Cognitive profiles associated with the fra(X) syndrome in males and females

Twenty-three fragile X [fra(X)] males (mean IQ 50, mean age 10 years) and 11 fra(X) females (mean IQ 84, mean age 11.3 years) were administered the Stanford-Binet Intelligence Scale, 4th ed. (S-B). The cognitive profiles generated from the S-B indicated a pattern of subtest strengths and weaknesses that was similar for both groups. Consistent weaknesses in both groups were found in quantitative skills and short-term memory recall for visually presented, abstract stimuli, whereas a consistent strength was observed for short-term memory recall of visually presented, meaningful stimuli. Strengths in verbal labeling and comprehension and deficits in spatial visualization and visual-motor coordination were identified by the S-B for the male group but not for the female group. Fragility in the female group was negatively correlated with the S-B score for the short-term memory area and the combined S-B scores for the verbal reasoning and quantitative reasoning areas. The specific, S-B-identified cognitive strengths and weaknesses associated with the fra(X) condition are potentially useful indicators for investigation of specific cognitive process deficits associated with the fra(X) condition and the design of appropriate educational interventions for fra(X) children.     

Neuropsychological dysfunction among affected heterozygous fragile X females.

Fragile X (or Martin-Bell) syndrome is an X-linked disorder that often produces mental retardation in males, but usually affects heterozygous females to a lesser degree. Here we report the results of a brief neuropsychological examination of 20 heterozygous fra(x) girls and women and two control groups of 20 individuals each. One control group was composed of fra(x)-negative mothers (obligate carriers) and sisters of male probands with fra(x) syndrome, whereas the other was composed of 14 head-injured and six learning disabled women and girls. In addition to general intellectual impairment, several specific cognitive deficits were consistently found in individuals with the Martin-Bell syndrome, suggesting focal neuropsychological dysfunction. Significant differences were noted between fra(x) individuals and controls on most cognitive and neuropsychological measures studied. Over one-third of the fra(x) individuals demonstrated neuropsychological symptoms characteristic of the full developmental Gerstmann syndrome, whereas another third had three or four of the five signs of possible parietal lobe dysfunction. In our sample, there was an association between improved performance and increasing age. Differences among heterozygous individuals in number of focal symptoms may reflect some variability in the penetrance of the fra(x) gene, as well as in the functional organization of the brain.     

Neuropsychological dysfunction among affected heterozygous fragile X females

Fragile X (or Martin-Bell) syndrome is an X-linked disorder that often produces mental retardation in males, but usually affects heterozygous females to a lesser degree. Here we report the results of a brief neuropsychological examination of 20 heterozygous fra(x) girls and women and two control groups of 20 individuals each. One control group was composed of fra(x)-negative mothers (obligate carriers) and sisters of male probands with fra(x) syndrome, whereas the other was composed of 14 head-injured and six learning disabled women and girls. In addition to general intellectual impairment, several specific cognitive deficits were consistently found in individuals with the Martin-Bell syndrome, suggesting focal neuropsychological dysfunction. Significant differences were noted between fra(x) individuals and controls on most cognitive and neuropsychological measures studied. Over one-third of the fra(x) individuals demonstrated neuropsychological symptoms characteristic of the full developmental Gerstmann syndrome, whereas another third had three or four of the five signs of possible parietal lobe dysfunction. In our sample, there was an association between improved performance and increasing age. Differences among heterozygous individuals in number of focal symptoms may reflect some variability in the penetrance of the fra(x) gene, as well as in the functional organization of the brain.     

Mode of inheritance influences behavioral expression and molecular control of cognitive deficits in female carriers of the fragile X syndrome.

The effect of mode of inheritance on expression of fragile X syndrome [fra(X)] was investigated in nonretarded female carriers. Examination included cognitive and molecular measures. A priori predictions about cognitive impairment and size of an unstable region of DNA containing a CGG repeat on the X chromosome were tested in age and education matched heterozygotes grouped according to parental inheritance. Nine carriers with a maternal fra(X) chromosome, 11 carriers with a paternal fra(X) chromosome and 15 control mothers of children with non X-linked developmental disabilities were tested. Inheritance was established through DNA linkage analysis. Cognitive skills were assessed using the Wechsler Adult Intelligence Scale-Revised and the Benton Visual Retention Test. Molecular status was assessed by Southern blot analysis of genomic DNA digested with Eco RI and Eag I, and probed with StB 12.3. Results supported the inheritance models' predictions. Heterozygotes who inherited the fra(X) from their fathers appeared to be a homogeneous group. They were indistinguishable from controls on cognitive measures and all had genomic insertions of less than 500 base pairs. In contrast, heterozygotes who inherited the fra(X) chromosome from their mothers appeared to be made up of 2 sub-populations. They were as a group deficient in measures of attention and visual memory, but not other measures, with scores of some women consistently below the other subjects. Further, they had some members with greater than 500 base pair inserts.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cytogenetic guidelines for fragile X studies tested in routine practice.

