@xx 3Y3? %I 53.00 + 0.00 Perpamon Press plc
NEUROPSYCHOLOGICAL DIMENSIONS OF THE FRAGILE X SYNDROME: SUPPORT FOR A NON-DOMINANT HEMISPHERE DYSFUNCTION HYPOTHESIS SIMONF. CROWE and DAVID A. HAY* Department
of Psychology.
LaTrobe
University,
Bundoora.
Victoria.
Australia.
3083
(Receired 26 January 1988: accepted 9 June 1989) study contends that males with the fragile X syndrome feature problems in the visuospatial sphere as compared with Down syndrome males matched on vocabulary ability. Fragile X males suffer impairments of constructional functions, as demonstrated by their poor performance on block construction tests and on drawing tasks. These problemsexist in association with visuoperceptive impairments. including the inability to reliably estimate angular relationships (Judgement of Line Orientation). They have shortened Digit and Corsi spans, and may feature some deficits in left hand co-ordination. The observation of a pervasive non-verbal deficit may also apply to carrier females, who despite functioning at an overall higher level, feature a similar pattern of deficits. It is possible that the deficit in non-dominant hemisphere functioning may be a pathognomonic feature of the chromosomal abnormality.
Abstract--This
INTRODUCTION A CONSIDERABLE literature has developed on the fragile X syndrome since the establishment of reliable conditions for the detection of the chromosomal stigmata [23]. The condition is characterized by a constriction (or fragile site) on the long arm of the X chromosome. Clinical features of the syndrome may include: macro-orchidism, large or prominent ears, elongated face, poor eye contact, hyperactivity, hand-biting, autism, hyper-extensible finger joints and mitral valve prolapse [16]. Estimates of the incidence of the syndrome vary with sampling methods. Extensive population surveys such as that of special schools and intellectual disability services in Sydney, Australia [26] estimates the incidence to be one per 2610 males and one per 2441 females. This makes the syndrome the most prevalent form of mental retardation of known aetiology after Down syndrome. The syndrome has been observed in many racial groups including American blacks, orientals, Sri Lankans, hispanics, Zulus, Australian aborigines and Hawaiians [7]. Behaviourally, the boys are generally passive, friendly and compliant [lo], although significant behavioural disturbance has been observed [13]. The retardation is usually of moderate degree but may vary from severe to mild. Some suggestion has been made that abilities may even extend into the normal range [4, 16,241, but this matter is as yet unresolved. *To whom correspondence
should
be addressed 9
10
SIMON F. CROWEand DAVID A. HAY
The most consistent cognitive feature so far reported with the syndrome is its effect on language processing. A number of researchers have reported delays in speech development [3,6,25]. Other observations include descriptions of verbal apraxia, lower performance in expressive as compared to receptive skills, dysfluencies and developmental delays in articulation [ 193. A generalized language disability has also been reported in this group [9]. with particular weaknesses in the areas of auditory reception, auditory sequential memory, visual closure and grammatic closure as assessed by the Illinois Test of Psycholinguistic Ability (ITPA). Although the observation of verbal disability is a common one, it is not universal [S]. A possible explanation of the language problems observed in this group has been proposed [12]. The consistent observation of better performance on simultaneous processing tasks as compared to sequential processing tasks on the Kaufman Assessment Battery for Children may reliably discriminate fragile X males from other learning disabled or intellectually disabled individuals. Less emphasis has as yet been placed on the non-verbal skills of the fragile X. One series of studies [15, 16,241 emphasized that many fragile X males and carrier females are more impaired on their performance of the non-verbal Block Design sub-test of the British Ability Scaies than on the Peabody Picture Vocabulary test (revised; PPVT-R). Fragile X males perform similarly on the PPVT and the Stanford Binet, despite the difference in what the two tests measure [19], and much better on these tests which are commonly considered to be strongly verbally weighted, than on the non-verbal Leiter Scales. Females with a single fragile X chromosome display a quite distinct neuropsychological profile. On the WISC-R these girls score lower than a control group of “learning-disabled”, non-fragile X girls on the Block Design, Digit Span and Arithmetic sub-tests of the scale [ 1I]. There are also reports [7, 181 of attentional difficulties, memory deficits and visuo-motor coordination problems in both retarded and non-retarded heterozygotes, in addition to the lowered sub-test scores on Arithmetic and Block Design. These observations may have common features with the suggestion [21] that there is a group within the learning-disabled population which feature: (1) well-developed “automatic” or over-learned auditory perceptual and verbal skills, (2) impaired visual-perceptualorganizational skills, (3) impaired tactile-perceptual abilities, more so on the left side of the body, (4) impaired psychomotor abilities, more so on the left side of the body; and (5) impaired non-verbal concept formation and related abilities. This group has been called nonverbal learning-disabled, and it has been suggested that their problem may be localized to the non-dominant hemisphere. Carrier females, who are only heterozygous for the fragile X marker, appear to show a spatial processing deficit more consistently than boys with the fragile X syndrome. The present study examines whether fragile X males display significantly poorer performance than control subjects on tests commonly considered to be indices of visuospatial skills. The study extends the Australian observation of non-verbal deficts [ 15, 16,241, to characterize more precisely the problems encountered by these individuals in the visuospatial sphere. The control subjects chosen for this study are Down syndrome individuals since: (1) the two groups feature a similarly chronic affliction, (2) Down are a group consistently reported not to show deficits in non-verbal processing [22], and (3) by incidence the two groups represent the first and second most common causes of intellectual disability of known aetiology. Thus any major differences observed should have an impact in the delivery of services to the two groups.
