-aged, and the progression can be very gradual. Yet nagging suspicion can creep into every corner of life, as it did for Martin.
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Of course, a cure, or even treatment that could slow the disease, would ease the tension greatly and extend life for the 30,000 Americans who have been diagnosed with Huntington's. Researchers are pinning down just how the genetic mutation ruins cellular mechanisms inside neurons, knowledge that might help point the way to therapies that have thus far proved elusive.
Lethal Knowledge
The Huntington's test is so certain because the disease is caused by a single gene--the huntingtin gene on chromosome 4 (the name of the gene is spelled differently than that of the illness). Typically this gene contains several occurrences of a set of DNA building blocks: cytosine, adenine and guanine, abbreviated as CAG. This set drives the production of the huntingtin protein. The more often the CAG sequence comes up in the gene, the more glutamine--an amino acid--in the huntingtin protein. In healthy genes the CAG sequence may appear up to 28 times. But if it occurs more than 35 to 40 times, the glutamine chain in the huntingtin protein becomes too long and causes trouble [see box on page 74]. The larger the number of CAG sets, the longer the chain, and the earlier and more severe the disease.
For Martin, the genetic test confirmed his grim suspicions. But he decided to see what he could do and went for counseling to the North Rhine-Westphalia Huntington Center at Ruhr University in Bochum, Germany. The center serves more than 600 Huntington's patients and their families. "I accept my fate as a fact," Martin told his counselors, then asked, "What can I do now that will help me later?" The team discussed the various ways the disease could play out.
The genetic mutation that overproduces the CAG sequence is inherited from a single parent. A child, therefore, has a 50 percent chance of getting the disease-causing form of the gene if either parent has it. The therapists in Bochum began by tracing the inheritance pattern of Martin's family. "My grandmother stepped in front of a train, and I think she knew what she was doing," Martin noted, insinuating that she knew she was doomed. "And Grandma's father became very strange when he got old." Martin's mother also clearly suffered from Huntington's disease, even though during her lifetime there was no definitive genetic diagnosis.
Martin and his sister Susanne finally dared to take the test because they could no longer stand the uncertainty--and because they wanted to plan the rest of their lives and careers. Susanne had the defective gene, too. Their siblings chose not to find out about their chances of impending death.
Today, two years after his weekend of dropping cups and forgetting phone numbers, Martin is showing the first verifiable symptoms: sudden twitches in his arms and legs. Susanne has been problem-free, yet she cannot help but wonder if certain harmless behaviors she never noticed before about herself are harbingers of difficulties to come. Disease symptoms typically begin when carriers are 35 to 45 years old, but even among close relatives the onset and course can differ significantly. No one wanted to think that Martin's 10-year-old son could already be falling victim--and the pediatrician treating him wanted to believe that the boy's pain, muscle weakness and subtle coordination problems were from other causes. But after six years of ailments and Martin's diagnosis, the boy was tested. Indeed, he had childhood Huntington's, a rarity brought on by an extremely elongated huntingtin gene.
Inexorable Progression
Huntington's disease had been known for centuries before it was given its definitive name. In the Middle Ages, victims of what was then called "the dance" made pilgrimages to Ulm, Germany, to pray in the chapel of Saint Vitus, leading to the ailment's name, Saint Vitus' dance. The first to recognize the condition as an inherited disease was the young American neurologist George Huntington in 1872. Together with his father, he had tracked cases in a family on Long Island, outside New York City, and was able to differentiate them from chorea minor, caused by a streptococcal infection that has similar symptoms. Today about one in 10,000 people in the U.S. suffers from Huntington's.
The symptoms that gave the disease its original name are the "dancing" movements--the exaggerated motions of the limbs that are its most frequent and striking effects. In the beginning, patients try to disguise these jerks and twitches as shrugs or try to translate them into deliberate motions such as stretches. But little by little their muscles go out of control. They are beset by sudden grimaces, and speaking and swallowing become increasingly difficult. In later stages, movements are slower; increased muscle contraction leads to painful contortions of the limbs that can last minutes or hours.
Characteristic mental symptoms often appear decades before the physical problems. The disease can cause repeated outbreaks of moodiness, yet patients who receive a positive test result can also fall victim to emotional swings driven by their knowledge of impending destruction. Relatives often notice personality changes--patients may become paranoid, tyrannize those around them with unfounded jealousy or react extraordinarily aggressively to trivial disagreements. As the disease advances, they may obsess about minor issues for days or weeks, burdening their families and destroying their social connections. Patients' cognitive abilities also wane; their memories deteriorate, and they find it increasingly difficult to concentrate. The problems progress to severe dementia and complete helplessness. Even early in the disease, the mounting mental breakdown can have catastrophic effects on a person's personal and professional lives, and suicide attempts are not unusual.
Communication Breakdown
Researchers who have been trying to better define the mechanisms that cause Huntington's muscular and mental challenges had to start by figuring out why the disease strikes at such varied ages. They have found that along with the huntingtin gene mutation, other inherited factors play an important role. For example, there can be great variation in how readily neuron receptors in the brain bind to glutamate, which serves as a messenger molecule that facilitates the transmission of information between neurons. The type of receptor protein a patient has helps determine how soon the disease will take hold.
