Biomedical subjects

R J Hagerman

Publications and source records attributed to R J Hagerman.

At least 37 records · Page 2Linked to original sources

PubMed2001

[Fragile X syndrome: a model of gene-brain-behaviour relationships].

INTRODUCTION: Sequencing of the fragile X mental retardation 1 (FMR1) gene and the measurements of the gene product FMRP, have enabled protein quantification of variations within the FMR1 gene and FMRP-clinical correlations. DEVELOPMENT: This paper will review our knowledge of the regulation of FMR1 gene expression and the genotype-phenotype relationships. The clinical variability is related to several factors including: 1) molecular variations at FMR1 leading to a range of FMRP levels, 2) the combined effect of background genes interacting directly or indirectly with FMRP, 3) environmental factors which can either enhance or impede development and the degree of dysfunction which ensues. CONCLUSION: Advances in neuroimaging, neurosciences, and knockout mice further our understanding of the gene-brain-behavior relationships in Fragile X Syndrome.

Animals↗

PubMed2000

Melatonin profiles and sleep characteristics in boys with fragile X syndrome: a preliminary study.

Sleep patterns and endogenous melatonin profiles in 13 fragile X boys between the age of 4.7 and 11.0 years were compared to those of 8 age-matched, normal control boys. Parents recorded sleep patterns on a Sleep Diary Chart for 14 consecutive days. Twelve saliva samples were obtained from 8 fragile X participants and all of the controls over 48 hours for the assessment of salivary melatonin profiles. The results showed greater variability in total sleep time and difficulty in sleep maintenance in fragile X boys compared with the control participants. Nocturnal melatonin production, expressed as both peak level and area under the concentration-time curve between 20:00 h and 08:00 h, were found to be significantly larger in fragile X boys than in controls. Additionally, the mean of the minimum daytime melatonin levels recorded was significantly higher for the fragile X group. Elevated levels in some fragile X boys relative to the range seen in controls, occurring either during the day or at night, or in both segments of the secretory profile for some individuals, may be due in part to overactivity of the sympathetic nervous system. Alternative molecular mechanisms leading to changes in melatonin profiles in fragile X are also discussed.

Age Factors↗

PubMed2000

Fragile X males with unmethylated, full mutation trinucleotide repeat expansions have elevated levels of FMR1 messenger RNA.

Fragile X syndrome normally arises as a consequence of large expansions (n >200) of a (CGG)(n) trinucleotide repeat in the promoter region of the FMR1 gene. The clinical phenotype is thought to result from hypermethylation of the repeat and adjacent upstream elements, with consequent down-regulation of transcription (transcriptional silencing). However, the relationship between repeat expansion and transcription has not been defined in the full mutation range. Using the method of quantitative (fluorescence) reverse transcriptase polymerase chain reaction, we demonstrated previously that FMR1 mRNA levels are substantially elevated in premutation (55 </= n < 200) male carriers. In the current work, we report that in fragile X males with unmethylated alleles in the full mutation range (n > 200), FMR1 mRNA levels remain significantly elevated (mean 3.5-fold elevation; P = 6.7 x 10(-3)) relative to normal controls, even for alleles exceeding 300 repeats. This conclusion is independent of any assumption regarding the transcriptional activity of methylated alleles. However, if it were assumed that all methylated alleles were transcriptionally silent, the FMR1 mRNA levels for cells with unmethylated alleles would be even higher (mean 4.5-fold elevation; P = 2.1 x 10(-4)). These observations show that the full-mutation CGG expansion per se is not a strong impediment to transcription and that the apparent up-regulation of the FMR1 locus remains active in at least some cells with full-mutation alleles.

Alleles↗

PubMed2000

Clinical involvement and protein expression in individuals with the FMR1 premutation.

Most individuals with the fragile X premutation are clinically unaffected; however, some show clinical manifestations, including learning difficulties, emotional problems, or even mental retardation. The basis of clinical involvement in these individuals is unknown. Premutation alleles are reportedly associated with normal levels of mRNA and protein (FMRP). To examine this issue in more detail, we studied six individuals with a premutation. We are reporting these cases to demonstrate a spectrum of phenotypic involvement which can be seen clinically. These cases include one individual with the premutation who has no evidence of FMR1 gene dysfunction but has mental retardation from other causes. Other cases presented here show varying degrees of FMR1 gene dysfunction as assessed by FMRP and FMR1 mRNA levels and various clinical features of fragile X. In two cases we observed a significant reduction in FMRP expression and an elevated FMR1 mRNA expression level associated with moderate cognitive deficit. Thus, the utilization of FMRP measures can be helpful in understanding for which premutation patients clinical involvement is caused by dysfunction of the FMR1 gene.

