Bcl-2 overexpression blocks activation of the death protease CPP32/Yama/apopain

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.     

Risk factors between analgesic use and chronic nephropathy in Thailand

The aim is this study is to compare the longitudinal changes in IQ scores of females and males with fragile X syndrome and controls and to assess the impact on IQ of molecular variations of the FMR-1 gene in males. Medical records from the child development unit at a university-affiliated children's hospital were retrospectively reviewed. Chart review yielded 35 males with fragile X (19 with a fully methylated full mutation, 9 with a mosaic pattern, and 7 with a partially unmethylated full mutation) 16 females with fragile X and a full mutation, 9 female controls, and 9 male controls who had repeated standardized IQ testing separated by 7 months to 13 years. The differences between the first and last IQ scores from the same IQ test were compared by t tests and subsequently by analysis of variance. Overall, a significant IQ decline was seen in 10/35 (28%) of fragile X males, 0/9 (0%) of control males, 6/16 (36%) of fragile X females, and 1/9 (11%) of control females. The initial t tests and analysis of variance showed a significant difference in IQ (p = 0.02) between fragile X males and control males but did not show a significant difference between males and females with fragile X syndrome or between fragile X and control females. When an analysis of covariance was carried out with the initial IQ as a covariable, a significant difference persisted between fragile X and control males, with a greater IQ decline in fragile X males. There were limitations in using the same IQ test. A comparison among the molecular subgroups of males yielded a significant IQ decline in 3/9 (33%) of mosaic males, 6/19 (32%) of fully methylated full mutation males, and 1/7 (14%) of partially methylated full mutation males. An analysis of covariance using the initial IQ and the intertest interval as covariables demonstrated significant differences between the fragile X molecular subgroups and the controls. Our findings show that a substantial percentage of both male and female fragile X patients and female control patients demonstrated significant IQ decline. There was a significant difference in the IQ change between fragile X and control males. There were no significant differences between fragile X and female controls. There were also significant differences in IQ decline among males with different molecular patterns compared with controls. Males with a mosaic pattern versus control males had the most significant decline of the molecular subtypes. Although the numbers were limited, there was no significant IQ decline in males with less than 50% methylation of the full mutation. This suggests that a small amount of FMR-1 protein production, which is often seen in males with less than 50% methylation, protects against significant IQ decline.     

Mouse running activity is lowered by Brucella abortus treatment: a potential model to study chronic fatigue

We examined the prevalence of the fragile X mental retardation (FMR1) full mutation and fragile X E mutation (FMR2) among preschoolers evaluated for language delay. A total of 534 preschoolers recruited from a Developmental Pediatric or Speech and Language Disorders clinic were tested with Southern blot and polymerase chain reaction DNA analyses; 3 were found to have the FMR1 full mutation. None of the 534 children tested positive for the FMR2 full mutation; however, 3 children had unusually small FMR2 alleles suggestive of FMR2 deletions. Screening for fragile X among language-delayed preschoolers is warranted, particularly when there is a family history of mental retardation, but regardless of sex or the presence of behavioral or physical features associated with the fragile X phenotype. The potential benefit of screening for FMR2 alterations is an unexpected implication of the study and is worthy of continued exploration.     

Profile of cognitive functioning in women with the fragile X mutation.

Two studies tested the specificity of the neurocognitive profile of women with fragile X syndrome (FXS). First, women with an FXS full mutation were compared with women with a premutation and women without FXS who grew up in FXS families. Women with FXS had a significantly lower IQ than the other groups, and analyses of subtest profiles showed they had a relative weakness on Arithmetic and strength on Picture Completion. Women with FXS performed worse than the other groups on executive function, spatial ability, and visual memory. Next, women with FXS were compared with women without FXS matched on age and IQ. A similar IQ profile was found, but women with FXS were worse than controls only on executive function. The authors also examined which neurocognitive indices were related to the underlying biology of the disorder. Overall, the results indicated that executive rather than visuospatial deficits were primary in the neurocognitive profile of FXS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Molecular biologic screening test (PCR) for fragile X syndrome