Despite its rarity, Huntington's has become a focal point for defining how neurodegenerative diseases in general--including Parkinson's and Alzheimer's--harm the brain. In the 13 years since the huntingtin gene was discovered, scientists have learned much about the mechanisms leading to the destruction of neurons. Because the huntingtin protein is the sole cause of deterioration in the case of Huntington's disease, it provides a path for investigation that is uncluttered by other complicating factors.
Huntingtin is not a "bad" protein per se. It appears to play a central role in embryonic development among mammals. But as humans with the mutated gene age, the overelongated protein apparently binds to other proteins vital to cellular survival, compromising their function.
The proteins affected include transcription regulators--proteins that ensure the accurate reading of genetic information. If huntingtin proteins bind to a transcription regulator within a cell, its genetic activity is disturbed and the cell's control of protein synthesis breaks down. Some of the proteins that cannot be synthesized are responsible for removing neurotransmitters (messenger molecules) such as glutamate from the synapses--the gaps between neurons across which communication occurs. If too much glutamate remains in the synapse, adjacent neurons are continually excited; the overactivity eventually damages the cells. This phenomenon, known as excitotoxicity, has been demonstrated in lab animals.
There is also increasing evidence that huntingtin is more involved than previously thought in neuronal processes. A protein known as huntingtin interacting protein 1 (HIP-1) aids in both the secretion and reuptake of messenger molecules within neuronal cells. The elongated huntingtin protein chain cannot correctly bind to HIP-1, causing a cascade of enzyme reactions that initiate apoptosis: programmed cell death. The neurons are driven to kill themselves.
Another theory is based on the observation that the elongated gene causes the huntingtin protein to misfold. The misfolded protein then disrupts a neuron's metabolism. Evidence indicates that several steps in the respiration chain in the mitochondria--the cell's "power plants"--no longer function correctly. Such a resulting shortage of energy would eventually kill the cell.
Search for a Cure
So far investigators have come up with few ideas for altering such fatal cellular disruptions. Various drug treatments have affected only the symptoms of Huntington's. For example, some neurologists prescribe neuroleptics to deal with muscle contractions. These drugs can have the unfortunate side effect of limiting the patients' mobility. Other doctors may treat their patients' psychological problems with antidepressants, sedatives or antipsychotic neuroleptics. Unfortunately, there is still no treatment for the loss of mental abilities--a prognosis that frightened Martin more than the impending muscular challenges.
Several labs around the globe are seeking drugs that could delay or even stop the destruction of neurons. One set of substances is the glutamate antagonists, which modulate the secretion of glutamate. One compound, riluzole, has already proved effective against another serious, rapidly progressing disease of the nervous system--amyotrophic lateral sclerosis, or Lou Gehrig's disease. The drug is currently in a Europe-wide clinical test involving 450 Huntington's patients.
Scientists also have hopes for minocycline, an antibiotic. In 2003 Robert M. Friedlander of Harvard Medical School showed that in mice with Huntington's, minocycline could inhibit the action of the enzymes that set off neuronal suicide.
Other substances could perhaps block the clumping of misfolded huntingtin proteins, which aggravates neuron death. In 2004 researchers at the Riken Brain Science Institute in Japan inhibited the aggregation of the proteins with trehalose, a sugar made by various desert plants. Blocking the clumping in mice delayed the disease's onset.
Physicians are exploring substances produced in the body, too, such as coenzyme Q and creatine. Coenzyme Q, ubiquitous in humans, is an antioxidant that captures oxygen free radicals and could limit damage by huntingtin proteins. Creatine, produced in the liver and kidneys, could improve energy storage in muscle and brain cells. In both cases, animal experiments have been successful, but there is no convincing evidence for efficacy in humans yet.
Researchers are testing gene therapies as well. In 2005 Beverly L. Davidson and Scott Q. Harper of the University of Iowa inhibited the action of the mutated huntingtin gene in mice. The team injected the animals' brains with RNA fragments that precisely mimicked the genetic instructions for the mutated huntingtin protein and thereby blocked its synthesis. The rodents produced less of the illness-inducing huntingtin protein.
Stem cells could provide aid. In 2000 Anne-Catherine Bachoud-Lvi of the Henri Mondor University Hospital in Creteil, France, implanted neuronal stem cells from aborted fetuses into the brains of Huntington's patients to see if they might take the place of destroyed cells. Two years later Robert A. Hauser of the University of South Florida made similar attempts. In both trials, some patients responded to the therapy, but others suffered from cerebral hemorrhages, causing their condition to worsen. All the patients had to be given additional drugs to block immune reactions to the foreign cells.
There is nothing, today, that Martin can take to block the relentless progress of his disease. But never before have so many new approaches for treatment been under investigation. Scientists from Europe and the U.S. are preparing for larger studies, and many victims, as well as others who have not had the blood test but are at risk because of their family histories, are ready to take part. With their help, hope remains for an eventual solution for patients such as Martin.
