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G S Fisch

Publications and source records attributed to G S Fisch.

At least 37 records · Page 2Linked to original sources
PubMed1994

Longitudinal changes in IQ among fragile X females: a preliminary multicenter analysis.

Longitudinal declines in IQ among fragile X [fra(X)] males have been reported previously by several investigators. Remarkably little is known about longitudinal changes in IQ scores among fra(X) females. Previously, one cross-sectional study showed a significant negative correlation between age and IQ scores. However, a recent investigation of girls with fra(X) syndrome noted longitudinal increases in IQ scores in 8 of 11 individuals. Therefore, the purpose of this preliminary multicenter study was to determine: (1) the characteristics of longitudinal changes in IQ among fra(X) females; and (2) whether these changes were comparable to those which have been observed among fra(X) males. IQ test and retest scores for 11 fra(X) females were obtained from 3 centers: Greenwood, South Carolina; Ibaraki, Japan; and Leuven, Belgium. To ensure high reliability, only test-retest scores from the Wechsler and Stanford-Binet tests were used. Age of subjects at initial testing ranged from 5 to 35 years. Mean intertest interval was 4.5 years. In contrast to a report of longitudinal increases, we found 9/11 (82%) subjects demonstrated decreases in IQ scores. Mean decline was 9 points. Females over 18 years of age showed little or no change in IQ scores. Decreases in scores appeared to be related to initial IQ score. Females in the earlier longitudinal report were higher functioning than those in our study, which may account for the observed difference in direction of change; or, change in IQ score may be related to size of the fra(X) mutation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Asymmetry of methylation with FMR-1 full mutation in two 45,X/46,XX mosaic females associated with normal intellect.

The full FMR-1 mutation is known to cause the fragile X syndrome [Fra(X)], but variable expression in females, including normal to deficient intellect, may be related to random X-inactivation (lyonization). We have evaluated 2 mosaic 45,X/46,XX females who are cytogenetically fra(X) positive, have an FMR-1 full mutation, and are of normal intellect. There were 50% fra(X) chromosomes in the 45,X cells of one of the females; this has not been reported previously. In both patients, there was a strong asymmetry of FMR-1 methylation with the normal allele being totally or 90% unmethylated and the mutant allele being similarly methylated. Thus, the apparent selective inactivation of the full mutant FMR-1 allele appears to have resulted in limited expression with normal intellect. The presence of the fra(X) chromosome in 45,X cells is unique; however, there may be no relationship to the asymmetric inactivation of the mutant allele which could be due to chance or a mechanism yet to be delineated.

Adolescent↗
PubMed1993

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.

Attention Deficit Disorder with Hyperactivity↗
PubMed1988

Social gaze, social avoidance, and repetitive behavior in fragile X males: a controlled study.

Preference for social gaze as well as the percentage occurrence of social gaze, nonverbal social avoidance, and nonverbal repetitive behaviors were examined in autistic and nonautistic prepubertal males with the fragile X syndrome (fra[X]) during social interaction with a parent or stranger. Comparison groups were nonhandicapped, Down syndrome, atypical pervasive developmental disorder, and autistic males. The subjects with fra(X) and the nonhandicapped and Down syndrome control subjects discriminated parent from stranger as evidenced by their avoidance behavior. The overall percentage of avoidance was higher, however, for both parent and stranger, among the males with fra(X). Autistic and atypical groups without fra(X) failed to discriminate parent from stranger in their avoidance behavior. Possible explanations for these group differences in terms of language level or degree of language demand were ruled out. Implications for research concerning the relations among fra(X), autism, and mental retardation were discussed.

Autistic Disorder↗
PubMed1987

Further evidence for genetic heterogeneity in the fragile X syndrome.