NEL’ROPSYC-HOLOGY
OF FRAGILE X
11
METHOD Su&cls Eight fragile X males. whose fragile X status was determined by karyotyping at the Royal Children’s Hospital in Melbourne. Australia [29]. were included in the study. The age range of the fragile X group was from 15 years 3 months to 28 years 8 months. and the mean was 22 years (SD =4.06). Testable individuals only were chosen to avoid floor effects on the psychometric instruments used. Testable was defined by the subject being able to complete the first two items of the PPVT-R and the WPPSI Block Designs, and the ability to maintain interaction with the experimenter during this time. The sample had a mean age equivalent score of 8 years 7 months (SD 3.05) on the PPVT-R (Form M) and a range from 4 years to 12 years 8 months. These subjects were drawn from a larger population of 44 fragile X males who had a mean age equivalent of 6 years 8 months (SD 3.08). The control group consisted of eight Down syndrome males matched on mental and chronological age. This group had a mean chronological age of 23 years 8 months (SD 6.78) and a range from I6 years 4 months to 38 years 3 months. The group had a mean age equivalent of7 years 1 month (SD 2.07) on the PPVT-R, with a range from 4 years 5 months to IO years I month. Using the same criteria these subjects were drawn from a larger sample of 75 Down syndrome subjects, who had a mean PPVT-R age equivalent of 5 years 2 months (SD 2.39). All subjects were right-handed as determined by a brief questionnaire of hand use conducted with the principle care-giver. In any case where a close match on chronological or mental age was not possible. the latter was used as the priority matching variable. All subjects were screened for alternative causes of neurological dysfunction. A number of the fragile X group had experienced birth difficulties, but it is impossible to determine if this has transpired as a consequence of the disorder itself. Apparatus The neuropsychological tests chosen were selected on the basis of both clinical experience and from the relevant literature. Tests believed to depend primarily on adequate left hemisphere or right hemisphere functioning were chosen to reflect a range of performance measures within the capacity of the subject group. While the tests are described as sensitive to specific hemispheric dyfunction, performance on a particular test may still be adversely affected by disruption in many areas of the brain. All tests employed in this study are standard neuropsychological measures, discussed fully in [I. 141. They were: (1) PPVT-R; (2) Judgement of Line Orientation; (3) Visual Achievement Forms from the Purdue Peceptual Motor Survey [ZO]; (4) Goodenough and Harris Draw a Person Test; (5) Corsi and Digit Span and Supraspan Learning; (6) Purdue Pegboard; (7) The Token Test and (8) The Leiter International Performance Scales. Only the supraspan procedure may be unfamiliar. The Digit Span test was adapted from the Wechsler Memory Scale, with the addition of two and three digit numbers to the digits forward format. Digits backwards proved beyond the ability of most subjects. After the span of these subjects had been determined, the number of trials required for the subjects to learn one item over span (supraspan) was assessed. This provided an index of the learning potential of these subjects in the verbal (Digit Supraspan) and the non-verbal (Corsi Supraspan) domains. The testing follows a similar format to that recommended by [l J, only with fewer digits due to the foreshortened memory spans of the subjects. Each subject had 25 trials with the supraspan sequence. If the subject achieved criterion (a single error free performance) before the 25th trial. the number of trials was deducted from 25 and the resultant figure was used in the data analysis. Procedure To minimize test anxiety from unfamiliar environments. all individuals were tested in their homes. with the exception of two who were tested in their residential institution. The PPVT-R had been administered on a previous occasion in the course of screening all subjects. The remainder of the tests were presented in the order in which they are listed above. The reasons for this order of presentation was purely the practical one of varying task demands to maintain interest and attention for the entire period of the assessment. The testing session went for approx 1: hr with a brief (15 min) break in the middle.