Several organizations have proposed guidelines for fra(X) studies on peripheral blood lymphocytes. To evaluate these guidelines, we reviewed 1,033 consecutive specimens referred for fra(X) analysis. Each specimen was cultured with medium 199 and RPMI 1640 with 5-fluorodeoxyuridine or excess thymidine. The karyotype and expression of fra(X) were established from 20 GTL- or QFQ-banded cells and by screening of up to 130 more banded cells. We found anomalies other than fra(X) in 37 (3.6%) of the patients. We found 4% or more fra(X) cells in 38 (3.7%) cases from 36 unrelated families, including 33 (3.9%) of 850 males and 5 (2.7%) of 183 females. Another 4 females had 1 to 3% fra(X) cells. Six specimens were fra(X)-positive in only one stress system, and 32 were positive in 2 systems. To find the first 2 fra(X) cells in males, we needed to study up to 36 cells in 31 cases, 50 in one case, and 57 in another. To find the first 2 fra(X) cells in females, we needed to study up to 17 cells in 4 cases and 57 in another. A strong family history of fra(X) occurred in 5 patients, and each one was fra(X)-positive. Some manifestations of the fragile X syndrome occurred in 507 cases, 17 (3%) of which were fra(X)-positive. Abnormalities considered unlikely to be the fragile X syndrome occurred in 103 cases, 3 (3%) of which were fra(X)-positive. Use of chromosome breakage and fra(3)(p14) as quality control indicators of the fra(X) stress systems was found to be unreliable.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cytogenetic guidelines for fragile X studies tested in routine practice

Several organizations have proposed guidelines for fra(X) studies on peripheral blood lymphocytes. To evaluate these guidelines, we reviewed 1,033 consecutive specimens referred for fra(X) analysis. Each specimen was cultured with medium 199 and RPMI 1640 with 5-fluorodeoxyuridine or excess thymidine. The karyotype and expression of fra(X) were established from 20 GTL- or QFQ-banded cells and by screening of up to 130 more banded cells. We found anomalies other than fra(X) in 37 (3.6%) of the patients. We found 4% or more fra(X) cells in 38 (3.7%) cases from 36 unrelated families, including 33 (3.9%) of 850 males and 5 (2.7%) of 183 females. Another 4 females had 1 to 3% fra(X) cells. Six specimens were fra(X)-positive in only one stress system, and 32 were positive in 2 systems. To find the first 2 fra(X) cells in males, we needed to study up to 36 cells in 31 cases, 50 in one case, and 57 in another. To find the first 2 fra(X) cells in females, we needed to study up to 17 cells in 4 cases and 57 in another. A strong family history of fra(X) occurred in 5 patients, and each one was fra(X)-positive. Some manifestations of the fragile X syndrome occurred in 507 cases, 17 (3%) of which were fra(X)-positive. Abnormalities considered unlikely to be the fragile X syndrome occurred in 103 cases, 3 (3%) of which were fra(X)-positive. Use of chromosome breakage and fra(3)(p14) as quality control indicators of the fra(X) stress systems was found to be unreliable. Our findings support most of the proposed guidelines for fra(X) studies but indicate a need for modifications of others. © 1992 Wiley-Liss, Inc.     

