Gilles de la Tourette syndrome:

Transcription

1 (Accepted 1 July 1988) Gilles de la Tourette syndrome: Genetic marker? J. M. ENOCH '*, A. ITZHAKI I, V. LAKSHMINARAYANAN I, J. P. COMERFORD2, M. LIEBERMAN and T. LOWE ' School of Optometry, University of California, Berkeley, CA 94720; 2New England College of Optometry, Boston, MA 02115; 3Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA 94305; 4Langley Porter Neuropsychiatric Institute, University of California, San Francisco, CA 94143; USA ABSTRACT. In an accompanying paper (and in other reports), visual field defects in Gilles de la Tourette syndrome (TS), a complex neuropsychiatric condition involving motor, vocal and behavioral anomalies have been described. Tourette syndrome is thought to be a dominant trait passed preferentially from fathers to sons over daughters. In this paper, visual field studies of families which include a proband who has a confirmed diagnosis of TS are presented. To date, all TS patients, all fathers and a majority of mothers of probands show characteristic visual field alterations. It will be important to determine whether these visual field determinations serve as a genetic marker for this complex of traits. Key words: Tourette syndrome; Goldmann visual fields ; kinetic perimetry ; genetics. INTRODUCTION In a companion article (Enoch et al., 1988a), we report the presence of anomalous kinetic visual field changes in individuals with Gilles de la Tourette syndrome (Shapiro et al., 1978 ; Golden, 1986). These are arcuate defects, nasal and temporal steps, enlargement and baring of the blind spot. Separately, in some individuals a loss of sensitivity in time is noted. We have termed the latter a fatigue effect. Tourette syndrome is a commonly inherited disorder (Pauls & Leckman, 1986; Kidd et al., 1980). It is important to evaluate par- * Reprint requests to : Prof. J. M. Enoch, School of Optometry, University of California, Berkeley, CA, 94720, USA ents, siblings and children of the probands to determine if manifestations of these noninvasive determinations are also present among these individuals. If so, then it is useful to ask if suchvisual field anomalies serve as a genetic marker. We have separately reported results on families of probands with diagnosed Tourette syndrome (Enoch et al., 1988b), and in this brief article, we report summary data on families studied to date, as well as some samples of the data obtained. These studies are important because, in addition to obvious genetic questions defining the nature of the transmission of the disorder, it would be useful to ask if this test, i.e., kinetic perimetry, can also reveal those who might exhibit Tourette syndrome later in life, and to distinguish those who Neuro-ophthalmology , Vol. 8, No. 5, pp Aeolus Press Amsterdam

2 J, M. Enoch et al. partially express this condition and/or carry the gene for this condition without an otherwise detectable manifestation. In a neuropsychiatric condition such as this one, a certain proportion of individuals refuse to obtain diagnostic assessment, even though they may be cognizant of the fact that they manifest some or many symptoms of Tourette syndrome (TS). TS is thought to be either an autosomal dominant trait or a complex dominant trait (Kidd et al., 1980; Kidd & Pauls, 1982 ; Baron et al., 1981). The fathers are said to transmit at a ratio of 4 (35) : 1 to sons over daughters. The findings we reported previously (Enoch etal., 1988b) and here (if in fact they are indicative of a genetic marker) suggest that more than one inheritance pattern may exist and/or that assortative mating may occur. It is difficult to draw definitive conclusions at this stage of the research. METHODS For all subjects, complete ophthalmological examinations were provided. The iris was not dilated for perimetry and the entrance pupil was never less than 3 mm in diameter during measurement. The refraction was carefully corrected to the plane of the perimeter cupola. The ophthalmic media were clear in all reported cases. In this study, we used a calibrated Goldmann Haag- Streit perimeter with kinetic and static capability. The senior investigator measured the large majority of visual fields reported and Goldmann kinetic perimetry was used since it is a sensitive indicator of paracentral visual field defects. Open angle glaucoma has been diagnosed in one eye of one father of a proband and one grandmother has been designated as a glaucoma suspect. RESULTS The code employed for the family trees is shown in Fig. 1. A distinction is made between fatigue effects and anomalies of the kinetic visual field which include arcuate and step abnormalities, and enlargement and baring of the blind spot. Sixteen families have been measured sufficiently to allow initial reporting. Fig. 2 shows a sample family, where the proband (female, black, la), has been diagnosed as having Tourette syndrome. The proband s visual fields are reported separately in the companion article (Enoch et al., 1988a). Both the proband s father and mother (Figs. 3 and 4) exhibit visual field defects. However, additional members of her family need to be examined. Fig. 5 shows a different pattern of visual field anomalies. Not only do both parents show visual field defects, but both grandparents on the KEY Male Tested 0 Female Tested [I: Not Tested r? Deceased Not Tested /-- f Proband Confirmed Diagnosis : Twrette Syndrome Visuol Field Anomaly Measured Keratoconus [3 Moderote to High Astigmatism 1 Fatigue Effects Noted Fig. 1. Symbols used for genealogical charts. 260

3 ml& I 52 I 46 Gilles de la Tourette syndrome: genetic marker? C.- ) St. Dance Vitus Halo per idol 21 (A) 22(8) Fig. 2. Family 1 genealogical chart. A) History of Seizures, Glaucoma Suspects B) Tics, Sniff, Obsessive Compulsive 2 3a Fig. 3. Family 1 visual fields of proband's father. (a) right eye (b) left eye. 261

