Abstracts: Tourette Syndrome
Comings, D.E., & Comings, B.G. (1985). Tourette syndrome: clinical and psychological aspects of 250 cases. . Am.J.Hum.Genet., 37: 435-450.
Tourette syndrome is a common hereditary neuropsychiatric disorder consisting of multiple tics and vocal noises. We summarize here clinical aspects of 250 consecutive cases seen over a period of 3 years. The sex ratio was four males to one female, and the mean age of onset was 6.9 years. Only 10% were Jewish, indicating that it is not more prevalent in Ashkenazi Jews. Only 33% had compulsive swearing (coprolalia), indicating that this is not necessary for the diagnosis. The most frequent initial symptoms were rapid eye-blinking, facial grimacing, and throat-clearing. In this series, it was clear that Tourette syndrome is a psychiatric as well as a neurological disorder. Significant discipline problems and/or problems with anger and violence occurred in 61%, and 54% had attention-deficit disorder with hyperactivity. Some degree of exhibitionism was present in 15.9% of males and 6.1% of females. Obsessive-compulsive behavior was seen in 32%. Other than tics and vocal noises, the most common parental complaints were of short temper and everything being a confrontation. There were no significant clinical differences between familial and sporadic cases. Whenever a child presents with a learning disorder, attention-deficit disorder, or significant discipline or emotional problems, the parents should be questioned about the presence of tics or vocal noises in the patient and other family members
Comings, D.E., & Comings, B.G. (1987). A controlled study of Tourette syndrome. I. Attention-deficit disorder, learning disorders, and school problems. Am.J.Hum.Genet., 41: 701-741.
Tourette syndrome (TS) is a common, hereditary, neurobehavioral disorder of childhood. To determine the frequency of various behavioral manifestations, we have compared 47 random normal controls to 246 patients with TS, 17 with attention-deficit disorder (ADD), and 15 with ADD secondary to a TS gene (ADD 2(0) TS). All subjects were examined prospectively with a 425-item questionnaire based on the Diagnostic Interview Schedule and the Diagnostic and Statistical Manual of Mental Disorders (DSM III). The TS patients were divided into grade 1 (too mild to treat [17.5%]), grade 2 (requiring treatment [58.9%]), and grade 3 (severe [23.6%]). Patients in all three grades of TS were significantly different from controls for DSM III symptoms of inattention, impulsivity, and hyperactivity. Sixty-two percent of TS patients had ADD, compared with 6.3% of controls; and 48.8% had ADD with hyperactivity (ADDH), compared with 4.2% of controls. In the majority of TS patients, the natural history of the disease was to start with ADDH and 2.4 years later develop motor and vocal tics. Among TS patients, 39% had previously received medication for ADDH or behavior problems, compared with 2% of the controls. Although stimulants can occasionally exacerbate tics, there was no evidence that stimulants cause TS and they are often a valuable adjunct to the treatment of TS. It is estimated that 10%-30% of ADDH is due to or associated with the presence of a TS gene. TS patients had a significantly increased frequency of (1) attending classes for the educationally handicapped, (2) placement in classes for the severely emotionally disturbed, (3) attending any special classes, (4) severe test anxiety, (5) stuttering, (6) letter, number, or word reversal, (7) reading very slowly, and (8) poor retention of material read. A reading-problem score (dyslexia) greater than or equal to 3 was present in 26.8% of TS patients, compared with 4.2% of controls. Number reversal, word reversal, and poor retention were significant even for the TS patients with tics too mild to treat. The multiple ways in which TS impacts school performance, as well as potential remedies, are discussed.
Comings, D.E., & Comings, B.G. (1987). A controlled study of Tourette syndrome. II. Conduct. Am.J.Hum.Genet., 41: 742-760.
To assess conduct in Tourette syndrome (TS), 47 controls, 246 TS patients, 17 attention-deficit-disorder (ADD), and 15 ADD patients with minor tics or a family history of TS (ADD 2(0) TS) were compared for the following behaviors: running away from home, lying, stealing, starting fires, vandalism, being in trouble with the law, fighting, shouting at parents or peers, attacking others, lack of respect for adults, short temper, hurting animals, feeling full of hate, being unable to stop fighting, and problems with drugs and alcohol. With the exception of running away from home and being in trouble with the law, TS patients were significantly different from controls in all other behaviors. When the components were combined for a total conduct score, only one (2.1%) of the controls had a score greater than 13, and he had TS. By contrast, 35% of the TS patients had scores greater than 13 (P < .0005). The correlation coefficient between the total conduct score and ADD score was .48. Although the presence of ADD was an important factor in determining conduct in TS, other factors such as depression and compulsive behavior also played a contributing role. There was little correlation between the total conduct score and the number of tics. It is estimated that among non-economically disadvantaged children, 10%-30% of conduct disorder may be due to the presence of a TS gene.