Cognitive profiles and the spectrum of clinical manifestations in heterozygous fra (X) females

We investigated the possibility that fra(X) heterozygotes had a distinct or specific set of mental deficits ("cognitive profile") which would allow for accurate diagnosis. Wechsler Intelligence Scale for Children-Revised (WISC-R) subtest scores obtained on 8 fra(X) school age girls were compared with similar scores obtained on 8 "learning-disabled" non fra(X) girls matched on the basis of Full Scale IQ (FSIQ). The Block Design subtest score was significantly lower in fra(X) girls. In a larger sample of 22 fra(X) females, a characteristic combination of low Arithmetic, Digit Span, and Block Design subtest scores was observed. The mean discrepancy between these 3 subtest scores from the total Verbal or Performance subtest means was significant for the fra(X) group but not for a comparison group of 20 learning-disabled females. Verbal IQ (VIQ) and Performance IQ (PIQ) discrepancy was not significant in fra(X) females. Percent fra(X) positive cells was negatively correlated with VIQ and FSIQ but not with PIQ.     

Learning styles of LD and NLD ADHD children.

Attention Deficit Hyperactive Disorder (ADHD) children (N = 26) with a learning disability (LD) and without (NLD) were compared on measures of information processing using the Learning Efficiency Test (LET). Method of presentation (visual vs. auditory), order of recall (ordered vs. non-ordered), and memory processes (immediate, short-term, and long-term) were assessed. While both groups showed more difficulty with short-term and long-term memory processes than with immediate memory processes, the ADHD-LD subjects demonstrated more difficulty processing information effectively. Ordered recall was significantly more difficult for both short-term and long-term memory processes than was unordered recall. While both groups demonstrated difficulty with auditory ordered recall under short-term and long-term conditions, the ADHD-LD subjects lost the most information under auditory conditions.     

Preliminary data on the effect of culture on the assessment of Alzheimer's disease-related verbal memory impairment with the International Shopping List Test

The International Shopping List Test (ISLT) is a measure of verbal learning and memory, developed specifically for use in people from different cultural and linguistic backgrounds. In this report, we describe two studies that examined the ISLT's ability to detect memory impairment and memory decline in patients with mild Alzheimer's disease (AD) from a range of cultural and linguistic backgrounds. In Study 1, the performance of Australian-English-speaking adults with mild AD was compared with that of native Australian-English- and Korean-speaking patients with mild AD. Compared with controls, patients with AD from both language groups showed large but equivalent impairments in total recall, delayed recall, rate of learning, and primacy and retention-weighted recall (RWR) measures on the ISLT. In Study 2, the rate of deterioration in verbal memory over 1 year was examined in groups of native Canadian-English, French, and Korean speakers with mild AD using the total recall, delayed recall, and RWR measures. Rates of change on all three measures were equivalent across the language groups, although the magnitude of deterioration was most pronounced for the total recall and RWR measures. Taken together, these results suggest that the ISLT is valid and reliable for the assessment of verbal learning and memory impairment and decline in patients with mild AD from diverse language groups.     

Retrieval Processes in Adults With ADHD: A RAVLT Study

Attention-deficit hyperactivity disorder (ADHD) is associated with memory deficiencies. In the current study we compared different aspects of verbal memory using standard and constructed measures of the Rey auditory verbal learning test (RAVLT). Performance on learning and recognition measures of RAVLT was similar in both ADHD and control groups. In contrast, adults with ADHD committed more double recalls and intrusion errors, indicating inaccurate recall processes. These findings suggest that memory problems in adults with ADHD may be caused by deficient executive processes that support retrieval from memory.     

Retrieval processes in adults with ADHD: a RAVLT study

Attention-deficit hyperactivity disorder (ADHD) is associated with memory deficiencies. In the current study we compared different aspects of verbal memory using standard and constructed measures of the Rey auditory verbal learning test (RAVLT). Performance on learning and recognition measures of RAVLT was similar in both ADHD and control groups. In contrast, adults with ADHD committed more double recalls and intrusion errors, indicating inaccurate recall processes. These findings suggest that memory problems in adults with ADHD may be caused by deficient executive processes that support retrieval from memory.     

Prenatal diagnosis of fragile X syndrome: results from parallel molecular and cytogenetic studies.

Since 1985, we have provided coordinated DNA-based and cytogenetic prenatal analysis for couples at risk for offspring afflicted with the fragile X [fra(X)] syndrome. To date, 40 pregnancies have been studied (22 males, 18 females). There were 5 males and 3 females identified to be at high risk by DNA but only 2 males and one female were demonstrated to be cytogenetically expressing the fra(X) prenatally. Of the other 3 males, one was a cytogenetic false negative (i.e. confirmed fra(X)+ at termination of pregnancy). The other 2 remain fra(X)- and are developing normally (undetected recombinants or non-penetrant male carriers). All fetuses at low risk were carried to term and are reported to be normal.     

