American Journal of Medical Genetics 39:173-179 (1991)

Tourette Syndrome and Autistic Disorder: A Significant Relationship Jeffrey Sverd Division of Child and Adolescent Psychiatry, Department of Psychiatry, North Shore University Hospital and Department of Psychiatry, Cornell University Medical College near normal to above normal intelligence [Bryson et al., 1988; Bartak and Rutter, 1976; Cohen et al., 1987; Folstein and Rutter 1987; Gillberg, 1984, 1989; Gillberg and Schauman, 1981; Kanner, 1973; Reiss et al., 1986; Schreibman, 1988; Smalley et al., 1988; Wing and Attwood, 1987; Wing and Gould, 1979; Zahner and Pauls; 19871. Although a number of medical, neurologic, and genetic conditions are associated with the disorder in the majority of cases etiology is unknown [Folstein and Rutter, 1987; h i s s et al., 1986; Smalley et al., 19881. Support for the role of genetic factors in idiopathic cases is a result of findings that up to 9.7% of families had more than one autistic sib [Folstein and Rutter, 1977, 1982; k i s s et al., 1986;Ritvo et al., 1989;Smalley et al., 19881, and rates of concordance for autism were significantly higher for monozygotic versus dizygotic twins [Folstein and Rutter, 1977,1987;Ritvo et al., 1985;Smalley et al., 19881. A recessive mode of inheritance has been hypothesized [Smalley et al., 1988; Ritvo et al., 19891. Studies of familial aggregation of disorders of intelligence, reading, and language in families of autistic KEY WORDS: Tourette syndrome, autistic disorder, pervasive developchildren suggested that a more generalized cognitive mental disorder, Asperger defect may be inherited [DeLong and Dwyer, 1988;Gillberg et al., 1987;Folstein and Rutter, 1977,19871.In the syndrome case of Asperger syndrome, considered by most investigators to be a mild variant of autism, familial aggregation of the syndrome points strongly to the role of geINTRODUCTION netic determinants [Bowman, 1988;DeLong and Dwyer, Autistic disorder or pervasive developmental disorder 1988; Gillberg, 1989; Gillberg and Gillberg, 1989; Gill(PDD) is a profound neurobehavioral disturbance char- berg et al., 1987; Wing, 1981; Wing and Attwood, 19871 acterized by impairments in social relatedness, delayed and reports of affective disorder in some Asperger synand deviant language, impaired capacity for imagina- drome patients [DeLong and Dwyer, 1988; Gillberg, tion, and the presence of repetitive, stereotypic, or 1985; Komoto et al., 1984; Wing, 19811 and relatives ritualistic behaviors [Bryson et al., 1988; Cohen et al., suggested a genetic link between autistic and affective 1987; Folstein and Rutter, 1987; Kanner, 1973; Reiss et disorders [DeLong and Dwyer, 19881. al., 1986; Schreibman, 1988; Smalley et al., 1988; Wing Although the accepted prevalence of autism is about 4 and Attwood, 1987;Wing and Gould, 19791.The severity per 10,000children, male to female ratio approximately of the core disturbances varies from case to case, amelio- 3:l [Smalley et al., 19881, recent studies permitting rates in some individuals, and 10-30% of patients show inclusion of less severe cases of PDD reported rates of 10 per 10,000 [Bryson et al., 1988; Cialdella and Mamelle, 19893. The results of one prevalence study of Asperger Received for publication April 30, 1990; revision received Sepsyndrome [Gillberg and Gillberg, 19891 and study of tember 5, 1990. relatives of PDD probands [Bowman, 1988;DeLong and Address reprint requests to Dr. Sverd, Department of PsychiaDwyer, 1988; Gillberg, 1989; Gillberg et al., 1987;Ritvo try, North Shore University Hospital, 400 Community Drive, Manhasset, NY 11030. et al., 1988; Wing, 19811suggested the possibility that

The histories of 10 children with autistic disorder or pervasive developmental disorder (PDD)cooccurring with familial Tourette syndrome (TS)are presented. Evidence from the histories of the patients and their relatives combined with other reports of cases of cooccurrence of TS and autism provides support for the hypothesis that TS may be responsible for cases of coocurrenceof the disorders, contributes significantly to the etiological heterogeneity of autistic disorder and that a portion of cases of autism may actually be a result of homozygosityfor the TS gene. In addition,the presence of affective disorders and autisticlike syndromes or mild disturbances of social relatedness in some of the pedigrees suggests the hypothesis that TS may be responsible for a subgroupof families with cooccurring affective and autistic disorders and for some cases of familial aggregation of autism-PDD.