Comings, D.E., & Comings, B.G. (1987). A controlled study of Tourette syndrome. III. Phobias and panic attacks. Am.J.Hum.Genet., 41: 761-781.
Comparison was made of the frequency of phobias and panic attacks in normal controls and in patients with Tourette syndrome (TS), attention-deficit disorder (ADD), and ADD secondary to a TS gene. For phobias the most significant difference between controls and TS patients was with respect to fear of public transportation (P = .002), followed by fear of being alone (P = .009), fear of being in a crowd (P = .01), fear of being in water (P = .025), fear of animals (P = .04), fear of public speaking (P = .05), and other fears (P = .05). Only 8.5% of controls had more than three simple phobias and none had more than five, whereas 26% of TS patients had more than three (P = .008) and some had as many as 13. As opposed to 19% of TS patients, none of the controls had phobias that interfered with their life (P = .001). Among female TS patients 55.1% had 3-13 phobias, compared with 8.7% of the female controls (P < .0005). There was no correlation between the ADD score and the number of phobias (r = -.010) and little correlation with the total number of tics (r = .14). Panic attacks were present in 8.3% of the controls and 33% of the TS patients (P = .0008). This frequency increased to 55.2% (P < .0005) for grade 3 (severe) TS patients. None of the controls, 15.9% of all TS patients (P = .002), and 31% of grade 3 TS patients (P < .0005) had more than three panic attacks in 1 wk. Total panic-symptom score (12 possible symptoms) was significantly greater than that in the controls in all grades of TS. The presence or absence of ADD had little effect on the total panic-symptom score, but the presence of ADD resulted in a significantly lower average age at onset of panic attacks (8.8 years) compared with those TS patients without ADD (15.4 years) (P = .03). These observations indicate that phobias and panic attacks are a significant part of the symptomatology of TS and provide the first clear indication that phobias and panic attacks can be due to the presence of a major gene. Am.J.Hum.Genet., 41, 761-781.
Comings, D.E., & Comings, B.G. (1987). A controlled study of Tourette syndrome. IV. Obsessions, compulsions, and schizoid behaviors. Am.J.Hum.Genet., 41: 782-803
To determine the frequency of obsessive, compulsive, and schizoid behaviors in Tourette syndrome (TS), we prospectively questioned 246 patients with TS, 17 with attention-deficit disorder (ADD), 15 with ADD due to a TS gene, and 47 random controls. The comparative frequency of obsessive, compulsive, and repetitive behaviors--such as obsessive unpleasant thoughts, obsessive silly thoughts, echolalia, palilalia, touching things excessively, touching things a specific number of times, touching others excessively, sexual touching, biting or hurting oneself, head banging, rocking, mimicking others, counting things, and occasional or frequent public exhibitionism--were significantly more common in TS patients than in controls. The frequency of each of these was much higher for grade 3 (severe) TS. Most of these behaviors also occurred significantly more often in individuals with ADD or in individuals with ADD secondary to TS (ADD 2(0) TS). When these features were combined into an obsessive-compulsive score, 45.4% of TS patients had a score of 4-15, whereas 8.5% of controls had a score of 4 or 5. These results indicate that obsessive-compulsive behaviors are an integral part of the expression of the TS gene and can be inherited as an autosomal dominant trait. Schizoid symptoms, such as thinking that people were watching them or plotting against them, were significantly more common in TS patients than in controls. Auditory hallucinations of hearing voices were present in 14.6% of TS patients, compared with 2.1% of controls (P = .02). These symptoms were absent in ADD patients but present in ADD 2(0) TS patients. These voices were often blamed for telling them to do bad things and were frequently identified with the devil. None of the controls had a total schizoid behavior score greater than 3, whereas 10.9% of the TS patients had scores of 4-10 (P = .02). This frequency increased to 20.6% in the grade 3 TS patients. These quantitative results confirm our clinical impression that some TS patients have paranoid ideations, often feel that people are out to get them, and hear voices.
