High functioning fragile X males: demonstration of an unmethylated fully expanded FMR-1 mutation associated with protein expression.

Fragile X (fra(X)) males with a standardized IQ score of 70 or higher represent a high functioning (HF) or nonretarded fra(X) male group. This group, which does not include nonpenetrant males, has received little research attention to date. Of 221 fra(X) males who had been evaluated through The Children's Hospital in Denver since 1981 and had completed cognitive or developmental testing, 29 (13%) were high functioning by the above definition. We found that HF males on the whole had a lower cytogenetic score and were younger than retarded fra(X) males, but there was no difference between these two groups in the number of typical fra(X) physical manifestations present. FMR-1 DNA testing was performed on 134 fra(X) males and methylation status was determined for 51 of these. A greater percentage of HF males had a mosaic pattern or an incompletely methylated full mutation than did retarded males. A unique DNA pattern, an unmethylated fully expanded mutation, was discovered in 3 of the highest functioning fra(X) males. Protein studies performed on 2 of these males demonstrated the presence of FMR-1 protein, albeit at lower levels than normal. FMR-1 protein was not present in retarded fra(X) males. Significant FMR-1 protein expression may be responsible for higher cognitive functioning in the 2 males with unmethylated fully expanded mutations compared to retarded fra(X) males.

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.

Molecular predictors of cognitive involvement in female carriers of fragile X syndrome.

OBJECTIVE: Fragile X syndrome is caused by a mutation involving expansion of a CGG trinucleotide repeat segment in the fragile X mental retardation-1 (FMR1) gene on the long arm of the X chromosome. This study was undertaken to determine the relative impact of three molecular characteristics of the FMR1 mutation--number of CGG repeats, methylation status, and X inactivation ratio--on the cognitive involvement of female carriers of fragile X syndrome. DESIGN: Retrospective study with new DNA analysis of known female carriers of fragile X syndrome. SETTING: Molecular studies were conducted in a university-based DNA diagnostic laboratory. Patients were originally ascertained through a regional fragile X clinic in a university-affiliated pediatric hospital. PATIENTS: Forty-eight female carriers of fragile X syndrome were studied, including 22 with a premutation (a small expansion to approximately 50 to 200 CGG repeats), 23 with a full mutation (a full expansion to > 200 CGG repeats), and three with both types of mutations (mosaics). RESULTS: Median IQ score was significantly lower for females with a full mutation than for females with a premutation. No significant relationship was found between IQ score and number of CGG repeats or percentage methylation of the mutant allele within each mutation category. In addition, no significant relationship was found between IQ score and the proportion of normal FMR1 alleles on the active X chromosome in the carrier female group as a whole or in either mutation subgroup. Comparisons of leukocytes and saliva-borne epithelial cells in certain full-mutation carriers revealed striking differences in FMR1 mutation sizes. CONCLUSIONS: Mutation category remains the most important predictor of affectedness in female carriers of fragile X syndrome. Our data do not support use of the proportion of normal FMR1 alleles on the active X chromosome as a predictor of cognitive involvement in female carriers with full mutations. Individual tissue-specific differences exist in the heterogeneous sizes of full mutations and in the presence of premutation/full-mutation mosaicism.

Molecular-clinical correlations in children and adults with fragile X syndrome.

INTRODUCTION: Fragile X syndrome is the most commonly known inherited form of mental retardation. The intellectual abilities range from a normal IQ with learning disabilities to severe mental retardation. In males, there is a tendency for IQ decline in childhood. The purpose of this study was to correlate variations of the molecular cytosine guanine guanine (CGG) amplification in the fragile X mental retardation-1 (FMR-1) gene with the clinical findings, including IQ and physical features. METHODS: Full-scale IQ and cytogenetic results in 116 individuals with the FMR-1 mutation were studied. The IQ testing was performed with age-appropriate standardized tests. Physical features were summarized in a physical index score for each patient. The FMR-1 results were determined with the OX1.9 probe and the following system was used: P1 indicates premutation; P2, large premutation to small full mutation; P3, full mutation; and P4, mosaic. RESULTS/CONCLUSIONS: The findings showed that those females with a small insert in the P1 range had a significantly higher IQ than other heterozygotes (P2, P3, and P4 categories). P4 males had a significantly higher IQ than P2 or P3 males. In cross-sectional age comparisons, the slope of the IQ decline was greater in P2 males than in P4 or P3 males.