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more subtle disturbances of social relatedness may exist and may be more common than previously recognized [Folstein and Rutter, 19871. Following the reports of Realmuto and Main [19821 and Barabas and Matthews [19831 of cases of coocurrence of Tourette syndrome (TS) and autism, Burd et al. [19871 observed a strikingly high number of their autism-PDD patients (12 of 59, 20%) had cooccurring TS and that the presence of TS was associated with a benign form of PDD. Kerbeshian and Burd [1986al also reported TS or tics in 4 patients with Asperger syndrome and normal intelligence. Sverd [1988] reported 2 children with cooccurring TS and benign PDD and a third child with benign PDD and a lip licking tic. Because relatives of the children reported by Sverd [ 19881had TS or tics and because the frequency of cooccurrence of the disorders (particularly the combination of benign PDD and TS) was far greater than would be expected by chance [Burd et al., 1987; Kerbeshian and Burd, 1986a; Sverd, 19881, Sverd hypothesized a causal link [Sverd, 1988; Sverd and Nolan, 19891. Comings and Comings [1988,1990]reported 19 cases of autism-PDD associated with TS attending their clinic and noted that the frequency ofthis association far exceeded that expected from a chance coocurrence and proposed that TS and autism are genetically related. The presence of cases of mental retardation and poor outcome in the Comings and Comings [1990] sample and in cases reported by other investigators [Barabas and Matthews, 1983; Burd and Kerbeshian, 1985; Kerbeshian and Burd, 1986b; Kano et al., 1987, 1988; Realmuto and Main, 19821 suggest that a significant association of the disorders may not be confined to higher functioning variants of autism [Burd et al., 1987; Sverd, 19881. It has been proposed that the inheritance of TS is best described as semidominant semirecessive where homozygotes express moderate to severe symptoms and heterozygotes express no or milder tic symptoms and a range of psychiatric disorders [Comings, 1989; Comings et al., 19891. In the case of autism, Comings and Comings [ 19901proposed that some children with the disorder are actually homozygous for the TS gene or actually suffering from a severe form of TS. The following is a report of10 additional children with autism-PDD cooccurring with TS or tics in whom family members showed evidence for the presence of pleiotropic manifestations of the TS gene. Evidence from the histories provide additional support for the hypothesis that TS contributes significantly to the etiological heterogeneity of autistic disorder [Comings and Comings, 1988, 1990; Sverd, 19881 and for the hypothesis that patients with autism and TS may actually be homozygous for TS [Comings and Comings, 19901.

METHODS Nine children and their families were referred from the general population to the author’s practice of child and adult psychiatry. Six of the children were referred because of behavioral disturbance and 3 (Cases 1,2, and 5) were identified during the course of psychiatric evaluation of a family member. None of the 9 children was

ascertained as result of a special effort to obtain referrals for autism or TS. The tenth child (Case 9), a resident of Nassau County, New York, was referred because of the author’s interest in study of children with benign forms of autistic disorder. All patients except one (Case 4) were evaluated within a 1.5 year period. The diagnoses of autistic disorder and TS were based upon DSM-III-R criteria [1987] and were made solely by the author, a board-certified child psychiatrist. The histories of 4 children and their families are presented as illustrative case examples and the remaining cases are presented in Table I. Pedigrees in Figure 1provide additional information.

