Phenotypic involvement in females with the FMR1 gene mutation.

Fragile X syndrome is the most common from of inherited mental retardation. Approximately half of females with the full mutation have significant cognitive deficits, whereas females with the premutation do not. Phenotypic effects seen in 281 females (IQs from 64 to 139) were analyzed. Results showed that females with the full mutation differ significantly from controls on selected anthropometric measurements, physical index score, and various behavioral features. Females with the premutation differed significantly from controls in regards to a few anthropometric measurements and the physical index score but not in behavioral features. These results suggest that phenotypic effects of the FMR1 mutation are not only common in females with the full mutation, but in females with the premutation as well.

Molecular/clinical correlations in females with fragile X.

Females who are affected by fragile X syndrome (FXS) can have significant physical, neuropsychological and emotional involvement. This study was designed to explore the relationships between these three domains and to learn how the degree of involvement in each of these phenotypic areas relates to molecular parameters including CGG repeat length and activation ratio (the proportion of normal FMR1 alleles on the active X chromosome). Three groups of females were studied: 35 women who grew up in a fragile X family but do not carry an FMR1 mutation, 92 women with a premutation, and 29 women with a full mutation. Correlations between neurocognitive, physical and emotional traits were calculated for each of the three groups. Within the full mutation group significant correlations were seen between schizotypal traits and full scale IQ. The Lie scale was significantly correlated with the physical findings index. The activation ratio correlated significantly with the measure of executive function (r = .50, P = .01). There was a trend toward correlations of activation ratio with the physical index score, outer ear prominence and IQ. CGG repeat number significantly correlated only with the physical index (r = .44, P = .01). Thus, activation ratio may be the more pertinent molecular parameter in full mutation women in determining the degree of cognitive and physical phenotypic involvement.

Molecular-clinical correlations in males with an expanded FMR1 mutation.

Fragile X syndrome is caused by an expansion of a CGG repeat in the FMR1 gene. The CGG repeat number of the FMR1 mutation and the percentage of cells with methylation of the gene were studied in 218 male patients. Physical and cognitive measurements were also performed. Patients were divided into three groups; those with full mutation and complete methylation (n = 160), those with full mutation and partial methylation (n = 12), and those with a mosaic pattern (n = 46). Statistical comparisons were made between males with the fully methylated full mutation and those with a mosaic pattern. Males having full mutation with complete methylation had the lowest IQ scores and greatest physical involvement. These significant differences were seen only in ages after puberty. CGG repeat length did not correlate with IQ or the physical index score in any group. These findings suggest that a partial production of FMR1 protein may predict milder clinical involvement in some males with fragile X syndrome.

Fragile X syndrome in a normal IQ male with learning and emotional problems.

The present case study features an adult male who was diagnosed with fragile X syndrome after the identification of this syndrome in his more affected brother. The patient presented with a Full Scale IQ within the broad range of normal and has been diagnosed with a schizotypal personality disorder. He shows significant deficits in the social and emotional aspects of daily life, but has striking cognitive strengths relating to reading and vocabulary as compared to most males affected with fragile X syndrome. DNA testing of blood leukocytes revealed that he has a fully expanded FMR1 CGG repeat mutation associated with almost complete lack of methylation. Protein studies demonstrate a limited production of FMRP, the protein produced by the FMR1 gene. It is believed that the near absence of methylation of the fully expanded mutation and the resultant expression of the FMR1 protein is responsible for the strong cognitive abilities of this fragile X patient.

Emotional and neurocognitive deficits in fragile X.

We have studied the neurocognitive deficit in premutation and full mutation women as compared to control women and to explore the relationship between those deficits and the incidence of emotional problems. Four groups of women were examined: two fragile X (fra(X)) negative control groups, one of which grew up in fra(X) families and one not; and two DNA positive groups, one with a premutation (CGG repeats < 200) and one with an expanded mutation (CGG repeats > 200). All women were assessed using the MMPI-2, the SADS-L, and a battery of neuropsychological tests. Full mutation women had lower scores on composite measures of executive function and nonverbal function. There was no difference between the groups in terms of the lifetime incidence of depressive and anxiety disorders on the SADS-L. Full mutation women displayed Lie scales higher than the other groups on the MMPI-2. Neurocognitive measures were not related to SADS-L diagnoses but were related to the Lie scale on the MMPI-2. Finally, number of CGG repeats was related to the neuropsychological variables and the Lie scale.

Symptoms of schizotypal personality disorder in fragile X women.

OBJECTIVE: The frequency of DSM III-R symptoms of schizotypal personality disorder as it relates to CGG amplification and to the cytogenetic expression of fragile X syndrome was explored. METHOD: Four groups of women were examined: 30 control mothers of children with developmental problems, 17 control women who grew up in fragile X families, 28 women cytogenetically negative but DNA positive for fragile X with a premutation, and 31 women who were DNA positive with an expanded mutation, most of whom were cytogenetically positive. All women were assessed using the Structured Interview for Schizotypy. RESULTS: Eight of the nine women who received the DSM III-R schizotypal personality disorder diagnosis came from the two fragile X groups: four from the premutation group and four from the expanded mutation group. Twenty percent of fragile X carriers who received the gene from their mother, but none who received the gene from their father demonstrated schizotypal personality disorder. CONCLUSIONS: Women who carry the premutation and women with the full mutation may both show schizotypal features, although less commonly than previously reported.

Psychopathology in fragile X syndrome.

The fragile X syndrome is the most common known familial form of mental retardation. Young males commonly demonstrate hyperactivity and a short attention span, as well as physical abnormalities, some of which may lead to a diagnosis of Pervasive Developmental Disorder. Heterozygous females frequently demonstrate both a range of involvement with learning disabilities in math, and social anxiety. The more classical physical and behavioral features of this syndrome are reviewed.

Social perspective-taking and adjustment in emotionally disturbed, learning-disabled, and normal children.

Preadolescent emotionally disturbed, learning-disabled, and normal boys were compared on social perspective-taking and behavioral measures to examine possible contributions of social cognitive deficits to children's adjustment problems. Antisocial-prosocial and withdrawn-gregarious behavior dimensions were studied through subscales derived from teacher ratings. Results indicated that across all groups, high perspective-taking was associated with significantly less withdrawal than was low perspective-taking; within groups, this finding was significant only for the emotionally disturbed boys. Contrary to theoretical assumptions, antisocial behavior was not significantly related to perspective-taking across the sample. Among emotionally disturbed boys, relatively higher affective perspective-taking was significantly correlated with higher antisocial behavior. This positive correlation for the emotionally disturbed group was significantly different from the nonsignificant negative correlation between antisocial behavior and perspective-taking among normals. Findings for learning-disabled boys were intermediate between results for emotionally disturbed and normal boys on both perspective-taking and behavioral measures, and the learning-disabled group generally did not differ significantly from either other group. Theoretical and clinical implications of the findings are discussed.