1/240. Partial seizures with focal epileptogenic electroencephalographic patterns in three related female patients with fragile-X syndrome. epilepsy and abnormal electroencephalographic (EEG) patterns have been reported in mentally retarded males with fragile-X syndrome, but the high incidence of epilepsy in such persons has been recognized only recently. These individuals have focal spikes in the EEG similar to the benign rolandic pattern. female carriers have very rarely been reported to have epilepsy or nonspecific abnormal EEG patterns. We report partial seizures with a focal epileptogenic EEG pattern in two sisters and their grandmother, who are all carriers of fragile-X syndrome. The sisters have mild developmental delay, but the grandmother is of normal intelligence. The mother of the two sisters is known to be a carrier of the fragile-x chromosome and is of normal intelligence, with no history of seizures. It is important for physicians to be aware of the possibility that females presenting with partial seizures of unknown cause may be fragile-X carriers, and enquiry for a family history of intellectual disability should be pursued. ( info) |
2/240. Monozygotic twin brothers with the fragile x syndrome: different CGG repeats and different mental capacities. Little is known about the mechanism of CGG instability and the time frame of instability early in embryonic development in the fragile x syndrome. Discordant monozygotic twin brothers with the fragile x syndrome could give us insight into the time frame of the instability. We describe monochorionic diamniotic twin brothers with the fragile x syndrome who had different CGG repeats and different mental capacities, whereas the normal mother had a premutation. The more retarded brother had a full mutation in all his cells and no FMR-1 protein expression in lymphocytes, whereas the less retarded brother had 50%/50% mosaicism for a premutation and full mutation and FMR-1 protein expression in 26% of his lymphocytes. The differences in repeat size could have arisen either before or after the time of splitting. The time of splitting in this type of twin is around day 6-7. Given the high percentage of mosaicism, we hypothesise that the instability started before the time of splitting at day 6-7. ( info) |
3/240. Deletion of 8.5 Mb, including the FMR1 gene, in a male with the fragile x syndrome phenotype and overgrowth. A four-year-old boy with severe psychomotor retardation, facial appearance consistent with the fragile x syndrome, hypotonia, and overgrowth was found to have a deletion including the fragile X gene (FMR1). The breakpoints of the deletion were established between CDR1 and sWXD2905 (approximately 200 kb apart) at Xq27.1 (centromeric) and between DXS8318 (612-1078L) and DXS7847 (576-291L) (approximately 250 kb apart) at Xq28, about 500 kb telomeric to the FMR1 gene. The total length of the deletion is approximately 8.5 Mb. The propositus's mother, who was found to be a carrier of the deletion, showed very mild mental impairment. Except for mental retardation, which is a common finding in all cases reported with similar deletions of chromosome Xq, this patient had generalized overgrowth, exceeding the 97th centile for height and weight. obesity and increased growth parameters have been reported in other patients with deletions either overlapping or within a distance of 0.5 Mb from the deletion in the present patient. Thus, it is suggested that a deletion of the 8-Mb fragment centromeric to the FMR1 gene might have an effect on growth. ( info) |
| This is the first report that details an association between fragile x syndrome (FXS) and selective mutism (SM). This 12-year-old girl with heterozygous full mutation at FMR1 has a long history of social anxiety and shyness in addition to SM. Her sister also has the full mutation and a history of SM that resolved in adolescence. A beneficial response to fluoxetine and psychotherapy is described. The FMR1 mutation appears to be the first gene mutation associated with SM and further studies are recommended to assess what percentage of patients with SM have the FMR1 mutation. ( info) |
| We report on a 15-year-old compound heterozygous young woman with fragile x syndrome who has a full mutation of 363 repeats on one x chromosome and a premutation of 103 repeats on the other x chromosome. As predicted, subsequent testing demonstrated that her father carries a premutation (98 repeats) as does her mother (146 repeats). There is only one previous report of a compound heterozygous female with fragile x syndrome. By quantitation of Southern blot signals, the activation ratio for the premutation (the proportion of the premutation on the active x chromosome) was determined to be 0.78. Immunocytochemistry of blood smears showed fragile X mental retardation-1 protein (FMRP) expression in 63.5% of lymphocytes. Cognitively, this woman is functioning in the mid-range of involvement for fragile X females. She attends regular classes and receives supplemental assistance for her learning disabilities. She experiences behavior characteristics typical of females with fragile x syndrome including severe shyness, anxiety, panic episodes, mood swings, and attention deficits. She has responded very well to appropriate treatment including fluoxetine for anxiety, methylphenidate for attentional problems, and educational therapy. ( info) |
6/240. mosaicism in a fragile X male including a de novo deletion in the FMR1 gene. In most cases the fragile x syndrome is caused by an amplification of the CGG trinucleotide repeat in the 5' untranslated region of the FMR1 gene, in combination with the hypermethylation of the proximal CpG island. Recently, also a few cases with deletions or a mosaic of a deletion and a full mutation in the FMR1 gene, leading to the same phenotype, have been described. Here we report the molecular analysis of a patient with typical fragile X phenotype and mosaicism of the FMR1 genomic region consisting of a premutation, a full mutation of the CGG repeats, and a 215 bp deletion, diagnosed by Southern blot hybridisation and polymerase chain reaction (PCR). sequence analysis of the deletion demonstrated that the 5' breakpoint of the deletion is located within a putative hotspot region 75-53 bp proximal to the CGG repeat. ( info) |