Genuine memory deficits in dementia

Controlled learning with effective cued recall is needed to distinguish between genuine memory deficits due to impairment of specific memory processes and apparent memory deficits due to impairment of other cognitive processes, such as attention, that can limit memory. Effective cued recall is needed for accurate measurement of memory in the elderly because cued recall reveals learning not shown by free recall. When a search procedure was used to control processing for effective encoding and cued recall, nondemented elderly adults recalled all or nearly all 16 items on each trial. Decreased recall by demented patients even after they carried out the same effective processing showed genuine memory impairment that was not due to other cognitive deficits. Cued recall was better than either free recall or recognition in discriminating elderly persons with dementia from those without dementia and by itself accounted for 75 % of the variation in dementia status. Cued recall was especially useful for identifying patients with mild to moderate dementia who were not identified by free recall. It is proposed that elderly persons who have decreased cued recall of a 16‐item list after controlled learning have genuine memory impairment and therefore are likely to be demented because other causes of amnestic syndromes are relatively infrequent in the aged. Controlled learning with effective cued recall should be useful for screening of elderly persons for dementia.     

Autosomal suppressor gene for fragile-X: an hypothesis

We suggest the existence of an autosomal suppressor gene, S, which is fairly common in the general population and acts to inhibit expression of the fra(X) gene, F. The suppression is effective in males who are hemizygous for F only if they are homozygous for S, while it is effective in females who are heterozygous for F if they are at least heterozygous for S. Thus, the fra(X) phenotype is not expressed in genotypes F-SS,FfSS, FfSs, while it is expressed in genotypes F-Ss, F-ss, Ffss. With a frequency of SS in the general population of approximately 20%, this hypothesis can explain the observed penetrance of about 80% in F- males and about 30% in Ff females. It can also explain the very low frequency of fra(X) expression in Ff females who are daughters or mothers of non-penetrant F- males, and a lower penetrance in siblings of non-penetrant F- males than in grandsons of these males. The model is in good quantitative agreement with other unique characteristics of fra(X) inheritance.     

Cognitive functioning and information processing of adult mentally retarded men with fragile-X syndrome

The present study describes cognitive skills and information processing strategies of mentally retarded fra(X) men. Fifty-eight fra(X) positive and 58 fra(X) negative adults, matched on sex, chronological age, length of institu-tionalisation, general cognitive level, and living conditions, were evaluated with the Bayley or McCarthy Scales of Mental Abilities. Mental ages were mostly situated in the severe mental handicap category and were found to be negatively influenced by chronological age. A relative strength in perceptual performance and non-verbal reasoning and a deficit in sequential information processing turned out to be typical of all mentally retarded subjects, irrespective of fra(X) or control status. Fra(X) adults could be significantly differentiated from control persons on the ground of a higher level of acquired knowledge because of better vocabulary and verbal-expressive skills. On the other hand, they were less able to imitate non-verbal patterns, had more difficulty with visual-motor integration and co-ordination, and applied less efficient general mental processing skills in solving new problems. The memory profile of fra(X) adults was strongly determined by the meaning and the complexity of the information that has to be reproduced. In this article the profile of cognitive strengths and weaknesses in the fra(X) group will be discussed and some general advice for training is suggested. © 1994 Wiley-Liss, Inc.     

What is associated with the fragile X syndrome?

In addition to mental retardation (MR), fragile X [fra(X)] syndrome has been associated with a variety of other disorders. Despite earlier reports, it has been shown that MR fra(X) males are at no greater risk for autism than is any MR male. Therefore, studies in which fra(X) has been associated with behavioral, developmental, and psychopathological disabilities were examined to determine whether fra(X) individuals were at an increased risk for these dysfunctions as well. Psychiatric disorders among fra(X) individuals were found not to occur more frequently than in other individuals with cognitive deficits. It was also observed that hyperactivity and attention deficit disorder among MR fra(X) individuals do not occur more frequently than in other MR individuals. Pooled results from studies of cognitive profiles used to characterize fra(X) phenotypes also indicated that there are no consistent patterns in either males or females. Plausible explanations for a variable phenotype include allelic heterogeneity and pleitropy. © 1993 Wiley-Liss, Inc.     

