Association of schizophrenia and partial trisomy of chromosome 5p

Schizophrenia Research, 7 ( 1992) I9 I - 196 0 1992 Elsevier Science Publishers B.V. All rights reserved

SCHIZO

191 0920-9964/92/$05.00

00229

Association

of schizophrenia and partial trisomy of chromosome 5p A case report

Dolores

Malaspinaa,b,c,

Dorothy

Warburtond,“, Xavier Amador”, Charles A. KaufmanrPbsc

Megan

Harrisa~b~C and

“Department qf Clinical Psychobiology, and ‘Department of Medical Genetics, News York State Psychiatric Institute, New York, NY, USA and ‘Department of Psychiatry. dDepartment of Genetics and Development, and ‘Depariment of Pediatrics. Columbia University College of Physicians and Surgeons, New York, NY, USA (Received

3 October

1991; revision

received

13 December

1991; accepted

20 December

1991)

A normal balanced chromosome 5 translocation carrier (5:14) (p14.l;q32.3) produced one offspring with a 5p deletion syndrome (cri du chat syndrome) and two with a partial trisomy (one with schizophrenia and the other with refractory epilepsy). We had hypothesized that the translocation might be complex and involve 5q, overlapping with a schizophrenia associated area described by Bassett et al., (1988). Cytogenetic study, however, indicated that there was no overlap in the involved chromosome 5 trisomy for this individual with schizophrenia and the trisomic region previously described. The probands with the trisomy and the cytogenetic findings are described in this report. Alternative interpretations are suggested to explain the association of schizophrenia and chromosomal abnormalities. Key words: Chromosome

5p; Partial

trisomy;

(Schizophrenia)

INTRODUCTION

The identification of cytogenetic abnormalities associated with an illness, the ‘favored locus approach’, has successfully directed genetic linkage searches for Duchenne muscular dystrophy (Boyd and Buckle, 1986; Francke et al., 1985; Davies et al., 1983) and familial Alzheimer’s disease (St. George-Hyslop et al., 1987). By focusing on a limited region of the genome (perhaps 10 CM to 100 CM) and, by possibly identifying other partially overlapping genetic anomalies, a narrow ‘obligate chromosomal region’ with a disease susceptibility gene can be better identified than through other

Correspondence to: D. Malaspina, Department of Clinical Psychobiology, Box 2, New York, NY 10032, USA.

Psychiatric Institute, 722 West 168th Street,

approaches to chromosomal location, such as linkage analysis. While the base rate of schizophrenic psychosis in individuals with sex chromosomal aneuploidies is reported to be increased approximately 3 fold (Propping, 1983) the associations of schizophrenia with autosomal aneuploidies is less well studied. This is probably because such abnormalities most often are associated with retardation and marked physical abnormality. Nonetheless, a number of cytogenetic anomalies have been associated with schizophrenia (reviewed in DeLisi et al., 1988) involving numerous chromosomal locations. These anomalies have initially directed linkage studies to chromosomes 2, 5, and X, while patterns of inheritance in some pedigrees directed studies to the pseudoautosomal regions of the sex chromosomes. Even if this cytogenetic abnormality represents only a rare form of schizophrenia, these associations are of value in under-

192

standing the pathogenesis and associated manifestations of the schizophrenia syndrome (Gurling, 1986). The purpose of this report is to describe a subject with schizophrenia and a partial trisomy of chromosome 5p. Various interpretations are suggested to explain the association of schizophrenia and chromosomal abnormalities.

METHODS

2

1

3

4

5

LEGEND

The case records of the Genetics Diagnostic Laboratory of the Presbyterian Hospital in the City of New York were screened for incidences of chromosomal abnormalities and schizophrenia. Of several hundreds of individuals found to have chromosomal rearrangements only one was known to have schizophrenia, but these patients were not routinely followed for psychiatric diagnosis. Two siblings with a partial trisomy of chromosome 5 (one with a schizophrenia diagnosis, and the other with refractory epilepsy), were identified after their sibling was found to have a partially deleted 5 and the cri du chat syndrome (Fig. 1). They had been intensively evaluated over 20 years ago (see De Capoa et al., 1967; the ‘L’ family) and they are the subject of the present report. The subject with schizophrenia (R) and her parents were interviewed with the Structured Psychiatric Interviews @CID; Spitzer et al., 1987) and clinical interviews. Detailed family history data were collected on the pedigree, and school and psychiatric records were obtained for affected offspring. R was also physically evaluated; both she and her parents had electro-oculographically recorded eye tracking. Blood was collected for cytologic evaluation and the establishment of lymphoblastoid cell lines for R and her parents.