CASE REPORTS Case 1 This family in which TS, autistic disorder, attention deficit hyperactivity disorder (ADHD),oppositional behavior, depression, alcoholism, anxiety, and somatoform disorders coexisted was ascertained through the 10 year old proband who, 1year after start of methylphenidate treatment for ADHD, showed motor and vocal tics. Questioning revealed the presence of undiagnosed familial TS. Father reported that during childhood he had a respiratory grunt similar to that of his son, had a life long history of eye, mouth, and nose tics, throat clearing, and knuckle cracking and was receiving alprazolam for panic attacks and somatoform symptoms. Parents recognized that Karen, 6.5 years old, showed symptoms of autism by age 1 year. At age 2.9 years she was not speaking, failed t o give parents eye contact, showed disregard for people, and absence of imaginative play. She was enrolled in special education and began to show interest in other children and to participate in class activities at 4 years and now engages adults in conversation, although she is literal and concrete in her answers, is echolalic, uses immature grammar, and sometimes shows insensitivity to the feelings of others. Her score on the WPPSI was Full Scale IQ 84, Verbal I& 81, Performance I& 89. At age 5.5 years, she began to show shoulder tics, mouth puckering, and a sucking noise. Mother was unaware of tics in her family but because she spoke rapidly and at length and reported that her maternal grandmother and uncle were alcoholic a TS gene may be present on her side of the family and Karen may be homozygous for TS. Case 2 This family in which TS coexisted with autistic disorder and a spectrum of psychiatric disorders including obesity (mother and daughter were 80 and 40 lb overweight, respectively) was also ascertained through a child who was referred because of ADHD. She showed eye blinking 4 weeks after initiation of methylphenidate treatment and prior to methylphenidate reported nighttime visual and auditory hallucinations. Kenneth was a 3.6 year old boy whose parents recognized abnormalities of social relatedness at age 2 months. He failed to give parents eye contact, regard other people, and respond to his name and noise stimuli. He showed absence of imaginative play, was fascinated

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TABLE I. Patients’ Symptoms of Autistic Disorder (DSM-111-R Criteria), Tourette Syndrome (TS), and Family History Family history of TS TS symptoms Autistic disorder and I.Q. Patient Case 5 Martin 5 years old

Case 6 Anna 4 years old

Case 7 Ronald 8 years old

Case 8 John 10 years old

Case 9 Paul 8 years old

Case 10 Fred 6 years old

No eye contact for parents. Ignored people. Did not respond t o name; felt to be deaf. Not speaking by age 2 then showed echolalia. Inappropriate social behavior. Brings up irrelevant topics. Distress over trivial changes in environment. Unusual attachment to objects. WPPSI Full Scale I& 81, Verbal I& 70, Performance I& 96. Poor eye contact. Disregarded people and ran into them as if they did not exist. Sometimes too attached t o mother. Inconsistent response to verbal stimuli. Preferred solitary play, Echolalic, pronominal reversal. Unable to initiate and engage in conversation. Lined up toys. Flicks light switch on and off. Hand flapping. Covers ears when upset. Acute episode of agitation and aggressivity. Merrill Palmer Scale age equivalent score of 44 months at age 49 months. Ignored people. Ran over children as if they did not exist. Poor eye contact. “Doesn’t know how to address children and get into their circle.” Brings up irrelevant topics, “out of blue.” No imaginative play. Used single words until age 3. Echolalic. Lined up toys. Markedly restricted interests and activities. Hyperactive. Average I& on Kaufman ABC. As an infant seemed “too good.” Didn’t like to be cuddled. Little eye contact and regard of people. Sometimes fixed gaze. Prefers solitary play. Could speak only 4-10 words by 4 years. Echolalic, staccato speech. No imaginative play. Flicks light switch on and off. Repetitively opens and closes doors of toy house. Hyperactive. Stanford-Binet Intelligence Scale I& score 45. Did not anticipate being held. Limited social relatedness. Poor eye contact. Prefers solitary play. Echolalia, pronominal reversal. Brings up inappropriate topics. Sing-song speech. Twirled self. Lined up toys. Fascinated with clocks. Oversensitivity to tactile stimuli. Silly giggling. WPPSI Full Scale I& 89. Verbal I& 94. Performance I& 86. “Was in own world,” little eye contact, resisted cuddling, seemed agitated. Did not respond to name. Did not speak until 3 years, perseverative and echolalic. Prefers solitary play. Lines up toys, insistence on sameness. Fascination with wheels of toy cars. Hyperactive. Detroits Tests of Learning Aptitude-estimated I& low average t o average.