Comings, B.G., & Comings, D.E. (1987). A controlled study of Tourette syndrome. V. Depression and mania. Am.J. Hum.Genet., 41: 804-821
To evaluate the role of depression and mania in Tourette syndrome (TS), we have examined 246 TS patients, 17 attention-deficit disorder (ADD) patients, 15 patients with ADD associated with TS, and 47 controls, using (1) the standardized National Institutes of Mental Health Diagnostic Interview Schedule questions for a life history of major depression and/or mania and (2) a modified Beck depression score for evaluation of depression at the time of the examination. The results were combined into depression, Beck, and mania scores. Among the controls, 2.1% had a depression score greater than 9, and none had a score greater than 10. Among the TS patients, 22.9% had a score greater than 9 and the scores ranged up to the maximum of 18 (P < .0005). None of the pure ADD patients had a score greater than 6, whereas 20% of the ADD-secondary-to-TS (ADD 2(0) TS) patients had scores greater than or equal to 9. Among grade 3 TS patients, 46.6% had scores greater than or equal to 9. There were no differences in the frequency of depression in the TS patients with or without ADD. Comparable results were obtained for the Beck depression score, except that the percent with a score greater than or equal to 8 was higher for the TS patients with ADD (23.7%) than for those without ADD (9.3%). There was a good correlation between the depression score and the Beck score (r = .63), but no correlation between the ADD-with-hyperactivity (ADDH) score and either the depression score (r = .086) or the Beck score (r = .077). Among the controls, none had a mania score greater than or equal to 4, compared with 19.1% of the total TS patients (P ¥= .0005), 11.8% of the ADD patients (P = .002), and 26.6% of the ADD 2(0) TS patients (P = .0005). Although some of the mania questions would be expected to be answered positively by ADDH patients, the correlation coefficient between the ADDH scores and the mania scores was only moderate (r = .29), whereas the correlation with the depression score was much higher (r = .63). There was minimal correlation between the number of tics and either the depression score (r = .267) or the Beck score (r = .193). We conclude that depression and manic-depressive symptoms are common in TS patients and are an integral part of the disorder rather than being secondary to motor or vocal tics.
Comings, D.E., & Comings, B.G. (1987). A controlled study of Tourette syndrome. VI. Early development, sleep problems, allergies, and handedness. Am.J.Hum.Genet., 41: 822-838
Developmental milestones, problems with bladder and bowel control, sleep disturbances, allergies, and handedness were compared in 247 consecutive Tourette syndrome (TS) patients, 17 patients with attention-deficit disorder (ADD), 15 patients with ADD secondary to TS (ADD 2(0) TS), and 47 random controls. There were no significant differences in age of first talking or walking. By contrast, there were significant differences in problems with bladder and bowel control between TS patients and controls, as measured by age of first toilet training, age of last bed-wetting, frequency of enuresis, and age that bowel control was achieved. Sleep problems were pervasive in TS patients, with a significantly increased frequency of sleepwalking, night terrors, trouble getting to sleep, early awakening, and inability to take afternoon naps as a young child. In all diagnostic categories, including mild (grade 1) TS patients, a total sleep-problem score was significantly greater than that in controls. The sleep disorders and other TS symptoms are consistent with TS as a disorder of disinhibition of the limbic system. Allergies and left-handedness have been evoked as contributing to or being associated with ADD and learning disorders. There were no significant differences in the frequency of allergies or left-handedness in TS patients compared with that in controls. We conclude that when there is a clearly defined genetic cause of ADD and learning disorders, it is not associated with an increased frequency of allergies or left-handedness.
Comings, D.E. (1987). A controlled study of Tourette syndrome. VII. Summary: a common genetic disorder causing disinhibition of the limbic system. Am.J.Hum.Genet., 41:839-866.
Tourette syndrome (TS) is one of the most common genetic disorders affecting man. Approximately one in 100 individuals manifests one or more of the aspects of the TS gene. This series of papers has emphasized that although motor and vocal tics are the hallmark of TS, the complete range of behavioral problems is much broader. This spectrum of behavior can be explained on the basis of the TS gene causing an imbalance of the mesencephalic-mesolimbic dopamine pathways, resulting in disinhibition of the limbic system.
Comings, D.E. (1990). Blood serotonin and tryptophan in Tourette syndrome. Am.J.Med.Genet., 36: 418-430.
Blood serotonin and tryptophan levels were studied in 1,440 individuals. These included patients with Tourette syndrome (TS), attention deficit hyperactivity disorder (ADHA), or ADHD with a family history of TS (ADHD 2 degrees TS); relatives (parents, sibs) of these patients; other patients with TS-like disorders; and controls. There were significant decreases in the serotonin/platelet ratio (P = 0.0001) and in tryptophan (P less than 0.0001) in unmedicated patients with TS. Parents of TS patients showed a comparable, significant decrease in serotonin/platelet ratio (P less than 0.0001) and in tryptophan (P less than 0.0001), and there was no difference between parents with and without symptoms. This suggested that these were trait markers for the Gts gene and agrees with the proposal that TS patients are homozygous for Gts gene and that both parents are Gts gene carriers. Although there was no decrease in the serotonin/platelet ratio in ADHD patients, tryptophan levels were significantly decreased and there was a significant decrease in both the serotonin/platelet ratio and in tryptophan in the parents of patients with ADHD including those without a family history of TS. This is consistent with a close link between TS and ADHD. The basic defect may be a dysregulation of serotonin metabolism. The low blood serotonin and tryptophan levels in TS are consistent with the wide range of behavioral disorders seen in TS and suggest tryptophan oxygenase as a possible candidate gene.
Comings, D.E., & Comings, B.G. (1990). A controlled family history study of Tourette syndrome. I. Attention deficit hyperactivity disorder, learning disorders and dyslexia. J. Clin. Psychiat., 51: 275-280.