Fragile X syndrome is the most common inherited from of familial mental retardation. It is caused by an expanded CGG repeat in the first exon of the fragile X mental retardation gene. A polymerase chain reaction based technique was used for the identification of full mutations among men. According to our conditions full mutations failed to amplify. An internal control was used at a CG rich region 147 bp upstream of the polymorphic region. The bands were visualised on silver stained polyacrylamide gels. From the 57 individuals studied molecular analysis was performed on 38 males and 16 females. From the 26 males with suspected fragile X syndrome 9 males resulted in no amplification of the 500 kb product, all having a positive cytogenetic result for fragile X syndrome. One cytogeneticly positive male had normal results by molecular studies suggesting a different mutation. All control males had normal results. The results on the 16 females studied were inconclusive. We suggest that our method is highly sensitive and specific for screening males for fragile X syndrome.     

Effect of the Fragile X Status Categories and the Fragile X Mental Retardation Protein Levels on Executive Functioning in Males and Females With Fragile X.

The effects of a fragile X disorder on executive function impairment were assessed in 144 extended families, which included individuals with fragile X premutation and full mutation and their relatives without fragile X. A modification of the maximum-likelihood estimators for pedigree data, as well as ordinal logistic regression, were used in data analysis. The most outstanding deficit, occurring especially in males, involved impaired capacity to use an intention to regulate purposeful behavior. This deficit occurred independently of general cognitive impairment but was related to depletion of fragile X mental retardation 1 gene protein product. The other executive function deficits were accounted for by the general cognitive impairment. Possible mechanisms of the effect of fragile X premutation on impairments of executive functioning are considered. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mental status and fragile X expression in relation to FMR-1 gene mutation

The fragile X mental retardation syndrome is caused by unstable expansion of a CGG repeat in the FMR-1 gene. Clinical expression is associated with a large expansion of the CGG repeat. The mutation in the FMR-1 gene and the cytogenetic expression of the fragile site at Xq27.3 have been studied in 52 fragile X male patients. The percentage of the cytogenetic expression of the fragile site at Xq27.3 positively correlates with the mean size of the full mutation in the FMR-1 gene (p < 0.0001) irrespective of the presence of additional premutation alleles. We noted a less frequent occurrence of additional premutation alleles in adult patients compared with juveniles, suggesting a continued mitotic instability in life. Additionally, the level of mental retardation has been ascertained in 35 patients using the Stanford-Binet or Terman-Merrill test of general intelligence. The presence of a full mutation in the FMR-1 gene seemed decisive for the occurrence of mental impairment in the patient. No correlation is observed between the degree of mental retardation and the size of the full mutation. The degree of mental retardation seemed not to be influenced by the presence of premutation alleles in part of the cells in addition to a full mutation. One patient is described with the 'Prader-Willi-like' subphenotype of the fragile X syndrome, showing a deletion in the FMR-1 gene in a part of his cells in addition to a full mutation.     

Comparison of the WAIS and WAIS—R: Different results for different IQ groups.

Using a procedure that eliminated repetition of identical items, thus avoiding order effects, we administered the Wechsler Adult Intelligence Scale (WAIS) and the WAIS—Revised to 108 subjects. All correlations between the two tests were significant and similar to those reported in the WAIS—R manual. For the group as a whole, verbal, performance, and full scale IQ scores on the WAIS—R were significantly lower than their respective WAIS scores; however, this difference was not consistent across IQ levels. Subjects of both average and borderline intelligence had WAIS IQ scores significantly above their WAIS—R scores. For the mildly retarded subjects, the performance IQs were equal for the WAIS and WAIS—R, whereas the WAIS—R verbal and full scale IQ scores were higher than the corresponding WAIS IQ scores. However, these score differences were small (1 point) and of little practical value. The differences of moderately retarded subjects, on the other hand, were large and in the reverse direction: the WAIS—R IQ scores were significantly higher than the WAIS IQ scores. Clinical implications of these findings are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cognitive Strengths and Weaknesses in Children and Adolescents Homozygous for the Galactosemia Q188R Mutation: A Descriptive Study.