RESULTS Family history Both parents were phenotypically normal; they produced five living offspring and one spontaneous abortion at five months gestation. The father and one child had balanced translocations and another child had a normal karyotype; both of these off-

ALC CRI GAD NAR OBS SCZ

Alcohol Abuse Cri du Chat Syndrome Generalized Anxiety Disorder Narcissistic Personality Disorder Organic Brain Disorder (Unspecified) Schizophrenia

STILLBORN PARTIAL TRISOMY 5p BALANCED TRANSLOCATION DELETION 5~ NORMAL KARYOTYPE UNTYPED Fig. 1. Pedigree

of L family.

spring are psychiatrically well and highly accomplished. The middle child had a classic cri du chat 5p deletion syndrome and died in childhood. The oldest sister (R) and youngest brother (T) had the partial trisomy; T had refractory epilepsy and expired at age 18 from complications of pneumonia, and R is presently living in a group home. A detailed family history investigation revealed no other suspected instances of schizophrenia or spectrum disorder in 44 members of the extended family. On SCID interview the father met criteria for DSM-IIIR generalized anxiety disorder and the mother had a history of alcohol abuse. Both of these syndromes accompanied the stresses of raising three profoundly ill children and were not currently present.

193

Case history of R R had clinical and SCID interviews by two psychiatrists and received a diagnosis of DSM-IIIR chronic paranoid schizophrenia. History revealed that R was a physically normal and attractive child who was considered bright by her family. She initially attended kindergarten alone and interacted with her classmates and teachers, but by age six she would not leave her house unaccompanied. School records indicate that her behavior decompensated and regressed and that her mother was ‘shocked to observe how unresponsive she was in the classroom’ in first grade. A psychiatric report at age 8 stated she was a ‘well developed and attractive child who had a serious disturbance in her ability to form object relationships . and an ever present substratum of anxiety’, and she was seen by several psychiatrists and diagnosed as having schizophrenia. Her IQ tested between 82 and 91 and she was placed in classes for the educable mentally retarded at age 9 in consideration of her disability and the mental retardation in her family. The most recent WAIS and cognitive assessment was completed when R was 16 years, 1 I months old. It was consistent with a diagnosis of schizophrenia, and inconsistent with mental retardation. Indeed, although she received a WAIS full scale IQ of 79, in the borderline range, (verbal IQ of 83, performance IQ of 77) there was substantial subscale scatter. The Peabody Picture Vocabulary Test revealed a mental age of 15-I years; and IQ of 91. The variance and pattern of test performance strongly suggested to the testing psychologist that she had the capacity to function in the average range of intelligence, ‘if not impeded by affective interferences’. R had a psychiatric hospitalization at age 17, after developing agitation and ‘fears’, refusing to go on stairs or ride in elevators and episodes of ‘freezing’. The hospital diagnosis was psychoneurotic disorder. She was thereafter placed in a sheltered workshop, which greatly distressed her since she did not consider herself retarded. On interview she was a clean but unkept appearing woman, physically normal except for mild alopecia and a kyphotic posture. Her affect was blunted and her mood constricted. She was cooperative but guarded and had an infantile manner. There was no psychomotor agitation or retardation. Her speech was subtly dysarthric and pres-

