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1.
Neurobehavioral effects of the fragile X premutation in adult women: a controlled study. 总被引:7,自引:3,他引:4
A L Reiss L Freund M T Abrams C Boehm H Kazazian 《American journal of human genetics》1993,52(5):884-894
Although previous studies have suggested that the fragile X premutation (fra [X] pM) does not cause deleterious effects, methodological constraints have prevented more definitive conclusions from being reached. In this report, we describe the neuropsychiatric and cognitive-neuropsychological status of 34 adult women with the fra (X) pM, as compared with a well-matched control group of 41 mothers of fra (X)-negative children with developmental disability. The results indicate that there are no meaningful differences between adult women with the fra (X) pM and control subjects with respect to cognitive abilities or profile, neuropsychological function, psychiatric diagnoses or symptoms, and self-rated personality profile. No measure for either group showed evidence of functioning outside the normal range except for a high lifetime prevalence of major depression in both groups. Additional exploratory analyses within the fra (X) group showed no significant effect of either the size of the fra (X) insert or X chromosome inactivation pattern in leukocytes, on any measure of neurobehavioral function. These findings provide additional information to professionals providing genetic counseling to, and assessment of, fra (X) families. 相似文献
2.
Frequency of the fragile X syndrome in institutionalized mentally retarded females in Japan 总被引:1,自引:0,他引:1
Summary The fragile X [fra(X)] syndrome was screened on 190 Japanese institutionalized females with moderate to severe mental retardation. Two inmates with severe mental retardation (IQ 20) had the fra(X) chromosome in 26% and 15% of the cells examined, indicating that the prevalence of the fra(X) syndrome was about 1% in all female inmates and was about 3.27% in severely mentally retarded females with known causes. However, no female with fra(X) syndrome was found in 35 moderately retarded females. Both had brothers with the fra(X) syndrome and the prevalence was 10% in females with a family history of mental retardation. In addition, the replication study of the fra(X) chromosome in the patients supported the proposal that an excess of the early replicated fra(X) chromosome is related to the mental capacity in heterozygous females. Therefore, the fra(X) syndrome should not be ignored even in severely mentally retarded females with a family history, though the heterozygotes are commonly normal to subnormal in their mental development. in addition, the replication study of the fra(X) chromosome may help to estimate mental development in the carrier children. 相似文献
3.
Rachel H. Tan Emma Devenney Carol Dobson-Stone John B. Kwok John R. Hodges Matthew C. Kiernan Glenda M. Halliday Michael Hornberger 《PloS one》2014,9(8)
Amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD) are multisystem neurodegenerative disorders that manifest overlapping cognitive, neuropsychiatric and motor features. The cerebellum has long been known to be crucial for intact motor function although emerging evidence over the past decade has attributed cognitive and neuropsychiatric processes to this structure. The current study set out i) to establish the integrity of cerebellar subregions in the amyotrophic lateral sclerosis-behavioural variant frontotemporal dementia spectrum (ALS-bvFTD) and ii) determine whether specific cerebellar atrophy regions are associated with cognitive, neuropsychiatric and motor symptoms in the patients. Seventy-eight patients diagnosed with ALS, ALS-bvFTD, behavioural variant frontotemporal dementia (bvFTD), most without C9ORF72 gene abnormalities, and healthy controls were investigated. Participants underwent cognitive, neuropsychiatric and functional evaluation as well as structural imaging using voxel-based morphometry (VBM) to examine the grey matter subregions of the cerebellar lobules, vermis and crus. VBM analyses revealed: i) significant grey matter atrophy in the cerebellum across the whole ALS-bvFTD continuum; ii) atrophy predominantly of the superior cerebellum and crus in bvFTD patients, atrophy of the inferior cerebellum and vermis in ALS patients, while ALS-bvFTD patients had both patterns of atrophy. Post-hoc covariance analyses revealed that cognitive and neuropsychiatric symptoms were particularly associated with atrophy of the crus and superior lobule, while motor symptoms were more associated with atrophy of the inferior lobules. Taken together, these findings indicate an important role of the cerebellum in the ALS-bvFTD disease spectrum, with all three clinical phenotypes demonstrating specific patterns of subregional atrophy that associated with different symptomology. 相似文献
4.
