Dissemination of genetic risk information to relatives in the fragile X syndrome: guidelines for genetic counselors.

Fragile X Syndrome, which affects 1 in 1,250 males, is the most common inherited condition causing mental retardation. Although carrier detection for the fragile X syndrome utilizing DNA has now been simplified, genetic counseling and the process of informing at-risk family members remains complex. The purpose of this paper is to offer practical guidelines to health professionals providing genetic counseling to fragile X families in order to facilitate the dissemination of genetic risk information to relatives. This paper was developed from a workshop held at the 4th International Fragile X Conference. The guidelines presented here represent a beginning in the development of an approach to informing relatives in fragile X families about genetic risk, and the identification of mechanisms to reduce the burden to families.

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.

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.

Evaluation of school children at high risk for fragile X syndrome utilizing buccal cell FMR-1 testing.

We describe a pilot project utilizing saliva to identify the FMR-1 mutation in high-risk special education students from four public school districts in Colorado. The program included presentations to special education teachers regarding fragile X syndrome, parental consent for testing, completion of a behavior checklist by the teachers, identification of special education students at high risk for fragile X syndrome, subsequent brief examination of face and hands, collection of a saliva sample by either Gatorade swish or brushing of the inside of the cheek, and analysis for the FMR-1 mutation by PCR. Equivocal samples were studied by direct DNA testing using Southern blot analysis, and abnormal results were confirmed by a blood analysis for the FMR-1 mutation. Mutant individuals received genetic counseling and medical and educational assessments to optimize treatment and intervention. This pilot project was met with enthusiasm by the schools. Of the first 439 students evaluated, 68% were male with an average age of 7.75 years; 13% were mentally retarded or autistic. Most students referred for the evaluation were learning disabled (51%) and/or had an Attention Deficit Hyperactivity Disorder (ADHD) (35%). The overall prevalence of the FMR-1 mutation was 5 of 439 or 1.1%. This relatively low yield is probably due to the high number of non-retarded but learning disabled students tested. Of the mentally retarded patients tested, 3.5% were positive for the FMR-1 mutation; however, of the non-retarded or learning disabled patients, only 0.79% were FMR-1 positive.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

SITE demonstration of the CF systems organic extraction process.

The CF Systems Organic Extraction Process was used to remove PCBs from contaminated sediment dredged from the New Bedford Harbor. This work was done as part of a field demonstration under EPA's Superfund Innovative Technology Evaluation (SITE) program. The purpose of the SITE program is to provide an independent and objective evaluation of innovative waste remediation processes. The purpose of this paper is to present the results of the SITE demonstration of this technology. Results of the demonstration tests show that the system, which uses liquefied propane, successfully removed PCBs from contaminated sediments in New Bedford Harbor. Removal efficiencies for all test runs exceeded 70 percent. Some operational problems occurred during the demonstration which may have affected the efficiency with which PCBs were removed from the dredged sediment. Large amounts of residues were generated from this demonstration project. Costs for using this process are estimated to be between $150/ton and $450/ton.