RESULTS To compare performances on each of the visuo-motor, and right and left hemisphere test batteries, three matched group Hotellings T2 tests were conducted, followed by comparable univariate analyses of variance oneach test. While the hazards ofmultiple univariate tests are well appreciated, the available procedures for correcting for this were not used here because of the often high correlations among tests within each of the batteries. The univariate tests should therefore be interpreted conservatively. Throughout the analyses raw scores were used unless scaled score equivalents were
12
SIMON F. CROWE and DAVID A. HAY
available as for example with the PPVT-R and the Leiter Scales. The means of both groups on the 12 tests are presented in Table 1. Right hemisphere functioning
The first comparison between the Down syndrome and fragile X groups was on tests generally regarded [14] to be sensitive to right hemisphere dysfunction. These were: Leiter International Performance Scales, Judgement of Line Orientation, the Visual Achievement Forms, Draw a Person test, and Corsi Span and Corsi Supraspan Learning. The correlation of each of the other right hemisphere tests with the Leiter was consistently higher for the Down group (mean r = 0.53, df= 6) than for the fragile X group (mean r = 0.09, df= 6). but given the small sample sizes, neither the correlations, nor the Down-fragile X differences in correlations were significant. A significant overall difference was found between the two groups (T’ = 158.26, F= 52.75, df= 6,2, P < 0.05) with the fragile X group performing below the Down syndrome group on all comparisons. A one-tailed test of significance was employed for the right hemisphere battery univariate tests as the direction of the effect was predicted. The analysis was repeated, covarying for the PPVT-R on which the initial matching was partly based. This increased the significance of the group differences (T’=411.35, F= 137.12, df=6, 2, .P
NEUROPSYCHOLOGICAL DIMENSIONS OF THE FRAGILE X SYNDROME: SUPPORT FOR A NON-DOMINANT HEMISPHERE DYSFUNCTION HYPOTHESIS SIMONF. CROWE and DAVID A. HAY* Department
of Psychology.
LaTrobe
University,
Bundoora.
Victoria.
Australia.
3083
(Receired 26 January 1988: accepted 9 June 1989) study contends that males with the fragile X syndrome feature problems in the visuospatial sphere as compared with Down syndrome males matched on vocabulary ability. Fragile X males suffer impairments of constructional functions, as demonstrated by their poor performance on block construction tests and on drawing tasks. These problemsexist in association with visuoperceptive impairments. including the inability to reliably estimate angular relationships (Judgement of Line Orientation). They have shortened Digit and Corsi spans, and may feature some deficits in left hand co-ordination. The observation of a pervasive non-verbal deficit may also apply to carrier females, who despite functioning at an overall higher level, feature a similar pattern of deficits. It is possible that the deficit in non-dominant hemisphere functioning may be a pathognomonic feature of the chromosomal abnormality.