D Belghiti F Razavi-Encha O Raoul G Hirbec F Guillot P Reinert A Sobel 《Annales de génétique》1986,29(4):261-263
The coincidence of fragile X syndrome (fra(X] and systemic lupus erythematosus (SLE) in the same family is reported here for the first time. A 16-year-old boy with typical fra(X) had a severe SLE with multiple organ involvement. His 12-year-old sister of normal intelligence had circulating antinuclear antibodies and proliferative glomerulonephritis. The fra(X) was not found in her karyotype. Except for abnormalities due to immunosuppressive treatment during pregnancy, the association of SLE and chromosome abnormalities has been only reported in Klinefelter's syndrome. The possible pathogenic role of sex hormonal abnormalities due to an extra X chromosome has been suggested in the occurrence of SLE. 相似文献
5.
Summary Clinical and cytogenetic aspects of a female infant with trisomy 21 and the fragile X [fra (X)] chromosome are reported. Most of the facial characteristics of the patient are those observed in Down syndrome, but some features such as long face with prominent forehead and lower jaw, and large ears are related to the fra (X) syndrome. The origin of an additional chromosome 21 may be ascribed to maternal first meiotic nondisjunction in our case. It has been suspected that female carriers of the fra (X) chromosome may be predisposed to meiotic nondisjunctional events. However, there is probably no relationship between the two chromosomal abnormalities in our case because of the maternal age at the delivery. 相似文献
6.
Auditory brain-stem responses (ABRs) were recorded from a group of 12 mentally retarded males with the fragile X (fra[X]). The responses were analyzed in terms of ABR thresholds, absolute latencies, and interpeak latencies. One patient had increased ABR thresholds, indicating hearing impairment. Five fra(X) subjects had prolonged I-V interpeak latencies. Comparisons between the fra(X) group (excluding one possible hard-of-hearing subject) and a control group of age-matched males with normal intelligence showed that the fra(X) group's interpeak latencies were significantly prolonged for the III-V and I-V but not for the I-III. This pattern of prolongation of interpeak latencies suggests that central, as opposed to peripheral, nervous-system dysfunction predominates in many patients having this syndrome. In addition, frequently observed prolongation of the transmission time may indicate that brain-stem white-matter functioning is also apt to be involved in this syndrome. 相似文献
7.
Martha Mayer Michael A. Abruzzo Patricia A. Jacobs Stanley C. Yee 《Human genetics》1985,69(3):206-208
Summary A cytogenetic survey of a population of 278 mentally retarded females on community placement is described. Thirty-five females had an aneuploid chromosome constitution and a single female was found to have the fra(X) syndrome. The frequency of the fra(X) syndrome among female retardates is discussed together with the apparent absence of de novo mutants among this class of fra(X) probands. 相似文献
8.
Fragile (X) X-linked mental retardation. II. Frequency and replication pattern of fragile (X)(q28) in heterozygotes 总被引:4,自引:4,他引:0
The frequency of cytologic expression and the replication pattern of the fragile (X) [fra(X)] were investigated in 28 fra(X) heterozygotes, of which 25 agreed to psychological assessment. One-third of the heterozygotes in this study are mentally retarded. The intellectually impaired carriers had a higher frequency of fra(X) and a higher proportion of early-replicating fra(X) than the normally intelligent carriers. The early-replicating fra(X) accounted for 39% of the variability in IQ and the late-replicating fra(X) for 12%. Age had a minimal inverse effect on fra(X) expression and replication pattern. Thus, it appears that mental retardation in females heterozygous for the fra(X) may largely be a function of the proportion of cells with an early-replicating, active X chromosome possessing the fragile site. 相似文献
9.
W. T. Brown E. C. Jenkins A. C. Gross C. B. Chan M. S. Krawczun C. J. Duncan S. L. Sklower G. S. Fisch 《Human genetics》1987,75(4):311-321
Summary The X-linked fragile X[fra(X)] syndrome, associated with a fragile site at Xq27.3, is the most common Mendeban inherited form of mental deficiency. Approximately 1 in 1060 males and 1 in 677 females carry the fra (X) chromosome. However, diagnosis of carrier status can be difficult since about 20% of males and 44% of females are nonpenetrant for mental impairment and/or expression of fra (X). We analyzed DNA from 327 individuals in 23 families segregating fra (X) for linkage to three flanking polymorphic probes: 52A, F9, and ST14. This allowed probable nonpenetrant, transmitting males and carrier females to be identified. A combined linkage analysis was conducted using these families and published probe information on F9 in 27 other families, 52A in six families, and ST14 in five families. The two-point recombination fraction for 52A-F9 was 0.13 (90% confidence interval, 0.10–0.16), for F9-fra(X) was 0.21 (0.17–0.24), and for fra(X)-ST14 was 0.12 (0.07–0.17). Tight linkage between F9 and fra(X) was observed in some families; in others loose linkage was seen suggesting genetic linkage heterogeneity. Risk analysis of carrier status using flanking DNA probes showed that probable nonpenetrant transmitting males were included in families showing both tight and loose linkage. Thus, in contrast to our previous conclusions, it appears that the presence or absence of nonpenetrant, transmitting males in a family is not an indicator of heterogeneity. To determine if heterogeneity was present, we employed the admixture test. Evidence for linkage heterogeneity between F9 and fra(X) was found, significant at P<0.0005. Nonsignificant heterogeneity was seen for 52A-F9 linkage. No heterogeneity was found for fra(X)-ST14. The frequency of fra(X) expression was significantly lower in families with tight F9-fra(X) linkage than in families with loose linkage. Cognition appeared to relate to linkage type: affected males in tight linkage families had higher IQs than those in loose linkage families. These findings of genetic heterogeneity can account in part for the high prevalence and apparent high new mutation rate of fra(X). They will affect genetic counseling using RFLPs. An understanding of the basis for genetic heterogeneity in fra(X) will help to clarify the nature of the unusual pattern of inheritance seen in this syndrome. 相似文献
10.