The X-linked fragile X [fra(X)] syndrome, associated with a fragile site at Xq27.3, is the most common Mendelian inherited form of mental deficiency. Approximately 1 in 1060 males and 1 in 677 females carry the fra(X) chromosome. However, diagnosis of carrier status can be difficult since about 20% of males and 44% of females are nonpenetrant for mental impairment and/or expression of fra(X). We analyzed DNA from 327 individuals in 23 families segregating fra(X) for linkage to three flanking polymorphic probes: 52A, F9, and ST14. This allowed probable nonpenetrant, transmitting males and carrier females to be identified. A combined linkage analysis was conducted using these families and published probe information on F9 in 27 other families, 52A in six families, and ST14 in five families. The two-point recombination fraction for 52A-F9 was 0.13 (90% confidence interval, 0.10-0.16), for F9-fra(X) was 0.21 (0.17-0.24), and for fra(X)-ST14 was 0.12 (0.07-0.17). Tight linkage between F9 and fra(X) was observed in some families; in others loose linkage was seen suggesting genetic linkage heterogeneity. Risk analysis of carrier status using flanking DNA probes showed that probable nonpenetrant transmitting males were included in families showing both tight and loose linkage. Thus, in contrast to our previous conclusions, it appears that the presence or absence of nonpenetrant, transmitting males in a family is not an indicator of heterogeneity. To determine if heterogeneity was present, we employed the admixture test. Evidence for linkage heterogeneity between F9 and fra(X) was found, significant at P less than 0.0005. Nonsignificant heterogeneity was seen for 52A-F9 linkage. No heterogeneity was found for fra(X)-ST14. The frequency of fra(X) expression was significantly lower in families with tight F9-fra(X) linkage than in families with loose linkage. Cognition appeared to relate to linkage type: affected males in tight linkage families had higher IQs than those in loose linkage families. These findings of genetic heterogeneity can account in part for the high prevalence and apparent high new mutation rate of fra(X). They will affect genetic counseling using RFLPs. An understanding of the basis for genetic heterogeneity in fra(X) will help to clarify the nature of the unusual pattern of inheritance seen in this syndrome.

Fragile X Syndrome↗
PubMed1986

Autism and the fragile X syndrome.

The fragile X chromosome is an important factor in inherited mental retardation in males. It has also been reported that infantile autism is associated with fragile X. Recently, an article reported an examination of a small sample of autistic children in whom the fragile X chromosome was not found. Its authors concluded that if an association between fragile X and autism exists, it is infrequent. In the present study of 144 autistic male subjects, 18 were found to have the fragile X chromosome, supporting other (epidemiological) findings that the association between fragile X and autism occurs relatively frequently.

Adolescent↗
PubMedDate not supplied

High dose folic acid treatment of fragile (X) males.

We conducted an experimental trial of high-dose folic acid given to five males, ages 8 to 26 years, with the fra(X) syndrome. In this double blind study, each subject received 250 mg per day of folic acid for 3 months, followed by placebo for 3 months, and folic acid again for an additional three months. Based on IQ tests, behavior ratings, the Autistic Descriptors Checklist, and parental ratings, there was little evidence to suggest any positive effects seen during the administration of high-dose folic acid. Therefore, this study has provided little support for a hypothesis of benefit of high-dose folic acid in the treatment of the fra(X) syndrome.

Adolescent↗
PubMedDate not supplied

Fragile X and autism: a multicenter survey.

We screened 183 autistic males for the fra(X) and found 24 (13.1%) to be positive. Adding the subjects of this study to those of 11 other surveys, of which 6 were positive and 5 were negative, a total of 614 autistic males have been screened. Overall 47 (7.7%) were positive. Based on this estimate and the prevalence of autism and fra(X), we estimate that 12.3% of fra(X) males are autistic. We have found that 17.3% of our fra(X) males were autistic and overall a 21.2% frequency has been reported, these higher figures are most likely due to biases in age and ascertainment. With an overall 7.7% frequency of fra(X) among autistic males and an estimated 12.3% of autism among fra(X) males, we conclude there is likely to be a significant association of fra(X) with autism. Because fra(X) appears to be the single most common cause of the condition, chromosomal testing is recommended for any autistic person with undiagnosed etiology.