Abstract--This
INTRODUCTION A CONSIDERABLE literature has developed on the fragile X syndrome since the establishment of reliable conditions for the detection of the chromosomal stigmata [23]. The condition is characterized by a constriction (or fragile site) on the long arm of the X chromosome. Clinical features of the syndrome may include: macro-orchidism, large or prominent ears, elongated face, poor eye contact, hyperactivity, hand-biting, autism, hyper-extensible finger joints and mitral valve prolapse [16]. Estimates of the incidence of the syndrome vary with sampling methods. Extensive population surveys such as that of special schools and intellectual disability services in Sydney, Australia [26] estimates the incidence to be one per 2610 males and one per 2441 females. This makes the syndrome the most prevalent form of mental retardation of known aetiology after Down syndrome. The syndrome has been observed in many racial groups including American blacks, orientals, Sri Lankans, hispanics, Zulus, Australian aborigines and Hawaiians [7]. Behaviourally, the boys are generally passive, friendly and compliant [lo], although significant behavioural disturbance has been observed [13]. The retardation is usually of moderate degree but may vary from severe to mild. Some suggestion has been made that abilities may even extend into the normal range [4, 16,241, but this matter is as yet unresolved. *To whom correspondence
should
be addressed 9
10
SIMON F. CROWEand DAVID A. HAY
The most consistent cognitive feature so far reported with the syndrome is its effect on language processing. A number of researchers have reported delays in speech development [3,6,25]. Other observations include descriptions of verbal apraxia, lower performance in expressive as compared to receptive skills, dysfluencies and developmental delays in articulation [ 193. A generalized language disability has also been reported in this group [9]. with particular weaknesses in the areas of auditory reception, auditory sequential memory, visual closure and grammatic closure as assessed by the Illinois Test of Psycholinguistic Ability (ITPA). Although the observation of verbal disability is a common one, it is not universal [S]. A possible explanation of the language problems observed in this group has been proposed [12]. The consistent observation of better performance on simultaneous processing tasks as compared to sequential processing tasks on the Kaufman Assessment Battery for Children may reliably discriminate fragile X males from other learning disabled or intellectually disabled individuals. Less emphasis has as yet been placed on the non-verbal skills of the fragile X. One series of studies [15, 16,241 emphasized that many fragile X males and carrier females are more impaired on their performance of the non-verbal Block Design sub-test of the British Ability Scaies than on the Peabody Picture Vocabulary test (revised; PPVT-R). Fragile X males perform similarly on the PPVT and the Stanford Binet, despite the difference in what the two tests measure [19], and much better on these tests which are commonly considered to be strongly verbally weighted, than on the non-verbal Leiter Scales. Females with a single fragile X chromosome display a quite distinct neuropsychological profile. On the WISC-R these girls score lower than a control group of “learning-disabled”, non-fragile X girls on the Block Design, Digit Span and Arithmetic sub-tests of the scale [ 1I]. There are also reports [7, 181 of attentional difficulties, memory deficits and visuo-motor coordination problems in both retarded and non-retarded heterozygotes, in addition to the lowered sub-test scores on Arithmetic and Block Design. These observations may have common features with the suggestion [21] that there is a group within the learning-disabled population which feature: (1) well-developed “automatic” or over-learned auditory perceptual and verbal skills, (2) impaired visual-perceptualorganizational skills, (3) impaired tactile-perceptual abilities, more so on the left side of the body, (4) impaired psychomotor abilities, more so on the left side of the body; and (5) impaired non-verbal concept formation and related abilities. This group has been called nonverbal learning-disabled, and it has been suggested that their problem may be localized to the non-dominant hemisphere. Carrier females, who are only heterozygous for the fragile X marker, appear to show a spatial processing deficit more consistently than boys with the fragile X syndrome. The present study examines whether fragile X males display significantly poorer performance than control subjects on tests commonly considered to be indices of visuospatial skills. The study extends the Australian observation of non-verbal deficts [ 15, 16,241, to characterize more precisely the problems encountered by these individuals in the visuospatial sphere. The control subjects chosen for this study are Down syndrome individuals since: (1) the two groups feature a similarly chronic affliction, (2) Down are a group consistently reported not to show deficits in non-verbal processing [22], and (3) by incidence the two groups represent the first and second most common causes of intellectual disability of known aetiology. Thus any major differences observed should have an impact in the delivery of services to the two groups.