Gilles de la Tourette's syndrome (TS) is a common, hereditary neuropsychiatric disorder. While its diagnostic feature is the presence of suppressible motor and vocal tics, a wide range of impulsive, compulsive, attentional, learning, mood, and anxiety disorders are also present in many patients. To determine if attentional and learning problems are part of the expression of the Gts gene (or genes), the authors analyzed family histories of 130 TS probands with 1851 relatives and 25 control probands with 541 relatives--a total of 2392 relatives. The frequency of attention- deficit hyperactivity disorder (ADHD) or learning disorders was significantly increased in the relatives of the TS probands. The data on first-degree relatives suggest that when the Gts gene is expressed in this form, in two thirds of the cases tics are also present and in one third they are not. These observations are consistent with the proposal that ADHD and learning disorders form an integral part of the expression of the Gts gene or genes.
Comings, D.E., & Comings, B.G. (1990). A controlled family history study of Tourette syndrome. II. Alcoholism, drug abuse and obesity. J.Clin.Psychiat., 51: 281-287.
The behaviors associated with Gilles de la Tourette's syndrome (TS), including impulsive, compulsive, attentional, learning, conduct, and mood disorders, have often been described as substrates for the development of alcoholism and/or drug abuse. As the authors' experience with TS pedigrees indicated that alcoholism and/or drug abuse were common in relatives of TS probands, they examined, by the family history technique, 1750 relatives over 14 years of age in 130 TS proband and 25 control families. Significant, life-disrupting problems with alcoholism and/or drug abuse were present in 14.5% of the relatives of TS probands compared with 4.4% of the control relatives (p < .00001). Among parents of TS probands, the ratio of affected fathers to mothers was 2:1. Marked obesity (> 100 lb) was present in 10.8% of the mothers and 3.2% of all relatives of TS probands compared with 0.8% of all control relatives (p = .01). In parents of TS probands, the ratio of marked obesity in fathers to that in mothers was 1:4.5. When the categories of alcoholism and/or drug abuse and marked obesity were combined, 17.4% of all relatives of TS probands were affected compared with 4.6% of all control relatives (p < .0001) and the ratio of fathers to mothers with these disorders was 1.1:1. Among all relatives of TS probands, 20.8% of those with tics and 17.4% of those without tics had problems with alcoholism and/or drug abuse or obesity or both. This finding suggests that when the Gts gene(s) is expressed in this form it is about equally likely to occur in persons with and persons without tics. The similarities between TS and early onset, male predominant, Type II alcoholism suggest that in some cases, alcoholism and/or drug abuse in males and severe obesity in females are related, genetically controlled, compulsive behaviors.
Comings, D.E., & Comings, B.G. (1990). A controlled family history study of Tourette syndrome. III. Other Psychiatric Disorders. J.Clin.Psychiat., 51: 288-291.
In a family history study, the frequency of affective disorders was significantly higher for all relatives of Gilles de la Tourette's syndrome (TS) patients than for all relatives of controls. Among the relatives of TS patients, the presence of any behavior disorder was significantly more frequent for first-, second-, and third-degree relatives and total relatives. Among all relatives, 30.6% of the relatives of TS patients versus 6.1% of control relatives (p < .0001) had some behavior disorder. Studies of first-degree relatives suggest that among those individuals expressing the Gts gene as some type of behavioral problem, about half have tics and half do not. These observations suggest that in addition to tics that Gts gene(s) can be expressed as a spectrum of behavioral disorders.
Comings, D.E., Himes, J.A., & Comings, B.G. (1990). An epidemiological study of Tourette syndrome in a single school district. J.Clin.Psychiat., 51: 463-469.
The first study showing that Tourette syndrome was much more common than generally believed. It was present in approximately 1 percent of school boys.
Comings, D.E., & Comings, B.G. (1991). Clinical and genetic relationships between autism-PDD and Tourette syndrome: A study of 19 cases. .Am.J.Med.Genet., 39, 180-191.
Children with autism or pervasive developmental disorder (PDD) and Tourette syndrome (TS) share a number of symptoms. Forty-one cases have been reported in which PDD patients subsequently developed TS. We term this PDD----TS. We describe an additional 16 such patients plus 3 families where a close relative of a TS proband had autism. There was a high frequency of alcoholism, drug abuse, obsessive- compulsive, and other behavior disorders in the relatives of these patients. This frequency was vi rtually identical to that observed in relatives of individuals with TS only. We suggest there is an intimate genetic, neuropathologic relatedness between some cases of PDD and TS. Many observations have led us to suggest that the genetic defect in TS may be a mutation of tryptophan oxygenase and that TS is inherited as a semidominant semirecessive trait, i.e., homozygosity for a common gene which shows some expression in the heterozygous state. We propose that some types of PDD are inherited in the same fashion and by the same gene. This would explain the similarity of symptoms, frequent evolution of PDD into TS, the apparent recessive inheritance of PDD despite no increase in consanguinity, the high frequency of behavior problems in the relatives of PDD----TS patients and the serotonin abnormalities.