The X-chromosome was studied in blood lymphocytes of 68 males with aspecific mental retardation (MR), their 57 relatives and 15 intellectually normal males. The incidence of a fragile X-chromosome (fra(X)) was found to be 4.7% in an unselected group of 42 patients, 50% among 10 probands in which pedigree data were suggestive of X-linked MR diagnosis, and 75% in the group of 15 patients selected for phenotype characteristic of the fragile X syndrome. The fra(X) was present in 1-43% of metaphases in different individuals, no such marker being observed in cells of 15 normal individuals. No significant difference was found when the incidence of the fra(X) was compared in cells cultured in the medium 199 with low folic acid content and the Eagle's medium supplemented with 5-fluorodeoxyuridine (10.62 +/- 2.94 SEM and 13.53 +/- 2.85 SEM, respectively). The possibility of false-positive diagnosis of the fragile X syndrome was quantitatively appreciated. A half of the patients showing a fra(C) in conventionally stained chromosomes were found to have fragile 6 autosome as the only marker in these cells, and in patients with the evident fragile (X) syndrome the fra(6) constituted about one-third of the fra(X) frequency. Both culture media employed were similar in the fra(6) induction. 相似文献
11.
A cytogenetic study of mentally retarded school children in taiwan with special reference to the fragile X chromosome 总被引:3,自引:3,他引:0
Summary A cytogenetic study was made on 341 mentally retarded children in the Provincial Nantou Rehabilitation Center for the Mentally Retarded and the St. Raphael Opportunity Center in Tainan. Of the 89 mentally retarded children with chromosomal abnormalities, 63 had Down syndrome, 13 had the fragile X [fra(X)] syndrome, and the remaining had other aneuploid constitutions. Family studies were possible for 2 of the 13 fra(X) probands. The results of this study illustrate the contribution of chromosomal abnormalities to the pathogenesis of mental retardation in children. 相似文献
12.
Skórka A Bielicka-Cymermann J Gieruszczak-Białek D Korniszewski L 《Genetic counseling (Geneva, Switzerland)》2005,16(4):377-382
The thrombocytopenia-absent radius (TAR) syndrome (MIM 274000) is a congenital malformation syndrome characterised by bilateral absence of the radii with present thumbs, hypomegakaryocytic thrombocytopenia and a number of additional features including skeletal and cardiac anomalies. Mental retardation, reported in about 7% of patients, is usually secondary to intracranial hemorrhage. In 1994 there was a single report of a girl with TAR syndrome and hypoplasia of the cerebellar vermis and corpus callosum and in 2003 another case of TAR syndrome with cerebellar dysgenesis has been reported. In 2000 there was first report of horseshoe kidney in association with TAR syndrome followed by a clinical study of 34 cases with TAR syndrome in 2002 where horseshoe kidney was noted in two cases. Here we report of a girl with TAR syndrome, severe mental retardation, agenesis of corpus callosum, hypoplasia of cerebellar vermis and horseshoe kidney. There is no previous report of a child with TAR syndrome and all those associated anomalies in the same patient. 相似文献
13.