sured. Her comprehension and vocabulary were quite normal. Associations were intact and there was no thought disorder or incoherence. She was found to be continuously somatically preoccupied, experiencing somatic delusions. She was referential and believed that people plotted against her and go out of their way to give her a hard time. She reports experiencing thought insertion, thought withdrawal, and hears multiple voices criticizing her; this frequently leads to fights with her work mates. At times she hears voices repeating her own thoughts. She demands constant visits to physicians but physical findings are persistently negative. R was cognitively quite intact (Mini-Mental Status 29/30), and able to do similarities abstractly but not to interpret proverbs. Neurological examination revealed mixed laterality, (R hand and eye, L foot); left/right confusion; dysmetria; agraphesthesia, right upper extremity paratonia and drift; and bilateral adventitious overflow. There were no other focal, soft, frontal release, or cerebellar findings. Minor physical anomalies were assessed with the Waldrop scale. She had positive findings of fine electric hair, partly covered epicanthus, hypertelorism, low set ears with adherent lobes, a furrowed tongue, third toe longer than the second toe, and a gap between the 1st and 2nd toes. Her score was IO; the mean score of the general population is four, and of adult male patients with schizophrenia is 6.8 (Guy et al., 1983). Qualitative ratings of smooth pursuit eye tracking were made (9-point scale, range I to 5 in 0.5 intervals, modified from Shagass et al., 1974) and the total number of blinks were counted. Eye tracking ratings were dichotomized into normal and abnormal. The rationale for the cut-off score used and description of the methods has been reported previously (Amador et al., 1991). R exhibited abnormal smooth pursuit eye movements with marked saccadic intrusions, as is seen in schizophrenia, while her parents performed in the normal range (Fig. 2). The finding of relatively intact smooth pursuit in the parents was unexpected given the fact that they were over 60 years of age and that an association between advanced age and impaired eye tracking has been reported (Kuechenmeister et al., 1977). The results of a fixation task yielded a similar pattern.

194 Chromosome

14

Chromosome

13 313 l-

_A’/

-13.2 -12 -11.1

ll-

.

11 22224.124

3-

-24

- 13 2

2

- 14

-31 32.132.3-

- 12

13.113.3-

-23

15-21

-32.2 22-

-23.1

23 2-

Fig. 2. Smooth pursuit eye tracking. (A) Proband with schizophrenia. (B) Mother. (C) Father, balanced translocation carrier. Asterisks indicate eye blinks.

Thus, psychometric abnormalities were characteristic of those seen with schizophrenia and not retardation. Other relevant findings were minor physical anomalies, soft neurological signs and abnormal smooth pursuit eye movements. Case history

qf T;

refractory

5

31

l-

31

3-

-23.3

i

-31.2

3:.:-

-32 -33.2

35 35

-35.2

I3-

-34

Balanced carrier 46, XV,?t(5;14)(~14.l;q32.3)

epilepsy

T, the brother of R, was the product of a normal pregnancy and delivery. He was a bright and healthy baby with normal early developmental milestones. Onset of a seizure disorder occurred at 8 months and was refractory to a series of anticonvulsant regimens. The seizure disorder probably resulted in a regression in intellectual function. He developed a highly aggressive and oppositional behavioral syndrome. It is unknown if he would have developed a behavioral disorder without the epilepsy, as had R. At age 12 he was institutionalized. He was noncooperative with formal intelligence testing. At age 15 years, 9 months his Stanford Binet mental age was 2 years, 4 months; IQ less than 20. His death at age 19 was from pneumonia, a complication of his seizure disorder.

Fig. 3. Karyotype

of balanced

translocation

carrier.

DISCUSSION Cytogenetic

data

The karyotype of the balanced carrier (father) was initially interpreted as a simple balanced reciprocal translocation, (46,XY,t(5:14) (p14.l;q32.3) (Fig. 3). High resolution banding indicated that all of the deleted 5p might not be on 14q. An 850 band resolution, however, did not identify any other rearranged chromosome in the complement.

This chromosomal aneuploidy may involve a candidate region conferring a genetic susceptibility to a schizophrenia syndrome. While the patient’s deceased brother had the same chromosomal aneuploidy and an aggressive behavioral disorder, his clinical course was dominated by a severe refrac-