Comings, D.E., & Comings, B.G. (1993). Sexual abuse or Tourette syndrome? Social Work, 38: 347-350.
In addition to motor and vocal tics, Tourette syndrome (TS) can be associated with a wide range of behavioral problems including attention deficit hyperactivity disorder, obsessive-compulsive behaviors, learning disabilities, conduct disorder, and inappropriate sexual behaviors. The latter, which occur in a minority of patients, can include coprolalia, copropraxia, coprographia, exhibitionism, compulsive masturbation, touching themselves or others in the crotch or breast, and sexually self-abusive behaviors. Children who display these behaviors are often assumed to have been sexually abused. When teachers, social service agencies, or other professionals are not familiar with TS, injustice to families can occur. Professionals should be aware that TS can be an alternative to sexual abuse as an explanation of such behaviors.
Comings, D.E., & Comings, B.G. (1993). SIDS and Tourette syndrome: Is there an etiologic relationship? J.Dev.Physical Disabil., 5: 265-279.
SIDS has been repeatedly linked to the presence of prolonged sleep apnea and defective arousal mechanisms. Multiple cases of SIDS may occur in some families, and siblings of SIDS infants are at a 3 to 10 times greater risk of SIDS than the general population. This suggests genetic factors can play a role. Sleep laboratory studies of adults with Tourette syndrome (TS) show that 23% have sleep apnea and 29% have abnormal arousals. Disorders of arousal such as enuresis, sleep walking, sleep talking and night terrors are common in children with TS. We report seven TS families in which one or more close relatives died of SIDS, or had apparent life-threatening episode (ALTE) and required apnea monitoring. Serotonin is the major neurotransmitter involved in sleep regulation and abnormalities of serotonin have been implicated in both SIDS and TS. These and other observations suggest that the Tourette syndrome gene (Gts) may be the genetic factor contributing to an increased risk of SIDS.
Knell, E., & Comings, D.E. (1993). Tourette syndrome and attention deficit hyperactivity disorder: Evidence for a genetic relationship. J.Clin.Psychiat., 54: 331-337.
BACKGROUND: Attention deficit disorder with or without hyperactivity (ADD) is present in 49% to 83% of patients with Tourette's syndrome (TS), and up to 50% of children with attention-deficit hyperactivity disorder (ADHD) have chronic tics or a family history of chronic tics. Two explanations have been offered for this association: (1) ADHD is part of the pleiotropic expression of the Gilles de la Tourette (Gts) gene(s), or (2) the presence of ADHD in TS is due to ascertainment bias.
METHOD: To avoid ascertainment bias, we examined 338 first-degree relatives of 131 TS probands utilizing a structured questionnaire and the DSM-III criteria for ADD and DSM-III-R criteria for ADHD. All probands and many relatives were personally interviewed.
RESULTS: Of the relatives with TS, 61% had ADD and 36% had ADHD. Of the relatives with chronic tics, 41% had ADD and 26% had ADHD. Log-linear analysis showed a major, significant association between tics and ADHD.
CONCLUSION: These results indicate that ADHD is part of the pleiotropic expression of the Gts gene(s).
Comings, D.E. (1994). Genetic factors in substance abuse based on studies of Tourette syndrome and ADHD probands and relatives. I. Drug abuse. Drug and Alcohol Dependence, 35: 1-16.
There have been relatively few studies of genetic factors in drug abuse. Childhood Attention Deficit Hyperactivity Disorder (ADHD) has been implicated as a risk factor, and pedigree studies of Tourette Syndrome (TS), a hereditary impulse disorder closely related to ADHD, show an increased prevalence of substance abuse in relatives. These observations suggest the genes for TS and ADHD may play an important role in the development of drug abuse. To examine this hypothesis 217 TS probands and 328 of their relatives, 58 ADHD probands and 35 of their relatives, and 50 controls were prospectively studied using a structured questionnaire based on the Diagnostic Interview Schedule. All subjects were Caucasians 16 to 49 years of age. The responses concerning the use of 8 different drugs and 8 different symptoms of drug abuse were compared. The results showed a highly significant increase in positive responses with increased loading for the TS and ADHD genes for 6 of the 8 drugs and all of the drug abuse symptoms. The percentage of positive responses in TS probands was markedly influenced by the presence of comorbid ADHD, as well as discipline, obsessive-compulsive, or alcohol problems. These results suggest that the genes responsible for TS and ADHD play an important role in drug abuse/dependence. The dopamine D2 receptor gene (DRD2) appears to be one of these genes since variants at this locus are significantly increased in frequency in TS, ADHD, conduct disorder and drug abuse.
Comings, D.E. (1994). Genetic factors in substance abuse based on studies of Tourette syndrome and ADHD probands and relatives. II. Alcohol abuse. Drug and Alcohol Dependence, 35: 17-24.