Abnormalities, Multiple↗

PubMed2000

Transcription of the FMR1 gene in individuals with fragile X syndrome.

Fragile X syndrome generally arises as a consequence of a large expansion of a CGG trinucleotide repeat element that is located in the GC-rich promoter region of the fragile X mental retardation gene (FMR1). In the conventional model for fragile X, clinical involvement arises as a consequence of silencing of the FMR1 gene, with the attendant loss of FMR1 protein (FMRP). However, it has recently been demonstrated that most males with large premutation alleles (100-200 repeats), or with unmethylated full mutation alleles, have FMR1 mRNA levels that are higher than normal, despite reduced levels of FMRP. In the current work, we extend and confirm these observations using quantitative (fluorescent) reverse transcription polymerase chain reaction on larger sample populations, establishing that even for smaller premutation alleles (55-100 repeats) the mRNA levels are significantly elevated (mean 2.1-fold elevation; P = 3.9 x 10(-3)), relative to normal controls. Thus, an abnormal molecular phenotype is established close to the upper end of the normal range. We also demonstrate that the levels of FMR1 mRNA are elevated in females with premutation alleles; however, the mRNA levels are more varied than in the males, and are attenuated in a manner that is consistent with the fraction of normal alleles that are active in any given individual. Finally, we demonstrate that in lymphoblastoid cells derived from a patient with a severe form of fragile X caused by a point mutation in the second KH domain of the gene, but with a normal CGG element (25 repeats), the FMR1 mRNA level is normal. Thus, although models in which FMRP level (or level of function) modulates transcriptional activity remain viable, other explanations for the elevated message levels, including direct (cis) effects of the CGG element on transcription, must also be considered.

Alleles↗

PubMed2000

Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in the fragile-X syndrome.

Fragile-X syndrome is a trinucleotide-repeat-expansion disorder in which the clinical phenotype is believed to result from transcriptional silencing of the fragile-X mental retardation 1 (FMR1) gene as the number of CGG repeats exceeds approximately 200. For premutation alleles ( approximately 55-200 repeats), no abnormalities in FMR1-gene expression have been described, despite growing evidence of clinical involvement in premutation carriers. To address this (apparent) paradox, we have determined, for 16 carrier males (55-192 repeats), the relative levels of leukocyte FMR1 mRNA, by use of automated fluorescence-detection reverse transcriptase-PCR, and the percent of lymphocytes that are immunoreactive for FMR1 protein (FMRP). For some alleles with>100 repeats, there was a reduction in the number of FMRP-positive cells. Unexpectedly, FMR1 mRNA levels were elevated at least fivefold within this same range. No significant increase in FMR1 mRNA stability was observed in a lymphoblastoid cell line (160 repeats) derived from one of the carrier males, suggesting that the increased message levels are due to an increased rate of transcription. Current results support a mechanism of involvement in premutation carriers, in which reduced translational efficiency is at least partially compensated through increased transcriptional activity. Thus, diminished translational efficiency may be important throughout much of the premutation range, with a mechanistic switch occurring in the full-mutation range as the FMR1 gene is silenced.

Fragile X Messenger Ribonucleoprotein 1↗

PubMed1999

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.

Abnormalities, Multiple↗

PubMed1999

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.

Aged↗

PubMed1999

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.

Adult↗

PubMed1999

FMRP expression as a potential prognostic indicator in fragile X syndrome.

Absence or deficit of FMR1 protein (FMRP) resulting from methylation of full mutation genes is the fundamental defect in fragile X syndrome. We used FMRP immunocytochemistry and detailed phenotypic assessment to investigate the relationship between degree of FMRP expression and the broad clinical spectrum of impairment in 80 individuals affected with fragile X syndrome. FMRP expression correlated with IQ in mosaic males (P=0.043), males with a partially methylated full mutation (P=0.0005), and females with a full mutation (P=0.046). In the females, FMRP expression also correlated with the number of fragile X physical features (P=0.0003). Even modest deficits in FMRP result in some manifestations of fragile X syndrome. In this initial study of 53 males, FMRP expression testing had a very high positive predictive value (100%, confidence interval of 29-100%) for a nonretarded IQ among males with expression of FMRP in > or = 50% of lymphocytes (3 males), suggesting that FMRP expression may have potential as a prognostic indicator in males with fragile X syndrome.