Children and adolescents (n = 25) with galactosemia homozygous for the common Q188R mutation (substitution of glutamine codon 188 with arginine) were group matched for sex and age with healthy control participants (n = 20). Participants were administered an abbreviated neuropsychological battery by a doctoral-level psychologist. Results indicate that children and adolescents with galactosemia function generally within the low average IQ range, with a small standard deviation (indicating a relatively homogeneous IQ profile), and have many features suggestive of left-hemisphere dysfunction. Word retrieval difficulties are a primary component of the galactosemia profile. In addition, participants with galactosemia have less well-developed executive functions. Child and parental reports of behavioral symptoms differ; parents reported that their children had more internalizing symptoms than the children with galactosemia self-reported. Cognitive complications in galactosemia appear to emerge even in well-treated children. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Environmental implications of excessive selenium: a review

Reports of autistic behaviors were examined for 30 school-age girls with fragile X (fraX) and 31 age- and IQ-matched controls through a structured interview administered to each girl's parent(s). IQ scores were obtained for each participant; anxiety, neuroanatomical, and molecular-genetic data were derived for girls with fraX. Girls with fraX had significantly more autistic behaviors than controls. These behaviors were qualitatively similar to those reported for boys with fraX, but were not correlated with IQ. Anxiety in girls with fraX was positively correlated with abnormal social and communication behaviors; posterior cerebellar vermis area was negatively correlated with measures of communication and stereotypic/restricted behaviors. Severity of stereotypic/restricted behaviors was negatively correlated with the prevalence of active non-fraX chromosomes. Thus anxiety and posterior cerebellar area measures had distinct associations with subsets of autistic behaviors; these associations may have important implications for understanding the neurobiology of autism.     

Fragile X syndrome and fragile XE mental retardation

There are two forms of mental handicap associated with fragile sites on the end of the long arm of the X chromosome. The well known common disorder Fragile X syndrome is associated with FRAXA and a rare non-specific form of mental handicap is associated with FRAXE. The cytogenetics of these fragile sites is considered. For Fragile X syndrome details are given of the molecular genetics, inheritance patterns, genetic counselling, methods for diagnosis of index cases, carrier detection and prenatal diagnosis. Series of prenatal diagnoses are briefly reviewed and technical and biological problems associated with this procedure are considered. Prenatal diagnosis of Fragile X syndrome using molecular genetic techniques is now a well established procedure, with the only significant problem being the inability to accurately predict phenotype in female fetuses with full mutations. Few prenatal diagnoses of Fragile XE non-specific mental retardation have been recorded. In principle the technical aspects of such a prenatal diagnosis should be little different from those for Fragile X syndrome. Incomplete knowledge of the phenotypic effect of the full mutation in males and females would make phenotypic prediction for any fetus shown to have such a mutation very difficult. At this stage all that could be determined with precision is that the mutation was present or absent in the fetus. Possible consequences of this are discussed.     

Effects of prednisolone on bone turnover in patients with corticosteroid resistant asthma

Many galactosaemics appear to have neuropsychological and/or linguistic problems in spite of dietary treatment. Because the neonatal screening program in Norway does not include galactosaemia, we have re-examined Norwegian galactosaemics. Of 16 known patients, 8 patients participated in the study. They had been diagnosed between 2 and 11 weeks of age, and were between 9 months and 19 years old at the time of this study. All had very low or 0 activity of galactose-1-phosphate uridyl transferase. As part of the study all were examined neurologically, and had an age-appropriate developmental/IQ test, an ABR and an EEG, and a comprehensive psycholinguistic evaluation. The three youngest patients had normal developmental/IQ tests, while the five older patients had IQ scores in or below low range of normal. The majority had delayed language development and three patients were classified as having verbal dyspraxia. ABR and EEG showed mild pathology in the oldest patient only. Galactosaemia appears to be associated with significant risks of developmental and language delays in this unscreened population.     