Wrist slapping, nail picking.

Father-eye blinking, rolling and squeezing. Self-referred for panic attacks. Mother-nail picking. Maternal uncle was late in talking and showed “behaviors similar” to those of patient.

Onset age 3 - e y e blinking, facial tics, repetitive face touching and pushing hair from face, growling noises.

Father-eye blinking. Uncle-head tics. Grandfather-mouth stretches, eye twitches, delusional episode. Great aunt-facial grimaces. Delusion she is world class musician. Great uncle-claimed he controlled weather with a machine. Maternal uncle-socially awkward as adult, socially isolated as school boy. Uncle-fidgety, tapped fingers. Grandfather-socially awkward.

Onset age &ye blinking, head jerks, shoulder shrugs, hand clapping, finger snapping, throat clearing, clucking noises.

Father-head jerks, shoulder shrugs, eye blinking. Doesn’t work. Paternal uncle-throat clearing, head jerks, doesn’t work. Paternal grandfather-strange, impulsive, fidgety.

Onset age 3 - e y e blinking, teeth grinding, mouth tics, facial grimaces, arm and hand tics, vocal tics.

Father and grandfather-rapid foot shaking. Aunt-hand shaking. Great uncle-lifelong psychiatric institutionalization. Mother-OBC; her cousin had speech delay.

Onset age &head jerks, facial tics, throat clearing, gutteral noise.

Father was a poor student and a daydreamer. As a child was withdrawn, stayed in room, and had few friends. As adult has acquaintances but doesn’t socialize. Paternal uncle-showers frequently. Cousin-15 years old withdrawn, not social, never really talked, does well in school. Mother-wrist and mouth tics. Maternal grandfather-50 lb overweight. Uncle-eye blinking.

At 5.5 years-lip smacking, finger tics, tongue movements while receiving stimulants-perhaps best explained as secondary to presence of underlvine TS.

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by clocks, textures of material, and ate only baby food and pasta. At age 2 he began to show improvement. For example “he no longer seemed to be looking right through you” and began to gesture and speak single words. He showed eye blinking, teeth grinding, and made a “whirring” noise. Performance on the Gesell Developmental Schedule suggested an I& 65. Mother reported that she had eye blinking as a child and leg shaking as an adult and that her brother had lifelong mouth tics, gutteral noises, and throat clearing. Kenneth’s 14 year old sister had throat clearing and a swallowing tic and was subsequently treated with fluoxetine and alprazolam for major depression and panic attacks and 17 year old sister showed trichotillomania. A 7 year old brother required low doses of imipramine for symptoms of separation anxiety disorder. Of interest is the report that this patient did not speak until 3 years of

age, did not respond to his name, and was felt to be deaf. However, he was affectionate, gestured to make needs known, understood verbal communication, and made eye contact. Father had a manic episode at age 18 and reported that his father compulsively checked locks and the stove and verbally repeated himself. Therefore, a TS gene may be present on the paternal side of the family and Kenneth may be homozygous for TS.

Case 3 The case of Victor, 11 years old, and his family may represent an example of familial aggregation of autism-PDD secondary to the TS gene or genes. Although his score on the WISC-R was Full Scale I& 113, Verbal I&114,Performance I& 109he was failing in his regular 6th grade class and had a longstanding history of atten-