195

tory epilepsy. Such a variation in the phenotype of a genetic diathesis, with a more benign course and presentation in females, a gender threshold effect, is seen in some neuropsychiatric syndromes, including Tourettes, attention deficit disorder with hyperactivity, and obsessive compulsive disorder. Likewise, his seizure disorder may have been etiologically distinct from his chromosomal abnormality. This chromosomal trisomy of 5 did not overlap with the segment previously described. The balanced carrier karyotype was, 46,XY,t(5: 14) (pl4.l;q32.3), possibly with some deleted 5~14. It is possible that there was a more complex rearrangement, although the 850 band resolution did not identify other rearranged chromosomes. Another possibility is that some of 5~14 was deleted in the ‘balanced translocation carrier’ and in the individuals with the partial trisomy. An individual has been described with a similar 5p partial deletion and a normal phenotype like this translocation parent (Overhauser et al., 1986). If this were the case here, it would lessen the extent of the trisomic area in R and T, perhaps explaining why they had fewer physical and distinct mental stigmata than other individuals that have been described with 5p trisomies (Schinzel, 1984). The association of schizophrenia and this chromosomal anomaly may exist by chance in this subject. The ascertainment of this family rested on our interest in cytogenetic anomalies associated with schizophrenia, and a coincidental relationship cannot be excluded. On the other hand, it may reflect involvement of a specific schizophrenia vulnerability gene, be a nonspecific manifestation of a cytogenetic abnormality or result from a distinct schizophrenia susceptibility gene that interacts with the chromosomal abnormality (a diathesisstressor model) to cause the schizophrenia syndrome. Many investigators had previously sought a schizophrenia locus on chromosome 5 (5ql1.25q 13.3) following a report of an uncle/nephew pair with that trisomy and schizophrenia (Bassett et al., 1988). As with our patient R, they lacked mental retardation, had minor physical anomalies and eye tracking dysfunction (Iacono, 1988). Of interest, all of these features are frequently found in schizophrenia. Using the trisomy 5q as a clue to a schizophrenia

susceptibility locus, Sherrington et al. (1988) claimed a genetic linkage for schizophrenia. This linkage has not been replicated, however, despite numerous investigations; (Kennedy et al., 1988; St. Clair et al., 1989; Detera-Wadleigh et al., 1989; Kaufmann et al., 1989; Aschauer et al., 1990). It is possible that another genetic vulnerability to schizophrenia was unmasked nonspecifically in these cases by chromosomal abnormalities. It is likely that a variety of epigenetic influences may interact with a genetic predisposition to schizophrenia, thereby permitting expression of the disorder (Gottesman and Shields, 1982). Presumably, alterations in brain function wrought by the chromosomal aneuploidy might operate in this fashion in R. The absence of any history of schizophrenia or related disorders in this rather extensive family would, nonetheless, suggest a sporadic form of schizophrenia. Given the relative rarity of chromosomal trisomies, the possibility of a causal relationship between this disorder and the chromosomal anomaly might be considered. In addition to a clinical diagnosis of schizophrenia, R demonstrated psychometric findings, smooth pursuit eye tracking dysfunction, minor physical anomalies, and soft neurological signs, all of which have been associated with schizophrenia. A parsimonious explanation for this cluster of findings is that they can all result from central nervous system developmental dysregulation arising during embryogenesis from the chromosomal aberration. Both the schizophrenia of R and the refractory seizures of T could be the result of specific and/or nonspecific CNS developmental dysregulation. While cytogenetic anomalies may direct the search for major genes underlying schizophrenia, their association to it may prove to be quite nonspecific, in the same way that such anomalies contribute nonspecifically to other complexes, multifactorial disorders like mental retardation. This explanation might also account for the wide variety of chromosomal aberrations that have been associated with the schizophrenia syndrome. Likewise, this may reflect the relatively high frequency of schizophrenia as compared to other genetic disorders which have been located by association with chromosome aberrations. It may be that the extent of the chromosomal aneuploidy contributes to a schizophrenia syn-

196

drome. Vast chromosomal abnormalities may lead to severe developmental abnormality and mental retardation, with smaller changes increasing the likelihood of psychotic and behavioral syndromes. Moreover, this would appear to be consistent with certain epidemiological similarities between schizophrenia and mental retardation (Hafner, 1988).

ACKNOWLEDGEMENTS This work was supported in part by NTMH Schizophrenia Academic Award K07MH00824 (D.M.) and Physician Scientist Award Kl 1MH00682 (C.A.K.), and by the W.M. Keck Foundation. The authors would like to thank Tiffany Mayr for her assistance in the preparation of this manuscript.

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