There are a lot of diseases that run in families. By that I mean, if family members have the disease, others in the family are at a greater risk. There is a tendency to say that this must be genetic, but many other things are familial: recipes, political leanings, and athletic supporting. If I and my sons picked the Denver Broncos in the Super Bowl, I am not sure anyone wants our DNA for evaluation.
In the study of disease, going from recognizing a familial pattern to an understanding of the underlying genetics is a crucial step. Alzheimer’s disease (AD) is an interesting example. For more than 90 percent of people, AD is a sporadic disease—there’s no clear-cut family pattern. However, if you have a close relative (parent, uncle, aunt, or sibling) with Alzheimer’s, your chances of getting it are about three times higher than those without such relatives. Understanding the actual genetics has been an unfulfilled challenge. At present, it appears that the genetics for the sporadic form of AD are complex, with multiple genes increasing a person’s risk of the disease, but no causative genetic mechanism has been established.
How does one get around this dilemma? One option is to study rare families with clear evidence of inheritance; that is, families with two (parent and multiple offspring) or three (grandparent, parent, and child) generations involved. With Alzheimer’s, such families exist, but are rare (probably less than two percent of all those with the disease). They have been the subjects of intense investigation, and virtually all have some genetic mutation relating to the metabolism of amyloid. There are multiple different genetic mutations involved, and many have been the basis for developing mouse models of AD. Based on these genetic defects, clinical trials have been undertaken in the human using agents designed to reverse the amyloid accumulation. So far, all have failed. I think it is fair to say that emphasis on amyloid as a single mechanism is fading, while other mechanisms are being sought.
In this issue, another mysterious neurological disease, Tourette Syndrome, has popped up with a possible genetic mechanism. Tourette Syndrome (often referred to as Tourette’s) is a tic disorder involving motor and phonic (sound) components. The motor components range from rapid eye blinking to abnormal facial movement. The phonic components also have a range of appearances including throat clearing and vocal words. In the notorious form of the disease, persons utter obscene words as part of the tic (so-called coprolalia). That form of the disease is rare, in less than 10 percent of subjects. The disease starts in late childhood, around 8-10 years, and symptoms diminish with age, making Tourette’s uncommon in older people.
A family with the father and all eight of his children with the disease was used for study of a possible genetic mechanism. This family was previously reported by Matt State and his colleagues at Yale, who found that the family had a mutation in the key enzyme involved in the synthesis of the neurotransmitter histamine. Following the strategy used in Alzheimer’s, Christopher Pittenger and his colleagues, also at Yale, knocked out this gene in mice, producing Tourette’s-like symptoms. Further, in the mouse, these symptoms could be ameliorated by infusing histamine to the brain. The level of another transmitter, dopamine, was elevated. This elevation, and the Tourette’s-like symptoms, were alleviated by the dopamine antagonist, haloperidol.
These findings open the door to all kinds of future exploration, including looking for this mutation in other families and trying therapies that modify dopamine. The big advantage of having a mouse model of a disease is that one can impose studies that could not be done in the human. Such studies might clarify the mechanism of a disease and point the way to a therapy for humans.