Autistic Disorder↗
PubMedDate not supplied

Folic acid treatment of fragile X males: a further study.

Investigations of the effect of high dose folic acid treatment of fragile X syndrome in males has produced mixed results. However, no study had examined the possible drug effects of folic acid on non-fragile X control males. Therefore, we examined the effect of folic acid on fragile X males using non-fragile X control males. Subjects were assigned randomly to an ABA or BAB design. Duration of either folic acid or placebo condition was 4 months. Folic acid or placebo was given in a double-blind fashion. At the end of each condition, the subjects' behavior was assessed. At the end of the study, parents were asked to complete a questionnaire. Using parents' responses, we examined 22 items on the Autistic Descriptors Checklist and two subscales from the Vineland Adaptive Behavior Scale which corresponded to areas of behavior parents' noted to have shown improvement. We did not find significant differences between fragile X males and control males, within subjects, nor across folic acid and placebo conditions. Thus, our follow-up study confirms and extends our original findings, as well as those of other researchers: namely, that no dramatic changes in behavior result from high dose folic acid. Moreover, subtle improvements observed in earlier investigations were not confirmed.

Adolescent↗
PubMedDate not supplied

Screening developmentally disabled male populations for fragile X: the effect of sample size.

The fra(X) or Martin-Bell syndrome is the most common cause of inherited mental retardation (MR) in males. It is also associated with a variety of unusual behavioral and developmental disorders. Recent studies found great variability in the estimated strength of association between "autism" and the fra(X) syndrome, but not between MR and fra(X). We examined 31 studies which investigated the association of fra(X) syndrome with either MR or "autism" and found that the conclusion of those researchers could be significantly affected by sample size. Different behavioral and cytogenetic protocols will also influence the strength of association between fra(X) and autism.

Autistic Disorder↗
PubMedDate not supplied

Genetic and other factors that contribute to variability in cytogenetic expression in fragile X males.

Variability in cytogenetic expression of fragile X has been observed by many investigators. One recent study of families of fragile X brothers concluded that frequency of expression was almost completely controlled by genetic factors. We investigated the extent of genetic control over frequency of expression by evaluating fragile X families from 3 different sources using hierarchal analysis of variance model to calculate the intraclass correlation and the index of heritability, h2. Proportion of variance attributable to families was computed from 2 estimation procedures: 1) a least squares method and 2) a maximum likelihood technique. Results were comparable with one another and indicated that, although genetic factors were significant, differences between laboratories contributed a larger proportion of the total estimated variance. These results partly confirmed previous findings but indicated that the degree of genetic control over the proportion of affected cells was lower than recently suggested.

Analysis of Variance↗
PubMedDate not supplied

Relationship between age and IQ among fragile X males: a multicenter study.

Longitudinal decline in IQ among fragile X males was reported recently. However, there are problems in retesting IQ that may affect scores. Two such factors are intertest time interval and score obtained on the first test. To determine the generality of IQ score changes, we examined 101 fragile X males from 6 centers. To ensure high test-retest reliability, only results from Stanford-Binet and Wechsler tests were used. Thus there were retest scores from 60 subjects. Test-retest reliability between first and last scores was very good (r = 0.85) and comparable to those seen in nonfragile X mentally retarded individuals. Also computed were z-scores of differences in IQ scores. The z-score differences were distributed about a mean at 1 SD below the expected zero value. Eighteen subjects showed statistically significant decreases in IQ, 6 showed statistically significant increases, while 5 showed the same scores. Z-score differences were not correlated with type of residence or elapsed intertest interval, but were negatively correlated with first score obtained, indicating a regression-to-the-mean effect. Using a multiple regression analysis, we found first score obtained, age tested, and age retested significant predictors of score differences, accounting for 19% of the total variance. These results suggest that factors previously identified as affecting retest scores have a smaller effect than originally thought. It is suspected that decline in IQ is associated with dynamic neurological processes and needs to be investigated further.