Tourette Syndrome and Autistic Disorder tional difficulties in school. As a child he ignored adults and children, “never seemed to have feelings, be hurt or embarrassed.” His early play consisted of lining up 200 toy cars and 40 stuffed animals. Although he began talking on time he made up his own words and was perseverative. He was obsessed with cars and the details of their body designs. Parents sought treatment because he continued to soil, was oppositional and aggressive toward his brother. Teachers reported “he acted weirdly,” made faces, and had difficulty with subjects that required discussion and thought. Beginning a t age 7 he showed eye blinking and squinting, shoulder shrugs, mouth stretches, teeth grinding, lip chewing and licking, and throat clearing. His father showed teeth grinding, mouth stretches, finger rubbing, was restless, had low-self esteem, and made job changes because of personality conflicts. Victor expressed concern that “other kids talked behind my back” and expressed low self-esteem, “the worst thing about me, is I hate myself.” Mother described her husband’s side of the family as cold. His older brother is very bright but “weird” and frequently passed up opportunities “to be successful because he would not drive more than 5 minutes to work.” He married “a woman who may be borderline retarded and their children go without the necessities of life because he spends money on his hobbies.” One sister had a child out of wedlock and became a topless dancer. Another brother, 30 years old, has a high I&, went to college, works as a chef, doesn’t talk to or acknowledge people, does not give eye contact, and if addressed answers in few words only. He lives with parents and rides his bicycle to work daily. Mother described that as a teenager she cut classes, hitch-hiked, and was “adventurous.” She reported that one of her cousins was schizophrenic.

Case 4 Stephen, 22 years old, was first seen after admission to the hospital following ingestion of 15 0.5 mg alprazolam tablets. He stated he was discouraged about his future and “wanted to see what it would be like to die.” Symptoms of autistic disorder were recognized by parents when he failed to give eye contact a t 9 months and by subsequent failure to respond to verbal stimuli and his name. Early speech was echolalic, play was nonrepresentational, and early interests consisted of staring a t and drawing hundreds of airplane propellers and sailboats. Arm flapping and toe walking were evident in the preschool years. He later showed interest in peers but engaged in inappropriate social behaviors and was unable to initiate and sustain conversation. At age 17 he experienced the first of a series of manic episodes for which he was hospitalized several times. Symptoms consisted of elevated mood, pressured speech, sleeplessness, auditory hallucinations, and delusions that he was a rock star. He was receiving lithium, carbamazepine, and fluphenazine. His score on the WISC-R was verbal I& 121, Performance I& 81. Tics which began at 5 years consisted of facial grimaces, stuttering, grunts, utterance of curse words, gutteral noises, and a coughing tic. Father had nose and

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facial tics, sniffling, stuttering, and compulsively collected magazines dating back to 1948. Although mother denied awareness of tics in her family, a TS gene may be present on her side of the family. Her sister had a manic episode and cyclical depressions and her daughter had postpartum depression. Mother’s paternal uncle had a psychotic episode.

DISCUSSION The 13 cases of autism-PDD associated with TS reported here and previously [Sverd, 19881 provide evidence for a significant relationship between TS and disorders of social relatedness. Assuming a prevalence of 4 to 10 cases of autistic disorder per 10,000 children [Bryson et al., 1988; Smalley et al., 19881 and 1case of TS per 169 children [Comings et al., 1990d1,the number of clinically ascertained cases of cooccurrence of the disorders observed far exceeds that which would be expected by chance alone. For example, 9 of the 13 children were under 16 years and resided in Suffolk County, New York, total population 1.3 million. Seven of the 9 children met criteria for TS and 2 met criteria for chronic motor tic disorder (CMT). Assuming a population of about 390,000 children under 16 years in Suffolk County, the finding of 7 cases of TS cooccurring with autistic disorder exceeds the 4 to 10 cases of cooccurPence of the disorders per 1.69 million children that would be expected with 100% ascertainment if the association was purely random. The significance of the phenomenon is even more apparent when considering the 6 cases of TS and I& > 70. The expected number of such cases occurring by chance would result in 1to 3 cases per 1.69 million children. Finally the presence in the sample of 3 girls with I& > 70 (2 of whom had TS, 1 CMT) far exceeds the number of these cases which would be predicted by a random association. Evidence for genetically transmitted TS is provided by the presence of TS and CMT in relatives of 9 of the cases and of probable mild manifestations of the tic disorder in relatives of the tenth case (Case 8). This observation combined with the presence in relatives without tics of a n array of psychiatric disturbances previously demonstrated to be significantly linked to TS [Comings and Comings, 1987a-g, 1990a-c; Pauls and Leckman, 1986; Sverd, 1990; Sverd and Nolan, 19891 provides support for the intriguing hypothesis that autism associated with TS may actually be the result of a homozygous condition for TS [Comings and Comings, 19901. Thus, in 8 of the 10 cases where information was available, evidence for pleiotropic manifestations of the TS gene was present on both maternal and paternal sides of the family. For example, in Case 9 tics were present in relatives of father and the mother showed a mild tic disorder. In other cases (e.g., Cases 2, 5, 8) the history of the presence of disorders such a s panic disorder, obsessive compulsive behaviors, and alcoholism suggests the possible presence of a TS gene. Of further interest regarding psychiatric disturbances in relatives, is the remarkable similarity of the array of disorders present in this sample and in another [Sverd, 19901 similarly ascertained for psychiatric reasons independent of TS, compared to that reported for patients