4 ~~~~ ~ J. M. Enoch et al. father's side show visual field defects also. The paternal grandfather had a retinal detachment in one eye with resultant poor visual acuity. He also was described as exhibiting obsessive-compulsive traits. The second eye (measured) showed visual field defects. The paternal grandmother is a glaucoma suspect. The data shown here were reported in detail as Family B in Enoch et al. (1988b). DISCUSSION AND CONCLUSIONS The kinetic perimetric tests performed serve as sensitive noninvasive visual indicators of anomalous function in patients and families with Tourette syndrome. All patients measured to date with a confirmed diagnosis of TS show characteristic kinetic visual field anomalies as do all fathers, many mothers and several siblings with and without associated symptoms. The fatigue effects may be adaptive or may be part of the syndrome and must also be considered from this point of view. Bible 1 provides the summary data from several families which were tested (up to early 1988) in this laboratory. It should also be pointed out that several uncies/aunts and grandparents have also been tested, but numbers of individuals are still too limited to provide proper numeric assessment. 3b 262

5 Gilles de la Tourette syndrome: genetic marker? 4a Fig. 4. Family 1 visual fields of proband s mother. (a) right eye (b) left eye. TABLE 1. Summary data. Visual field defects Fatigue T.S. patients 24/24 100% 11/24 46% Father 16/16 100% 4/16 25% Mother 12/15 80% 1/15 7% Brothers 4/7 57% 1 /7 14% Sisters 5/8 63 % 4/ In a majority of families studied both parents show visual field anomalies rather than the father alone. However, in no case examined to date have we recorded a visual field anomaly only in the mother of a Tourette syndrome child. Automated static perimetric techniques were not used and are not recommended for this population of patients. This point is discussed in the companion paper (Enoch et al., 1988a) and elsewhere (Enoch et al., 1988b). If the visual field anomalies described are a marker for Tourette syndrome, then the collective data presented suggests that there may be more than one form of genetic transmission of Tourette syndrome and/or assortative mating. No clear picture emerges. It is important to determine if the measured visual field changes may be regarded as a genetic marker for TS. TS probands, their families, and a control population must be studied in far greater depth. Other important studies are required. Detailed 263

6 J. M. Enoch et al FGz7l E. Retinal Detachments 7 A, Childhood Seizures 8. Strabismus C. Partial Albinism Nystagmus D. Glaucoma Suspect 5 Fig. 5. Family 2 genealogical chart. in one eye I El

7 Gilles de la Tourette syndrome: genetic marker? consideration of the functional changes which are occurring is required. Simplification of test procedures for possible wider application and screening is necessary, and correlation with other test procedures is also warranted. It is too early to be able to predict whether a young child will manifest TS on the basis of these tests alone. Questions to be considered include: When do these first visual field signs first occur, and are they progressive changes? The latter studies will require longitudinal evaluations. Separately, we are alert to the presence of ker- atoconus and or high astigmatism (see younger brother of proband in Fig- 1) because in our mod- dividuals with keratoconus and two with high astigmatism. To date no apparent familial evidence of covariance has emerged. In this study, the most interesting finding to date is the fact that the majority of the mothers of TS children also exhibit signs of apparently characteristic kinetic visual field anomalies. This has been a totally unexpected finding. ACKNOWLEDGEMENTS Supported in part by a grant from the National Institutes of Health, NEI EY03674, and a postdoctoral fellowship to A. REFERENCES BARON, M., SHAPIRO, E. & SHAPIRO, A. : Genetic analysis of Tourette syndrome suggesting a major gene effect. Amer. J. hum. Genet. 35: , 1981 ENOCH, J. M., ITZHAKI, A., LAKSHMINARAYANAN, V., COMERFORD, J. P., LIEBERMAN, M. & LQWE, T. : Gilles de la Tourette syndrome : visual effects. Neuro-Ophthalmology (Amsterdam) 8: , 1988a ENOCH, J. M., ITZHAKI, A., LAKSHMINARAYANAN, V., SURENDRAN, T., COMERFORD, J. & LOWE, T. : Anomalous kinetic visual fields found in family members of patients with a confirmed diagnosis of Gilles de la Tourette syndrome. Amer. J. hum. Genet. (submitted), 1988b GOLDEN, G. S. : Tourette syndrome: Recent advances. F ediat. Neurol. 2: , 1986 KIDD, K. K. & PAULS, D. L. : Genetic hypothesis for Tourette syndrome. In: A. J. Friedhoff and T. N. Chase eds. : Gilles de la Tourette Syndrome. Advances in Neurology 35: , 1982 KIDD, K. K., PRUSOFF, B. A. & COHEN, D. J.: Familial pattern of Gilles de la Tourette syndrome. Arch. gen. Psych. 37: , 1980 PAULS, D. L. & LECKMAN, J. F. : The inheritance of Gilles de la Tourette s syndrome and associated behaviors. Evidence for autosomal dominant transmission. New Engl. J. Med. 315: , 1986 SHAPIRO, A., SHAPIRO, E., BRUNN, R. & SWEET, R. : Gilles de la Tourette Syndrome. Raven Press, New York