The fragile X premutation in carriers and its effect on mutation size in offspring. 总被引:9,自引:3,他引:6
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G S Fisch K Snow S N Thibodeau M Chalifaux J J Holden D L Nelson P N Howard-Peebles A Maddalena 《American journal of human genetics》1995,56(5):1147-1155
The pattern of inheritance in the fragile X (fra(X)) mutation follows a multistage intergenerational process in which the premutation evolves into the full mutation and the characteristic phenotype of the fra(X) syndrome after passing through oogenesis or a postzygotic event. Findings from our multicenter study confirm a strong direct relationship between fra(X) premutation size in the mother and probability of a full mutation in offspring with the mutation. Remarkably, the best-fitting equations are nonlinear asymptotic functions. The close approximation to both the logistic model and Gompertz suggests a process of accumulation of errors in DNA synthesis, as has been proposed previously. We also note that a larger-than-expected number of daughters of transmitting males have premutations that are smaller than their fathers', and that proportion is significantly higher than the proportion of daughters whose premutations are smaller than their mothers'. Intergenerational decreases in premutation size have been reported in other trinucleotide-repeat disorders and also appear to be parent-of-origin specific. Thus, while intergenerational expansion to the full mutation in fra(X) may manifest a postzygotic event, decreases in mutation size may occur during or prior to meiosis. 相似文献
14.
Acrocallosal Syndrome is a rare genetic disorder which is characterized by moderate to severe mental retardation, agenesis or hypoplasia of the corpus callosum and polydactyly of fingers and toes. The spectrum of this syndrome is very variable. Prominent forehead, broad nasal bridge, short nose and mandible, hypertelorism, epicanthic folds, large anterior fontanelle and tapered fingers, omphalocele and inguinal hernia are some other common findings in this syndrome. Twenty percent of the patients have associated brain abnormalities such as cerebral atrophy, hypothalamic dysfunction, small cerebrum, micropolygyria, hypoplasia of pons, hypoplasia of cerebellar hemispheres, hypoplasia of medulla oblongata, agenesis or hypoplasia of cerebellar vermis and corpus callosum abnormalities. Here we present a 10-month-old female infant with clinical and radiological findings indicative of acrocallosal syndrome. She was noted to have craniofacial abnormalities suggestive of acrocallosal syndrome, optic atrophy and polydactyly. MRI revealed cerebral atrophy, corpus callosum agenesis, dilated lateral ventricules and unilateral right temporal lobe hypoplasia, the latter not previously reported in the spectrum of this syndrome. Based on this observation we conclude the importance of screening brain abnormalities and present temporal lobe hypoplasia as a new additional anomaly in this syndrome. 相似文献
15.
Arrieta I Criado B Martinez B Telez M Nuñez T Peñagarikano O Ortega B Lostao CM 《Annales de génétique》1999,42(4):197-201
Fragile X syndrome is the most common inherited form of mental retardation. The syndrome is associated with a CGG repeat expansion in the 5'UTR of the first exon of the FMR1 gene. This gene maps to Xq27.3 and coincides with the cytogenetic fragile site (FRAXA). The present study deals with the prevalence of fragile X syndrome among individuals with mental retardation of unknown cause from institutions and special schools from the Spanish Basque Country. Results of cytogenetic and molecular studies, performed in a group of 134 unrelated individuals (92 males and 42 females) are presented. The cytogenetic marker at Xq27.3 was identified in 12 patients. Other chromosomal abnormalities were found in two cases that this and previous studies confirmed as Angelman and Prader-Willi syndromes. Two males, in whom the cytogenetic marker was identified, were found negative for FRAXA and FRAXE expansion at the molecular level. The present study shows that the frequency of the FRAXA full mutation in individuals of Spanish non-Basque origin is in the range of other Spanish populations. In the sample of Spanish Basque origin we have not found cytogenetic FRAXA site expression, and the CGG repeat size of FMR1 gene is in the normal range. The significance of these results are discussed. 相似文献
16.
Patients with the ciliopathy Joubert syndrome present with physical anomalies, intellectual disability, and a hindbrain malformation described as the “molar tooth sign” due to its appearance on an MRI. This radiological abnormality results from a combination of hypoplasia of the cerebellar vermis and inappropriate targeting of the white matter tracts of the superior cerebellar peduncles. ARL13B is a cilia-enriched regulatory GTPase established to regulate cell fate, cell proliferation, and axon guidance through vertebrate Hedgehog signaling. In patients, mutations in ARL13B cause Joubert syndrome. To understand the etiology of the molar tooth sign, we used mouse models to investigate the role of ARL13B during cerebellar development. We found that ARL13B regulates superior cerebellar peduncle targeting and these fiber tracts require Hedgehog signaling for proper guidance. However, in mouse, the Joubert-causing R79Q mutation in ARL13B does not disrupt Hedgehog signaling nor does it impact tract targeting. We found a small cerebellar vermis in mice lacking ARL13B function but no cerebellar vermis hypoplasia in mice expressing the Joubert-causing R79Q mutation. In addition, mice expressing a cilia-excluded variant of ARL13B that transduces Hedgehog normally showed normal tract targeting and vermis width. Taken together, our data indicate that ARL13B is critical for the control of cerebellar vermis width as well as superior cerebellar peduncle axon guidance, likely via Hedgehog signaling. Thus, our work highlights the complexity of ARL13B in molar tooth sign etiology. 相似文献
17.