NEL’ROPSYC-HOLOGY
OF FRAGILE X
11
METHOD Su&cls Eight fragile X males. whose fragile X status was determined by karyotyping at the Royal Children’s Hospital in Melbourne. Australia [29]. were included in the study. The age range of the fragile X group was from 15 years 3 months to 28 years 8 months. and the mean was 22 years (SD =4.06). Testable individuals only were chosen to avoid floor effects on the psychometric instruments used. Testable was defined by the subject being able to complete the first two items of the PPVT-R and the WPPSI Block Designs, and the ability to maintain interaction with the experimenter during this time. The sample had a mean age equivalent score of 8 years 7 months (SD 3.05) on the PPVT-R (Form M) and a range from 4 years to 12 years 8 months. These subjects were drawn from a larger population of 44 fragile X males who had a mean age equivalent of 6 years 8 months (SD 3.08). The control group consisted of eight Down syndrome males matched on mental and chronological age. This group had a mean chronological age of 23 years 8 months (SD 6.78) and a range from I6 years 4 months to 38 years 3 months. The group had a mean age equivalent of7 years 1 month (SD 2.07) on the PPVT-R, with a range from 4 years 5 months to IO years I month. Using the same criteria these subjects were drawn from a larger sample of 75 Down syndrome subjects, who had a mean PPVT-R age equivalent of 5 years 2 months (SD 2.39). All subjects were right-handed as determined by a brief questionnaire of hand use conducted with the principle care-giver. In any case where a close match on chronological or mental age was not possible. the latter was used as the priority matching variable. All subjects were screened for alternative causes of neurological dysfunction. A number of the fragile X group had experienced birth difficulties, but it is impossible to determine if this has transpired as a consequence of the disorder itself. Apparatus The neuropsychological tests chosen were selected on the basis of both clinical experience and from the relevant literature. Tests believed to depend primarily on adequate left hemisphere or right hemisphere functioning were chosen to reflect a range of performance measures within the capacity of the subject group. While the tests are described as sensitive to specific hemispheric dyfunction, performance on a particular test may still be adversely affected by disruption in many areas of the brain. All tests employed in this study are standard neuropsychological measures, discussed fully in [I. 141. They were: (1) PPVT-R; (2) Judgement of Line Orientation; (3) Visual Achievement Forms from the Purdue Peceptual Motor Survey [ZO]; (4) Goodenough and Harris Draw a Person Test; (5) Corsi and Digit Span and Supraspan Learning; (6) Purdue Pegboard; (7) The Token Test and (8) The Leiter International Performance Scales. Only the supraspan procedure may be unfamiliar. The Digit Span test was adapted from the Wechsler Memory Scale, with the addition of two and three digit numbers to the digits forward format. Digits backwards proved beyond the ability of most subjects. After the span of these subjects had been determined, the number of trials required for the subjects to learn one item over span (supraspan) was assessed. This provided an index of the learning potential of these subjects in the verbal (Digit Supraspan) and the non-verbal (Corsi Supraspan) domains. The testing follows a similar format to that recommended by [l J, only with fewer digits due to the foreshortened memory spans of the subjects. Each subject had 25 trials with the supraspan sequence. If the subject achieved criterion (a single error free performance) before the 25th trial. the number of trials was deducted from 25 and the resultant figure was used in the data analysis. Procedure To minimize test anxiety from unfamiliar environments. all individuals were tested in their homes. with the exception of two who were tested in their residential institution. The PPVT-R had been administered on a previous occasion in the course of screening all subjects. The remainder of the tests were presented in the order in which they are listed above. The reasons for this order of presentation was purely the practical one of varying task demands to maintain interest and attention for the entire period of the assessment. The testing session went for approx 1: hr with a brief (15 min) break in the middle.
RESULTS To compare performances on each of the visuo-motor, and right and left hemisphere test batteries, three matched group Hotellings T2 tests were conducted, followed by comparable univariate analyses of variance oneach test. While the hazards ofmultiple univariate tests are well appreciated, the available procedures for correcting for this were not used here because of the often high correlations among tests within each of the batteries. The univariate tests should therefore be interpreted conservatively. Throughout the analyses raw scores were used unless scaled score equivalents were
12
SIMON F. CROWE and DAVID A. HAY
available as for example with the PPVT-R and the Leiter Scales. The means of both groups on the 12 tests are presented in Table 1. Right hemisphere functioning
The first comparison between the Down syndrome and fragile X groups was on tests generally regarded [14] to be sensitive to right hemisphere dysfunction. These were: Leiter International Performance Scales, Judgement of Line Orientation, the Visual Achievement Forms, Draw a Person test, and Corsi Span and Corsi Supraspan Learning. The correlation of each of the other right hemisphere tests with the Leiter was consistently higher for the Down group (mean r = 0.53, df= 6) than for the fragile X group (mean r = 0.09, df= 6). but given the small sample sizes, neither the correlations, nor the Down-fragile X differences in correlations were significant. A significant overall difference was found between the two groups (T’ = 158.26, F= 52.75, df= 6,2, P < 0.05) with the fragile X group performing below the Down syndrome group on all comparisons. A one-tailed test of significance was employed for the right hemisphere battery univariate tests as the direction of the effect was predicted. The analysis was repeated, covarying for the PPVT-R on which the initial matching was partly based. This increased the significance of the group differences (T’=411.35, F= 137.12, df=6, 2, .P