Prior studies have suggested childhood ADHD as a risk factor for alcohol abuse in adults. Gilles de la Tourette syndrome, a hereditary tic and impulse disorder, is clinically and genetically similar to ADHD. To examine the hypothesis that individuals carrying the Gts gene are at increase risk to develop alcohol use problems, the same TS and ADHD probands, relatives and controls used in the prior study of drug abuse were studied using a structured questionnaire based on the Diagnostic Interview Schedule and the MAST test. The frequency of a positive response to any of 16 different questions concerning alcohol abuse showed a highly significant increase with increased genetic loading for Gts and ADHD genes. The percentage of more than one positive response in TS probands was markedly influenced by the presence of comorbid ADHD, discipline, obsessive-compulsive or drug abuse problems. Comorbid drug abuse problems were the best predictor of alcohol abuse problems. These results suggest that the genes responsible for TS and ADHD play an important role in alcohol abuse/dependence as well as drug abuse/dependence. One of the elements common to all of these disorders may be mutant genes affecting serotonin metabolism.
Comings, D.E. (1994). The role of genetic factors in human sexual behavior based on studies of Tourette syndrome and ADHD probands and their relatives. Am.J.Med.Gen. (Neuropsych. Genet.), 54 : 227-241.
Most significant variations in the expression of human sexuality are considered to be the result of learned behavior or psychological problems. Tourette syndrome (TS) is a common, hereditary tic and disinhibition disorder sometimes associated with compulsive use of obscene words (coprolalia) and previously reported to be occasionally associated with exhibitionism. To further explore the relationship between the Gts genes and sexual behavior, questions concerning a wide range of such behaviors were administered to 1,040 subjects, 14 years of age or older, consisting of 358 TS probands, 101 non-proband relatives with TS, 359 non-TS first degree relatives, 79 attention deficit hyperactivity disorder (ADHD) probands, 70 unaffected relatives of the ADHD probands, and 73 controls. The behaviors included magnitude of sex drive, sex orientation, exhibitionism, transvestitism, transsexualism, sadism, masochism, pedophilia, fetishism, aversion to being touched, and aversion to sex. While most of these behaviors occurred in a distinct minority of TS subjects, there was a significant positive correlation between each behavior examined and the degree of genetic loading for the Gts gene(s). The nature of these behaviors and their association with TS suggests many are variants of obsessive-compulsive disorder. Studies in animals indicate that changes in serotonin and dopamine play a significant role in the sexual behavior and many lines of evidence are consistent with the hypothesis that TS is due to genetic changes in serotonin and dopamine metabolism. These studies suggest that genetic factors play a much greater role in a wide range of forms of sexual expression than previously thought.
Comings, D.E. (1995). The role of genetic factors in conduct disorder based on studies of Tourette syndrome and ADHD probands and their relatives. J.Dev.Behav.Pediatr., 16: 142-157.
To examine the role of genetic factors in oppositional defiant disorder (ODD) and conduct disorder (CD), 38 variables relating to the relevant DSM-III-R criteria as well as other angry and aggressive behaviors, were examined in 1177 TS and ADHD probands, their first degree relatives and controls. Two techniques were used: 1) a genetic loading technique comparing the frequency of symptoms in groups with progressively less genetic loading for Gts and ADHD genes, and 2) comparison of the frequency of symptoms in relatives with, versus relatives without, TS or ADHD. When significant the latter rules out ascertainment bias and inappropriate controls. For TS the results were significant with most p values being < 10-8. The same trends were seen in the smaller number of ADHD families. A polygenic model is proposed in which TS and ADHD alone represent lesser degrees of genetic loading and expression and TS+CD'ADHD represent a higher degree of genetic loading and expression of genes common to all three disorders. These studies emphasize the important role of genetic factors in ODD and CD. The therapeutic implications are discussed.
Comings, D.E. (1995). Genetic factors in depression based on studies of Tourette syndrome and Attention Deficit Hyperactivity Disorder probands and relatives. Am.J.Med.Gen.(Neuropsych.Genet.), 60 : 111-121.
Tourette syndrome (TS) is a common, neuropsychiatric disorder which has many similarities to attention deficit hyperactivity disorder (ADHD). TS probands have a high frequency of a variety of behavioral disorders including depression. The depression may be due to a pleiotrophic effect of the Gts genes, proband ascertainment bias, or a result of coping with the chronic tics. To distinguish between these hypotheses we examined the responses to 17 Diagnostic Interview Schedule questions to evaluate the 9 DSM-III-R criteria for major depressive episode in 1080 adults consisting of TS and ADHD probands, their relatives and controls. Using a Bonferonni corrected p there was a significant progressive increase in 16 of 17 depressive symptoms and for a life time history of a major depressive episode in groups with increased genetic loading for Gts genes. Similar trends were seen in the small number of ADHD probands and their relatives. There was also a significant increase for these variables in non-proband TS relatives versus non-TS relatives, indicating the association of depression with Gts genes was not due to ascertainment bias or the inappropriate choice of controls. Multiple linear regression analysis indicated that obsessive-compulsive behaviors, sex, ADHD, drug abuse, and age all showed a more significant effect on depressive symptoms than the number of tics. The presence or absence of TS in the relatives had a much greater effect on risk for depression than the presence or absence of an episode of major depression in the proband. These results are consistent with the hypothesis that Gts and ADHD genes play a major role in depression.
