By STEPHANIE GALL ’14
A nutritional supplement called creatine has been shown to slow the onset of Huntington’s disease, a neurodegenerative disorder characterized by involuntary movements and cognitive decline. Huntington’s disease affects roughly one in every 10,000 Americans. It is caused by a mutation that expands the gene, called HTT, that codes for the synthesis of huntingtin protein. The individual’s age at the time of the disease’s onset is unpredictable, and while most people with the mutation get sick in their 30s, 40s or 50s, the disease does not affect some individuals until their 70s or later. In a recent study conducted at Massachusetts General Hospital, researchers found that high doses of creatine slowed the progression of Huntington’s disease among individuals at risk who aren’t yet experiencing symptoms. Creatine is an amino acid, or protein component, that humans produce naturally; it’s also found in meat and fish. The supplement is popular among athletes, since it converts a low-energy molecule known as adenosine diphosphate (ADP), into the high-energy molecule adenosine triphosphate (ATP), which provides cells with energy.
Additionally, the researchers’ innovative study design—the first of its kind—makes it possible for individuals to participate in treatment studies without knowing their genotype, meaning patients do not know whether or not they possess the mutation that leads to Huntington’s.
“We chose to include both those individuals who got tested as well as those who were at risk to reduce the potential coercion of genetic testing,” Dr. Herminia Rosas, the principal researcher, said. “We hope that this generates active discussions about those issues related to requiring genetic testing in future clinical trials.”
Unlike other neurodegenerative diseases that can arise from genetic and environmental factors, Huntington’s disease can only be caused if the person possesses the mutated HTT gene. Huntington’s disease is an autosomal dominant disorder, meaning the gene is not found on either of the sex chromosomes and just one copy of the mutated gene is sufficient to cause the disease. Because only one gene is responsible for the illness, doctors can accurately predict whether or not someone will get sick. However, there is no way of knowing when the disease will start affecting an individual.
“This makes genetic testing even more complicated,” Rosas said. “Huntington’s disease is a slowly progressive disorder. People are born with the genetic mutation, yet most people don’t get sick until midlife, likely due to cumulative effects. There is also clinical heterogeneity so in some people, cognitive difficulties present earlier; in others, the movements come first.” Accordingly, Rosas’ work seeks to develop biological assessments—like brain imaging and blood tests—that can accurately predict when symptom onset will occur and monitor the disease’s progression. With this information, Rosas explained, “we might be able to intervene before symptoms arise, allow people to lead full and active lives and … make clinical trials more efficient.”
People known to either have the gene mutation or have a 50 percent risk of contracting Huntington’s disease participated in the study. All individuals underwent genetic testing, but the results of the test were not told to either the patients or the researchers. As a result, the study had greater success recruiting participants than past experiments, and the stress potentially associated with knowing one’s genetic status was avoided.
Participants were randomly divided into two groups and given either a creatine supplement of up to 30 grams per day or a placebo for six months. During this time, physicians saw the participants regularly. After the six months had elapsed, all participants were provided with creatine supplements for one year. MRIs, blood tests and cognitive assessments were administered at the beginning, at the six-month mark and at the end of the study. The subjects received high doses of the supplement, though not above what their bodies could comfortably withstand. The primary side effect that the subjects reported was gastrointestinal discomfort.
Compared to subjects without the mutation, patients with the mutation had greater brain atrophy in a number of brain regions and performed less well on cognitive assessments of visuospatial function, recollection of events and recognition memory, as magnetic resonance imaging (MRI) showed. Repeated MRIs over a long period of time may effectively monitor disease progress in future clinical studies, potentially providing a way for physicians or researchers to anticipate the symptoms. Among individuals with the mutation for Huntington’s disease, creatine supplements were shown to slow the rate at which the brain’s cortex thinned, which is a consequence of the disease’s onset. This result suggests that creatine may prove useful in staving off the disease’s detrimental effects.
Before patients use creatine supplements for treatment, the researchers are working to make the supplement available by prescription, rather than over the counter. “The nutritional supplements that are being studied are pharmaceutical grade and not currently available commercially,” Rosas said. The quality of nutritional supplements can vary depending on the manufacturer since they are not under the control of the Food and Drug Administration, so a pharmaceutical grade supplement would ensure that patients receive good quality creatine.
In addition providing findings concerning creatine, the study is especially notable for its research design. The subjects did not have to know whether or not they had the mutation in order to participate in the experiment. Of those who do have the mutation, Rosas said, “some people are overwhelmed solely by knowing that they are at risk, some get tested in the hopes that the information will lead to something positive; often times it only makes them more anxious. Most of those at risk want to make a difference because they know that this disease affects not just the individual but has broader implications for families.”
Even among individuals at risk for Huntington’s disease, only about 10 percent are genetically tested. Scientists have debated how researchers ought to conduct genetic testing. Some people feel empowered to actively stave off the disease after finding out that they are at risk for Huntington’s disease, but others find the test results to be a source of increased stress. As Rosas found, most people end up getting tested for others rather than themselves, and those who knew their status were the most likely to drop out of the study. Rosas explained that for some people, the daily creatine supplement reminded them of the fact that they would one day get sick.
Rosas and her colleagues are currently examining whether creatine can slow the progression of Huntington’s disease in people who are already experiencing symptoms. Their findings may shed light on how people already affected by the disease may improve their everyday functioning.