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and relatives referred for TS [Comings and Comings, 1987a-g, 1990a-dl. In addition, the presence of possible autistic-like syndromes or mild disturbances of social relatedness in relatives of 5 of the 10 children suggests the hypothesis that TS may be responsible for subtle disturbances of social relatedness and some cases of familial aggregation of autism-PDD [Bowman 1988; DeLong and Dwyer, 1988; Gillberg, 1989; Gillberg et al., 19871. For example, in the case of Kenneth (Case 3) the brother showed some but not all abnormalities associated with autism and the father and cousin ofPaul (Case 9) showed mild disturbances of social relatedness. The presence of affective disorders in TS patients and relatives reported here and elsewhere [Bleich et al., 1985; Burd and Kerbeshian, 1984; Comings and Comings, 1987d, 199Oc; Corbett et al., 1969; Robertson et al., 1988; Sverd, 1990; Sverd and Nolan, 19891 and the report of the presence of affective disorders in some autistic patients and relatives including the case of Stephen (Case 4) who had TS, autism, and manic episodes [DeLong and Dwyer, 1988; Gillberg, 1985; Komoto et al., 1984; Wing, 19811 suggest that TS may be responsible for a subgroup of families with cooccurring autistic and affective disorders. If a case such as Stephen’s of cooccurring TS, austim, and mania was a result of a chance association the expected prevalence of the phenomenon would be 1 case or less in 10,000,000 assuming prevalence rates of TS for boys of 1 in 100 [Comings et al., 1990dI 1in 100 for mania [Robins et al., 19841,and 10 or less cases per 10,000 for autistic disorder [Bryson et al., 19883. In summary the histories of the patients combined with other reports [Barabas and Matthews, 1983; Burd and Kerbeshian, 1985; Burd et al., 1987; Comings and Comings, 1990; Kano et al., 1987,1988; Kerbeshian and Burd 1986a,b; Realmuto and Main, 1982; Sverd, 19881 suggest that TS contributes significantly to the etiological heterogeneity of autism-PDD. Because of the increasing number of reports of cases of TS cooccurring with autism and I& < 70, including 2 reported here [Barabas and Matthews, 1983; Burd and Kerbeshian, 1985; Comings and Comings, 1990; Kano et al., 1987, 1988; Kerbeshian and Burd, 1986b; Realmuto andMain, 19821the significant association of TS to autistic disorder would appear to be more considerable than previously suggested [Burd et al., 1987; Sverd, 1988; Sverd and Nolan, 19891 and to include both high and low functioning variants of autism. Underrepresentation of cases of cooccurrence of TS and severe autism in this report and others [Burd et al., 1987; Kerbeshian and Burd, 1986a; Sverd, 19881 may be a result of failure to diagnose TS because of similarity of symptoms in the 2 disorders [Comings and Comings, 1990; Wing and Attwood, 19871 and failure to distinguish tics from stereotypies [Kano et al., 1987,19881which may be present in higher frequency in severe cases of autism [Bartak and Rutter, 19761. Finally if the hypothesized role of homozygosity for the TS gene is correct and additional genetic or environmental factors are identified [Comings and Comings, 19901,more precise identification of couples a t risk for having autistic offspring may be possible.

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