Say "Tourette Syndrome," and most people think of a rare behavioraldisorder, marked by involuntary bursts of obscene gutterances, facialgrimaces and muscle tics.
That picture, stereotyped in several episodes of the TV series "L.A.Law," is true as far as it goes. But, said medical geneticist DavidComings _ who directs one of the largest Tourette Syndrome (TS)clinics in the U.S., at City of Hope National Medical Center, inDuarte, Calif._ "that TV program was not a valid representation. Ittypified only the upper one percent of extreme TS."
He added, "When a TV producer comes to me and asks for a TSpatient to show this disorder, it's very difficult for me to findsomeone with symptoms that severe."
Comings, who has seen over 3,000 TS cases in his medical practicesince 1981, told BioWorld Today that in fact there are some threemillion school-age children with documented, inherited, TS or itsclosely associated attention deficit hyperactivity disorder (ADHD).
When he and his associates surveyed a California school district, theyfound one in a hundred boys and one in 200 or so girls diagnosablewith TS.
Parents and teachers know it well, from the grimacing, stuttering,funny noises, absent attention span, learning disability, and trips tothe principal for obnoxious misbehavior.
Yet Comings pointed out that "if there's anything nice about thesebehavioral TS hallmarks, it is that about 95 percent of cases arereadily treatable by one or two medications such as Ritalin,Clonidine, which is neuroleptic, Halodol, or Prozac _ sometimes incombination."
He added a caveat: "It's important first to diagnose the disorder, andmake sure that it's biological, not environmental. Once you make thathurdle, it often can be brought under control quite nicely." To besure, he observed, "Such medication gets parenting off the hook tosome extent."
Often, the young miscreant is aware of his or her TS inheritance _"sometimes to a nauseating extent," Comings observed. "They say,`It wasn't me; it was my Tourette's that made me do it.'"
He strictly "tries to discourage that, and hold them responsible fortheir non-tic behavior, regardless of what's going on."
Disentangling Polygenic, Multifactorial Ills
Comings has a paper in the current issue of the American Journal ofMedical Genetics: Neuropsychiatric Genetics, dated May 31, 1996.Its title tells its story: "Polygenic inheritance of Tourette Syndrome,stuttering, attention deficit hyperactivity, conduct and oppositionaldefiant disorder: The additive and subtractive effect of the threedopaminergic genes _ DRD2, DbH and DAT1."
The key word, he pointed out, is "polygenic," and explained: "Peopledoing linkage studies of genetic diseases have picked up manyimportant genes. Claims have been made for linkage analysis in suchbehavioral disorders as schizophrenia and manic depression, butthey've kind of fallen apart. Nobody can really agree, and none ofthem get very high statistical probability scores."
Many researchers, Comings among them, he said, "think multiplegenes are involved, that these are multifactorial disorders. And eachgene may account for only a part of the picture."
So on that basis, he and his co-authors started to look at several genesequences at once, instead of one at a time. "We chose threedopamine genes to start with, because everyone agrees that in TS,something is at least partly wrong with the dopamine neurotransmittersystem." These were DRD2, the dopamine D2 receptor, DbH,dopamine-beta hydroxylase, DAT1, the dopamine transporter gene.
(That last is the site of action of Ritalin and Dexadrine, used to treathyperactivity.)
He found that each of the three genes played a modest role, but theyall added up to only eight percent of the genetic variation in thebehavioral scores they obtained from their patient and relativepopulations.
His team analyzed DNA from 484 subjects with TS and kindredsymptoms, their close relatives, and control individuals. "We hadthem all fill out a 35-page questionnaire," Comings, recounted,"answering as to a wide range of behaviors _ hyperactivity, mood,depression, sleep, sex, drug use and so on. That gave a quantitativescore, and it turned out that people with differing genotypes haddifferent average scores for some of these three genetic markers."
To assess their polygenic impact, Comings and his team divided theirrespondents into four groups: those with all three markers, two, oneor none. "We found a progressive increase in scores across thesegroups," he recalled. "It was additive."
A Forensic Test For TS?
He has since run similar polygenic linkage surveys of completelydifferent populations _ drug addicts, gamblers, smokers, others withcompulsive addictive behaviors _ and found the same additive effectin the same dopamine genes.
Can a genomic test for such a TS inheritance serve in court to proveguilt or innocence, la forensic DNA?
"You've touched on something," Comings replied, "that's been asubject of fascination for me for a long time. A major caveat: It's nota diagnostic test for TS or hyperactivity or anything. It's still onlypart of the picture. You can have people with TS who don't have anyof these dopamine genes, or without TS who carry all three."
Looking ahead, he continued: "When we find another 10 or 15 or 20of these genes, maybe we can get a clue as to a person's profile in arape case, for instance, just by examining some of his genes."
The City of Hope geneticists now are "looking at about 10 othergenes _ dopamines, serotonins, GABA, cannabinoids _ and findingthat every one of them has a little bit of the TS picture."
Tourette Syndrome owes its acronym, Comings recalled, to a Frenchneurologist, Gilles de la Tourette, "who in 1885 pointed out that itwas genetic, and associated not only with motor and vocal tics, butwith compulsive behavioral syndromes. Tourette," he went on,"pretty well nailed the disorder down, but then it disappeared off theface of the earth for the longest time, because psychoanalyticpsychiatrists of the Freudian school assumed it was all secondary tosexual urges.
"Then in the 1960s, a New York psychiatrist named Arthur Shapirofound it responded very nicely to haloperidol, and realized it was abiological rather than a psychiatric disorder."
Perhaps the outstanding TS role model of our own day, Comingsmentioned, is Philadelphia Phillies outfielder Jim Eisenreich, whokeeps his own disorder under tight control. He welcomes hyperactivekids to his dugout, and between games has served as spokesman forthe American TS Association. n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.