Adolescent↗

PubMed1999

Electrodermal responses to sensory stimuli in individuals with fragile X syndrome: a preliminary report.

The fragile X mutation and fragile X syndrome are associated with hyperarousal, hyperactivity, aggression, and anxiety. These may be related to strong reactions to auditory, tactile, visual, and olfactory stimuli [Hagerman, 1996b; Hagerman and Cronister, 1996]. However, almost no data exist describing hyperarousal and sensory sensitivity in individuals with the fragile X mutation. This study establishes a reliable laboratory paradigm for examining reactions to sensory stimuli. We found the pattern of electrodermal responses (EDRs) to stimulation in one sensory modality predicted the pattern of EDRs in four other sensory systems. In addition, the EDR pattern of individuals with the fragile X mutation was related to their FMR-protein expression. Finally, EDRs in individuals with fragile X syndrome were significantly different from those of normal controls, demonstrating greater magnitude, more responses per stimulation, responses on a greater proportion of trials, and lower rates of habituation. The findings support the theory that individuals with fragile X syndrome have a physiologically based enhancement of reactions to sensations. Because electrodermal activity indexes sympathetic nervous system activity, the data suggest that the over-arousal to sensation may involve the sympathetic system.

Adolescent↗

PubMed1999

Fragile X syndrome and selective mutism.

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.

Child↗

PubMed1999

Compound heterozygous female with fragile X syndrome.

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.

Adolescent↗

PubMed1999

Sensory-modulation disruption, electrodermal responses, and functional behaviors.

It was hypothesized that children clinically identified with sensory-modulation disruptions (SMD) would have atypical physiological responses to sensation, and that such responses would predict parent-reported behavioral responses to sensation. Nineteen children with clinically identified disruptions, aged 3 to 9 years, mean 6.0 years, and 19 age- and sex-matched healthy (control) children, aged 3 to 9 years, mean 6.6 years, were examined. The subjects were presented with five stimuli. Ten trials were conducted for each stimulus and the electrodermal activity of the child was recorded. Four children with SMD did not show electrodermal responses (EDR) to stimulation; all control children responded. Excluding non-responders, children with SMD showed more and larger EDR than control children. Participants with disruptions habituated more slowly to repeated stimulation, as measured by the number of responses to stimuli and proportion of stimuli that evoked responses. Children with atypical EDR had more parent-reported abnormal behavioral responses to sensation. Children with clinically identified SMD respond physiologically differently to sensory stimuli than typically developing children; these differences have ramifications for functional behavior.

Aggression↗

PubMed1999

Epilepsy and EEG findings in males with fragile X syndrome.

PURPOSE AND METHODS: One hundred and ninety-two fragile X male patients were investigated for seizures and EEG findings, 168 in a retrospective and 24 in another prospective study, to characterize the natural history of seizures, epilepsy, and EEG abnormalities in males with this syndrome. RESULTS: Seizures were documented in 35 (18.2%) of 192 patients; they never started before the age of 2 years or after the age of 9 years. Seizures were frequently of the complex partial type and less frequently of the partial motor and generalized type. Seizures involving frontal and temporal lobes were commonly seen and were usually well controlled by anticonvulsants. In the majority of young fragile X patients studied, an age-related paroxysmal EEG pattern was found, which showed neurophysiologic characteristics very similar to those of the centrotemporal spikes. CONCLUSIONS: These findings confirm that fragile X syndrome can be considered a genetic model of epilepsy.

Adolescent↗

PubMed1998

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.

Adolescent↗

PubMed1997

Fragile X syndrome. Molecular and clinical insights and treatment issues.

The fragile X syndrome is the most common inherited cause of mental retardation that is known. The prevalence of mental retardation from this syndrome ranges from 1 in 1,250 to 1 in 4,000 in the general population, although the prevalence of female carriers has been reported to be as high as 1 in 259. The discovery of the FMR1 gene mutation in 1991 has simplified diagnosis, enhanced our understanding of the spectrum of involvement in the fragile X syndrome, and stimulated research regarding the normal function of the FMR1 protein in brain development. Advances have also occurred in the treatment of the fragile X syndrome, and psychopharmacologic and educational interventions are reviewed here.

Adult↗

PubMed1996

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.

Adolescent↗