Comings, D.E. (1995). Tourette Syndrome: A Behavioral Spectrum Disorder. In W. J. Weiner & A. E. Lang (Eds.), Behavioral Neurology of Movement Disorders. (pp. 293-303). New York: Raven Press.
Tourette's syndrome is a fascinating, complex, hereditary, neuropsychiatric spectrum disorder in which the tics are only one of many symptoms. Data to date suggest the mechanism of inheritance is just as complex as the disorder itself and involves the coming together of a number of common genes that affect dopamine and serotonin metabolism. Because these neurotransmitters modulate the function of many areas of the brain, the result is a wide spectrum of behavioral disorders. As such TS provides a significant challenge to the physician. Because many of the newer medications are quite effective, taking on the treatment of this challenging and complex behavioral spectrum disorder can be extremely rewarding.
Comings, D.E. (1995). Tourette syndrome: A hereditary neuropsychiatric spectrum disorder. Ann.Clin.Psychiatry, 6, 235-247.
The objective was to determine if the high frequency of behavioral problems in Tourette syndrome (TS) probands is the result of the pleiotrophic expression of the Gts genes or due to ascertainment bias. It was possible to distinguish between these two hypotheses by comparing the frequency of these behaviors in nonproband relatives with TS to relatives without TS. Twenty behavioral problems were prospectively assessed in a consecutive series of 361 TS probands, 113 nonproband TS relatives, 380 relatives without TS, and 68 controls, by the administration of a questionnaire based on the Diagnostic Interview Schedule and the DSM-III-R. Significance was set at a very conservative level of p ¥= .001. Except for problems with smoking, reading and compulsive eating, all other behaviors were significantly more common in nonproband TS relatives than in relatives without TS. The relatives were also dichotomized on the basis of each of the behavioral problems. Regardless of the behavioral trait used, there was a higher frequency of all other behaviors in those who were positive versus those who were negative for that behavior. Ranking according to the number of behaviors that were significant indicated that mania, obsessive-compulsive behaviors and schizoid behaviors represented higher degrees of expression of the Gts genes than chronic tics. These results indicate that the Gts genes cause a spectrum of behavioral disorders in addition to chronic tics, indicate that TS is a behavioral spectrum disorder, and emphasize the role of genetic factors in a wide range of human behaviors.
Comings, D.E. (1997). Genetic aspects of childhood behavioral disorders. Child Psychiatry Human Devel., 27, 139-150.
The evidence is reviewed to support the concept that many disruptive, childhood and adolescent behavioral disorders including ADHD, Tourette syndrome, learning disabilities, substance abuse, oppositional defiant disorder and conduct disorder, are part of a spectrum of inter-related behaviors that have a strong genetic component, are polygenically inherited, share a number of genes in common that affect dopamine, serotonin and other neurotransmitters, and are transmitted from both parents. Some of the implications of this hypothesis in relation to diagnosis and treatment are reviewed, including the possibility that the genes involved may be increasing in frequency.
Comings, D.E. (1998). Some genetic aspects of human sexual behavior. In L. Ellis (Ed.), Males, Females, and Behavior: Toward Biological Understanding. (pp. 1-12). New York: Praeger.
In addition to motor and vocal tics, Tourette syndrome (TS) can be associated with a wide range of behavioral problems including attention deficit hyperactivity disorder, obsessive-compulsive behaviors, learning disabilities, conduct disorder, and inappropriate sexual behaviors. The latter, which occur in a minority of patients, can include coprolalia, copropraxia, coprographia, exhibitionism, compulsive masturbation, touching themselves or others in the crotch or breast, and sexually self-abusive behaviors. Children who display these behaviors are often assumed to have been sexually abused. When teachers, social service agencies, or other professionals are not familiar with TS, injustice to families can occur. Professionals should be aware that TS can be an alternative to sexual abuse as an explanation of such behaviors.
Comings DE. (1999). Tourette syndrome a polygenic disorder. CNS Spectrums. 4:14-15.