Adolescent↗
PubMedDate not supplied

Longitudinal changes in IQ among fragile X males: clinical evidence of more than one mutation?

Longitudinal changes in IQ among mentally retarded (MR) fragile X [fra(x)] males have been reported previously. While age is associated with decline in IQ, not all males are so affected. This suggests that there may be more than one subtype of affected fra(X) male. Therefore, we examined the distribution of standardized difference scores (Zdiff) in IQ to determine if subjects were from an admixture of at least 2 populations. Cluster analysis of Zdiff scores was used to partition subjects into 2 groups. Goodness-of-fit tests indicated that scores were more likely to come from an admixture. Discriminant functions (DF) were calculated to determine predictive validity of Zdiff scores. To eliminate the effect of skewing, a power transform was applied to Zdiff scores and DFs recomputed. Zdiff and transformed scores provided similar results. The mean and variance for one group showed no differences in test-retest scores as would be expected from examining any population while the mean for the second group indicated significant decline in IQ nearly 4 standard errors below the first test score. These results suggest that there may be clinical evidence for 2 types of fra(X) mutation: One which causes MR but is static, and a second mutation which causes MR but is dynamic and contributes to an apparent longitudinal decline in cognitive function.

Adolescent↗
PubMedDate not supplied

Is autism associated with the fragile X syndrome?

In addition to mental retardation (MR), fragile X [fra(X)] has been associated with other developmental disabilities, autism in particular. Recently, several studies have concluded that the association of fra(X) with autism is at best weak and perhaps nonexistent. This study examined reports of previously published data from an epidemiological perspective to determine if the prevalence of fra(X) among autistic males was significantly different from that among MR males. Nineteen studies of autistic males and 21 studies of MR males were analyzed from 59 examined. Of 5601 MR males tested, 307 (5.5%) were cytogenetically positive. Of 1006 autistic males, 54 (5.4%) were positive. Analysis indicated no statistical difference between these proportions (Z = 0.014; p greater than .50). An odds ratio (OR) was also computed to determine the risk of autism from fra(X). Estimated OR approximately 1.0 [0.73, 1.32]. Attributable risk (AR), the proportionate excess risk of autism associated with exposure to fra(X) was AR approximately 0.0. That is, there was no attributable risk of autism from fra(X). The association of fra(X) with autism may reflect the association with MR that generally accompanies autism, as several earlier reports have noted. However, the similarity in prevalence of fra(X) among autistic and MR males may be biased in the studies which find no instances of fra(X) among autistic males represent 12% of the pooled sample.

Autistic Disorder↗
PubMedDate not supplied

Factors which contribute to cytogenetic frequency of expression in families of fragile X females.

Frequency of expression in mentally retarded (MR) fragile X (fra[X]) males has been shown to be affected by genetic factors and laboratory procedures. Among MR females, factors that contribute to cytogenetic expression have been more problematic in part due to lower frequency of expression and X-inactivation. We examined fra(X) sisters to determine whether genetic factors affecting frequency of expression in sisters were comparable to those in brothers. Evaluations obtained from 2 data sets for a total of 66 families in which at least 2 affected brothers and/or 2 affected sisters were found cytogenetically positive were selected. Of 166 subjects chosen, 118 were male and 48 were female. Sibs were evaluated using an analysis of covariance (ANCOVA) with 2 factors (family, sex) adjusted for the covariate, age. Results indicated that interactive effects (family-by-sex) and main effects (family, sex, age) were significant but the interactive effect of age-by-sex was not. Consequently, one-way analyses of variance (ANOVA) of the effect of family were calculated separately for brothers and sisters. Correlation coefficients between family and cytogenetic frequency was r = .84 for brothers and r = .79 for sisters. Analysis of these coefficients indicated that they were not significantly different from one another (Z = 0.85, p greater than .40). While other factors may affect cytogenetic expression, whatever familial factors control frequency of expression among brothers appear to affect frequency of expression among sisters as well.

Aging↗