Screening for CGG trinucleotide repeat expansion in the fragile X mental retardation 1 gene in schizophrenic patients

Patients diagnosed using DSM-III-R criteria as having schizophrenia and other related disorders (n = 128) were assessed for CGG trinucleotide repeat expansion in the fragile X mental retardation 1 (FMR-1) gene. One subject, a woman with schizophreniform disorder, was found to have a premutation of the gene. Her case report is given. The present investigation supports the view that mutation or premutation of the FMR-1 gene is not of importance for the aetiology of the vast majority of schizophrenic patients.     

The pineal complex and melatonin affect the expression of the daily rhythm of behavioral thermoregulation in the green iguana

A person's intelligence (or IQ) has long been synonymous with cognitive and general abilities to function daily on an effective level. When traumatic brain injury occurs, there is a natural desire to find some measure that identifies the amount of damage that has occurred and whether it is permanent or temporary. Given the popularity of the IQ test, there is a tendency to use this measure as such a yardstick. It is argued that such a global measure is not appropriate. The predominant reason that it is not a wise choice is that IQ test does not tap into many of the critical areas of a person's functioning, such as personality regulation, shorter-term memory, various types of attentional capacity, and the ability to organize and plan effectively. Rather, to truly and accurately reflect a person's neuropsychological strengths and weaknesses requires the use of many different measures, not just a single one such as an IQ score.     

Improved peripheral nerve conduction, EEG and verbal IQ after bone marrow transplantation for adult metachromatic leukodystrophy

A 28-year-old woman with a 4 year history of slowly progressing 'frontal dementia' was diagnosed as having adult metachromatic leukodystrophy and was followed for 4 years after bone marrow transplantation (BMT). MRI, neurophysiological tests (EEG, ENeG, VEP, SEP and BAEP) and neuropsychological assessment were performed before, and repeatedly after BMT. MRI showed symmetrical white matter lesions in the frontal and parieto-occipital lobes and in the corpus callosum. EEG showed frontal and temporal slow wave abnormalities and nerve conduction was slow. Neuropsychological tests showed cognitive impairment in executive functions, decline in visuospatial-constructive and spatial memory tasks and disorganized thinking. IQ was low (52), with slightly better values for verbal IQ than for performance IQ. After BMT, the patient was followed for 4 years. Clear improvements were seen in EEG, in peripheral nerve conduction and in neuropsychological tests (especially in verbal IQ). MRI findings were unchanged. We believe that the improvement in our patient resulted from the bone marrow transplantation.     

Insert size and flanking haplotype in fragile X and normal populations: possible multiple origins for the fragile X mutation

A number of recent studies have found non-random association between the fragile X mutation and genotypes for the closest-linked flanking markers, suggesting either a limited number of 'founder' mutations or, alternatively, a predisposing haplotype for the fragile X expansions. Using three microsatellite markers within 150 kb of FRAXA, we have compared haplotypes in a series of fragile X males and in a control population and find a markedly different distribution in the two samples, with apparently greater haplotype diversity in the fragile X sample. In the control sample, various non-random associations of CGG repeat numbers with flanking haplotypes were recorded which provide a clue to the likely origins of the fragile X mutation, suggesting more than one mechanism for the initial expansion event.     

Perspectives and molecular diagnosis of the fragile X syndrome

The fragile X syndrome is the most common mendelianly inherited form of mental retardation. The underlying mutation is usually a triplet repeat (CGG) that is variable in length and undergoes a tremendous length amplification in affected individuals. The mutation leads to absence expression of a gene, which apparently functions as an RNA binding protein. Molecular diagnostic testing for the mutation is conducted using direct genomic Southern blot analysis and polymerase chain reaction. Because the mutation is so common and a single type of mutation accounts for most individuals with the disease, widespread genetic screening can be considered.