In your recent fine symposium on Tourette syndrome (TS), Walkup struggles with the relationship between TS and the many other disorders which are commonly comorbid with TS. In his Table 4, in addition to ADHD and OCD he lists major depression, separation anxiety disorder, social phobia, generalized anxiety disorder, PTSD, bipolar disorder, PDD, substance abuse, ODD, CD, and others. We have previously shown that most of these symptom complexes are significantly increased in frequency in the TS relatives of TS probands, compared to relatives without TS 2-6. This rules out ascertainment bias and suggests these conditions all share one or more common etiologies. In Table 3, Walkup proposes nine possible explanations for this range of comorbidity, including TS being the cause, a risk factor for, or a precursor for other psychiatric disorders; or other psychiatric disorders being the cause, a risk factor for, or a precursor for TS. I suggest that none of these nine possibilities accurately portrays the real reason for these comorbidities and that the following sentence is all that is needed to explain both Table 3 and 4: "Psychiatric disorders, including TS, are polygenically inherited and each share many but not all genes in common." Depending on the polygenic mix individuals can have TS only, ADHD only, OCD only, TS + ADHD, TS + OCD or TS + ADHD + OCD. The higher the genetic loading the greater the risk they will have all three.
Polygenic disorders are due to the additive effect of multiple genes, each accounting for a small percent of the variance. Lod score and most other linkage techniques lack the power to identify genes with such small effects. This explains why none of the linkage studies of TS have identified any TS genes. By contrast, association studies do have the power to identify these small effects. With this technique we have identified over 20 genes for dopamine, serotonin, norepinephrine, GABA, and other neurotransmitters and neuropeptides that have a significant additive effect on ADHD in TS probands. Tics per se, CD, ODD and other comorbid conditions, used a subset of these genes. I have suggested elsewhere that because polygenic disorders are much more common than single gene disorders, and because they are caused by the additive effect of multiple genes, the gene defects must be fundamentally different than the mutations causing single gene disorders i.e. they must be common and they must have only a moderate effect on gene function. If they had a major effect they would be single gene disorders. As a corollary to this, I have suggested that all genes come in a wide range of common hypo- and hyper-functional variants. As a result, everyone is at risk to inherit a number of these variants. When the number passes a certain threshold, and the genes affect the function of neurotransmitters and neuropeptides, they are at risk to develop a range of behavioral disorders. The greater the genetic loading for these variants the greater the severity of the disorder and the greater the number and likelihood of comorbid conditions.
Segregation analyses of TS, using only tics or OCD as the phenotype, have suggested TS is inherited as a autosomal dominant or co-dominant trait. While some have suggested I define TS differently than others, I use the same DSM criteria for diagnosing TS probands as others. However, if TS is consistently and significantly associated with a wide range of other phenotypes that share similar hypo- and hyper-functional genetic variants, and this spectrum of phenotypes is not taken into account in the segregation analyses, then the true polygenic nature of TS is likely to be missed. One way around these flawed segregation analyses is to examine the individual genes themselves, as we have done.
These issues are important because the identification of the genes involved in TS as well as other psychiatric disorders will provide significant insights into their cause and effective treatment. If the wrong models and the wrong techniques are used, these genes will never be identified.
Comings, D.E. (2001) Clinical and Molecular Genetics of ADHD and Tourette Syndrome: Two Related Polygenic Disorders. Ann. N.Y. Acad. Sci. 931: 50-83.
ADHD is a polygenic disorder due to the additive effect of genes affecting dopamine, norepinephrine, serotonin, GABA, and other neurotransmitters. Some of the specific loci involved are dopamine genes - DRD2, DRD4, DRD5, and the dopamine transporter; norepinephrine (NE) and epinephrine (EPI) genes - dopamine __hydroxylase, ADRA2A, ADRA2C, PNMT, norepinephrine transporter, MAOA, COMT; serotonin genes - TDO2, HTR1A, HTR1DA, serotonin transporter; GABA genes - GABRB3; androgen receptor and other genes. This model is consistent with the all of the present knowledge about ADHD including a) the increased frequency of ADHD in the relatives of ADHD probands, b) the presence of a wide spectrum of comorbid behaviors (depression, anxiety, learning, conduct, oppositional-defiant, conduct and substance abuse disorders) in ADHD probands and their relatives on both parental sides, c) the close relationship to Tourette syndrome (TS), d) the failure to find the genes for TS using linkage analysis, e) the brain imaging studies showing hypometabolism of the frontal lobes, f) the relationship between dopamine D2 receptor density and regional blood flow, g) the correlation between tics and dopamine D2 receptor density in TS, h) the motor hyperactivity of dopamine transporter and dopamine D3 receptor gene knockout mice, i) the LeMoal and Shaywitz dopamine deficiency animal models of ADHD, j) the NE models of ADHD, k) the failure to explain ADHD on the basis of any single neurotransmitter defect, l) the response of ADHD to dopamine and _2-adrenergic agonists, m) the small percentage of the variance of specific behaviors accounted for by each gene, and numerous other aspects of ADHD. The implications of the polygenic model for the understanding, diagnosis and treatment of ADHD and TS, as well as other psychiatric disorders, are reviewed.