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P#12

: Comings, D.E., Comings, B.G., & Knell, E. (1989). Hypothesis: Homozygosity in Tourette syndrome

ABSTRACT:

We review evidence suggesting that many individuals with Tourette syndrome (TS) may be homozygous for a "Tourette syndrome" gene. This is based on experience with pedigrees on 1,200 TS families, comparison of the occurrence of tics or associated behaviors such as obsessive-compulsive behavior, panic attacks, attention deficit hyperactivity disorder, and/or severe alcohol or drug abuse, on both the maternal and paternal side in 170 TS families compared to control families, biochemical studies of blood serotonin and tryptophan levels, and other evidence. These observations suggest the inheritance in TS may be best described as semi-dominant, semi- recessive. Some of the implications of this proposal are discussed. Am.J.Med.Genet., 34 , 413-421.

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P#13

: Comings, D.E. (1990). Blood serotonin and tryptophan in Tourette syndrome.

ABSTRACT:

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. Am.J.Med.Genet., 36, 418-430.

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P#14

: Comings, D.E., & Comings, B.G. (1990). A controlled family history study of Tourette syndrome. I. Attention deficit hyperactivity disorder, learning disorders and dyslexia.

ABSTRACT:

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. J.Clin.Psychiat., 51, 275-280.

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P#15

: Comings, D.E., & Comings, B.G. (1990). A controlled family history study of Tourette syndrome. II. Alcoholism, drug abuse and obesity.

ABSTRACT:

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. J.Clin.Psychiat., 51, 281-287.

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P#16

: Comings, D.E., & Comings, B.G. (1990). A controlled family history study of Tourette syndrome. III. Other Psychiatric Disorders

ABSTRACT:

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. J.Clin.Psychiat., 51, 288-291.

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P#18

: Comings, D.E., Himes, J.A., & Comings, B.G. (1990). An epidemiological study of Tourette syndrome in a single school district

ABSTRACT:

The first study showing that Tourette syndrome was much more common than generally believed. It was present in approximately 1 percent of school boys. J.Clin.Psychiat., 51, 463-469.

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P#19

: Comings, D.E., & Comings, B.G. (1991). Clinical and genetic relationships between autism-PDD and Tourette syndrome: A study of 19 cases

ABSTRACT:

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. Am.J.Med.Genet., 39, 180-191.

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P#20

: Comings, D.E., Comings, B.G., Muhleman, D., Dietz, G., Shahbahrami, B., Tast, D., Knell, E., Kocsis, P., Baumgarten, R., Kovacs, B.W., Levy, D.L., Smith, M., Kane, J.M., Lieberman, J.A., Klein, D.N., MacMurray, J., Tosk, J., Sverd, J., Gysin, R., & Flanagan, S. (1991). The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders.

ABSTRACT:

1. Objective. Blum et al reported the 1 allele of the Taq I polymorphism of the dopamine D2 receptor gene was present in 69% of alcoholics compared to 20% of controls. By contrast, Bolos et al. reported no significant difference in the prevalence of the 1 allele in alcoholics versus controls, and no evidence that the D2 gene was linked to alcoholism. We hypothesized that these seemingly conflicting results might be because increases in the prevalence of the 1 allele may not be specific to alcoholism. Thus we examined other disorders frequently associated with alcoholism, or believed to involve defects in dopaminergic neurotransmission. 2 Design. Case comparison study. To minimize the effect of racial differences in gene frequencies, the study was restricted to non-Hispanic Caucasians. 3. Setting. Ambulatory and hospitalized patients. 4. Results. Among all known controls (N = 314), 24.5% carried the 1 allele. Of the 69 controls known to be non-alcoholic, 14.5% carried the 1 allele. The prevalence of the 1 allele was significantly increased in patients with Tourette syndrome (44.9%, n=147), attention deficit hyperactivity disorder (46.2%, n=104), autism (54.5%, n=33), alcoholism (42.3%, n=104), and post-traumatic stress disorder (45.7%, n=35). After correction for multiple comparisons (requiring p <0.0009 for significance) all remained significant except PTSD. The prevalence of the 1 allele was not significantly increased in patients with depression, panic attacks, Parkinson's disease, or obesity. The prevalence of the 1 allele in drug addiction and schizophrenia was only significant when compared to non-alcoholic controls and no correction was made for multiple comparisons. 5. Conclusions. These results suggest the 1 allele of the dopamine D2 receptor gene is associated with a number of behavior disorders where it may act as a modifying gene rather than the primary etiological agent. J.Am.Med.Assn., 266, 1793-1800.

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