A. Donald Merritt,M.D.

Mental retardation has been associated with fra(X) but comprehensive psychological evaluation has rarely been applied to 2 major behavioral questions 1) the extent of individual variation in IQ among fra(X) males and the possibility of some fra(X) males being of normal IQ; and 2) whether there is a depression in general IQ or whether specific abilities are impaired. The problems of developing an effective battery of tests for assessing fra(X) are discussed. These questions were examined in 54 individuals, comprising fra(X) males, their obligate carrier mothers and those sisters shown to have the fra(X). Among noninstitutionalised males nonverbal IQ as measured on a Block Design test ranged from 100 to 0, and vocabulary scores while generally higher, ranged from 79–33. The males scored low on a digit span memory task, while performance on a memory of objects task was adequate. Despite lower overall scores, a similar pattern and variability emerged in institutionalised males. Daughters were extremely variable in performance and the mothers performed much better, supporting the view that women who have children are a selected subset of fra(X) syndrome individuals. The performance of one male is discussed in detail. His vocabulary and nonverbal IQ scores were normal, despite his having other specific cognitive deficits. The pattern of abilities and behavior seen in fra(X) may result in an overestimation of intelligence and underestimation of penetrance when based on clinical impressions rather than formal psychological assessment. The implications of this for molecular and for population genetic approaches to fra(X) are discussed.     

Individual variation and specific cognitive deficits in the fra(X) syndrome

Mental retardation has been associated with fra(X) but comprehensive psychological evaluation has rarely been applied to 2 major behavioral questions 1) the extent of individual variation in IQ among fra(X) males and the possibility of some fra(X) males being of normal IQ; and 2) whether there is a depression in general IQ or whether specific abilities are impaired. The problems of developing an effective battery of tests for assessing fra(X) are discussed. These questions were examined in 54 individuals, comprising fra(X) males, their obligate carrier mothers and those sisters shown to have the fra(X). Among noninstitutionalised males nonverbal IQ as measured on a Block Design test ranged from 100 to 0, and vocabulary scores while generally higher, ranged from 79-33. The males scored low on a digit span memory task, while performance on a memory of objects task was adequate. Despite lower overall scores, a similar pattern and variability emerged in institutionalised males. Daughters were extremely variable in performance and the mothers performed much better, supporting the view that women who have children are a selected subset of fra(X) syndrome individuals. The performance of one male is discussed in detail. His vocabulary and nonverbal IQ scores were normal, despite his having other specific cognitive deficits. The pattern of abilities and behavior seen in fra(X) may result in an overestimation of intelligence and underestimation of penetrance when based on clinical impressions rather than formal psychological assessment. The implications of this for molecular and for population genetic approaches to fra(X) are discussed.     

Prevalence of fra(X) and other specific diagnoses in autistic individuals in a Danish county

In a Danish county (the island of Funen) cytogenetic screening for fragile X [fra(X)] of 32 autistic individuals aged 0-23 years showed a prevalence of 2/20 among boys and 0/12 among girls. In both cases additional fra(X) positive relatives were found. In 3 patients other chromosome aberrations were demonstrated and in one female Rett syndrome was diagnosed, initially suspected from observations of her behavior on videotapes. The presence of an underlying cause of autism in 6/32, of the patient group encourages an active search for a specific diagnosis among autistic males and females. Future screening of autistic individuals should include 1) fra(X) search also in females, 2) search for other chromosomal disorders, and 3) observation of behavior, in order to diagnose, i.e., Rett syndrome.     

Short-term memory and cognitive variability in adult fragile X females

We investigated the possibility that adult fragile X [fra(X)] heterozygotes have a distinct or specific cognitive profile, with a particular focus on visuospatial and/or memory deficits. With a sample of 13 adult fra(X) female carriers (2 fra(X) positive) and age-matched control women, we performed 2 tests: Wechsler Adult Intelligence Scale-Revised (WAIS-R) and the Revised Visual Retention Test (RVRT). An identifiable cognitive profile was not evident in the study group, but significant differences were evident in RVRT performance in number correct and number of errors when compared to controls and normative data. The combination of the WAIS-R and RVRT data suggests that the short-term memory component of the tasks may be of more significance than visuospatial performance in the deficits observed.