7/240. Tissue heterogeneity of the FMR1 mutation in a high-functioning male with fragile x syndrome. Few studies have been conducted comparing the FMR1 mutation in multiple tissues of individuals affected with fragile x syndrome. We report a postmortem study of the FMR1 mutation in multiple tissues from a high-functioning male with fragile x syndrome. This man was not mentally retarded and had only a few manifestations of the disorder such as learning disabilities and mild attention problems. Southern blot analysis of leukocytes demonstrated an unmethylated mutation with a wide span of sizes extending from the premutation to full mutation range. A similar pattern was seen in most regions of the brain. In contrast, a methylated full mutation of a single size was seen in the parietal lobe and in most non-brain tissues studied. Therefore, there were striking differences in both FMR1 mutation size and methylation status between tissues. Lack of mental retardation in this individual may have been due to sufficient expression of FMR1 protein (FMRP) in most areas of the brain. Immunocytochemistry showed FMRP expression in regions of the brain with the unmethylated mutation (superior temporal cortex, frontal cortex, and hippocampus) and no expression in the region with the methylated full mutation (parietal). Neuroanatomical studies showed no dendritic spine pathology in any regions of the brain analyzed. ( info) |
8/240. Strong similarities of the FMR1 mutation in multiple tissues: postmortem studies of a male with a full mutation and a male carrier of a premutation. Studies of the FMR1 mutation in multiple tissues are important to further our understanding of CGG repeat expansion in development and of the frequency and possible clinical significance of inter-tissue heterogeneity in fragile x syndrome. With some exceptions, most cases reported have shown strong similarity of the mutation size and methylation status between tissues. However, there have been only a few studies of multiple tissues including regions of the brain. We report on two postmortem studies of multiple tissues, one of a male with a full mutation (fully methylated) and one of a male carrier of a premutation. The male with the full mutation (TH) had a typical presentation of fragile x syndrome, including mild mental retardation. He had a methylated full mutation of two predominant sizes in all 12 tissues analyzed, including three regions of the brain. The male carrier of a premutation (GC) was clinically unaffected, and the mutation was the same size in all 14 tissues examined including seven regions of the brain. Therefore, both cases demonstrated lack of inter-tissue heterogeneity, suggesting strong somatic stability after the period of expansion to the observed mutation size(s). Also, both cases showed consistency between clinical phenotype and mutation characteristics in the brain. ( info) |
9/240. fragile x syndrome and an isodicentric x chromosome in a woman with multiple anomalies, developmental delay, and normal pubertal development. We report on an individual with developmental delays, short stature, skeletal abnormalities, normal pubertal development, expansion of the fragile X triplet repeat, as well as an isodicentric x chromosome. S is a 19-year-old woman who presented for evaluation of developmental delay. pregnancy was complicated by a threatened miscarriage. She was a healthy child with intellectual impairment noted in infancy. Although she had global delays, speech was noted to be disproportionately delayed with few words until age 3.5 years. Facial appearance was consistent with fragile x syndrome. age of onset of menses was 11 years with normal breast development. A maternal male second cousin had been identified with fragile x syndrome based on dna studies. The mother of this child (S's maternal first cousin) and the grandfather (S's maternal uncle) were both intellectually normal but were identified as carrying triplet expansions in the premutation range. S's mother had some school difficulties but was not identified as having global delays. Molecular analysis of S's fragile X alleles noted an expansion of more than 400 CGG repeats in one allele. Routine cytogenetic studies of peripheral blood noted the presence of an isodicentric X in 81of 86 cells scored. Five of 86 cells were noted to be 45,X. Cytogenetic fra(X) studies from peripheral blood showed that the structurally normal chromosome had the fragile site in approximately 16% of the cells. Analysis of maternal fragile X alleles identified an allele with an expansion to approximately 110 repeats. FMRP studies detected the expression of the protein in 24% of cells studied. To our knowledge, this is the first patient reported with an isodicentric X and fragile x syndrome. Whereas her clinical phenotype is suggestive of fragile x syndrome, her skeletal abnormalities may represent the presence of the isodicentric X. Treatment of S with 20 mg/day of Prozac improved her behavior. In the climate of cost con trol, this individual reinforces the recommendation of obtaining chromosomes on individuals with developmental delay even with a family history of fragile x syndrome. ( info) |
10/240. fragile x syndrome with FMR1 and FMR2 deletion. We report a 13 year old boy with fragile x syndrome resulting from a de novo deletion of the FMR1 and FMR2 genes extending from (and including) DXS7536 proximally to FMR2 distally. The patient has severe developmental delay, epilepsy, and behavioural difficulties, including autistic features. He has epicanthic folds, in addition to facial features typical of fragile x syndrome, and marked joint hypermobility. We compare our patient to the three other cases reported in which both FMR1 and FMR2 are deleted. This case has the smallest deletion reported to date. All four patients have epilepsy and a more severe degree of mental retardation than is usual in fragile x syndrome resulting from FMR1 triplet repeat expansion. Three of the patients have joint laxity and two have epicanthic folds. We suggest that these features, in particular severe developmental delay and epilepsy, may form part of the characteristic phenotype resulting from deletion of both FMR1 and FMR2 genes. The diagnosis in this case was delayed because routine cytogenetics showed no abnormality and standard molecular tests for FMR1 triplet repeat expansion (PCR and Southern blotting) failed. Further dna studies should be undertaken to investigate for a deletion where clinical suspicion of fragile x syndrome is strong and routine laboratory tests fail. ( info) |