Summary Among 243 institutionalized mentally retarded males in Japan, 13 patients (5.3%) with the fre(X)(q27) from nine families were detected. These 13 patients accounted for 8.6% of 152 male inmates with unknown causes of mental retardation in the population. One out of nine pedigrees had an apparently unaffected male transmitter of this disorder. Our data agree with the frequencies of the fra(X) syndrome in various retarded populations, most of which were Caucasians, suggesting that the prevalence of the fra(X) syndrome in Japanese is not significantly different from those in Causasians. 相似文献
18.
Blank MC Grinberg I Aryee E Laliberte C Chizhikov VV Henkelman RM Millen KJ 《Development (Cambridge, England)》2011,138(6):1207-1216
Heterozygous deletions encompassing the ZIC1;ZIC4 locus have been identified in a subset of individuals with the common cerebellar birth defect Dandy-Walker malformation (DWM). Deletion of Zic1 and Zic4 in mice produces both cerebellar size and foliation defects similar to human DWM, confirming a requirement for these genes in cerebellar development and providing a model to delineate the developmental basis of this clinically important congenital malformation. Here, we show that reduced cerebellar size in Zic1 and Zic4 mutants results from decreased postnatal granule cell progenitor proliferation. Through genetic and molecular analyses, we show that Zic1 and Zic4 have Shh-dependent function promoting proliferation of granule cell progenitors. Expression of the Shh-downstream genes Ptch1, Gli1 and Mycn was downregulated in Zic1/4 mutants, although Shh production and Purkinje cell gene expression were normal. Reduction of Shh dose on the Zic1(+/-);Zic4(+/-) background also resulted in cerebellar size reductions and gene expression changes comparable with those observed in Zic1(-/-);Zic4(-/-) mice. Zic1 and Zic4 are additionally required to pattern anterior vermis foliation. Zic mutant folial patterning abnormalities correlated with disrupted cerebellar anlage gene expression and Purkinje cell topography during late embryonic stages; however, this phenotype was Shh independent. In Zic1(+/-);Zic4(+/-);Shh(+/-), we observed normal cerebellar anlage patterning and foliation. Furthermore, cerebellar patterning was normal in both Gli2-cko and Smo-cko mutant mice, where all Shh function was removed from the developing cerebellum. Thus, our data demonstrate that Zic1 and Zic4 have both Shh-dependent and -independent roles during cerebellar development and that multiple developmental disruptions underlie Zic1/4-related DWM. 相似文献
19.
Qiang Wang Bo Xiang Wei Deng Junyao Wu Mingli Li Xiaohong Ma Yingcheng Wang Lijun Jiang Grainne McAlonan Siew E. Chua Pak C. Sham Xun Hu Tao Li 《PloS one》2013,8(9)
Reduced Gray matter (GM) volume is a core feature of schizophrenia. Mapping genes that is associated with the heritable disease-related phenotypes may be conducive to elucidate the pathogenesis of schizophrenia. This study aims to identify the common genetic variants that underlie the deficits of GM volume in schizophrenia. High-resolution T1 images and whole genome genotyping data were obtained from 74 first-episode treatment-naïve patients with schizophrenia and 51 healthy controls in the Mental Health Centre of the West China Hospital, Sichuan University. All participants were scanned using a 3T MR imaging system and were genotyped using the HumanHap660 Bead Array. Reduced GM volumes in three brain areas including left hOC3v in the collateral sulcus of visual cortex (hOC3vL), left cerebellar vermis lobule 10 (vermisL10) and right cerebellar vermis lobule 10 (vermisR10) were found in patients with schizophrenia. There was a group by genotype interaction when genotypes from genome-wide scan were subsequently considered in the case-control analyses. SNPs from three genes or chromosomal regions (TBXAS1, PIK3C2G and HS3ST5) were identified to predict the changes of GM volume in hOC3vL, vermisL10 and vermisR10. These results also highlighted the usefulness of endophenotype in exploring the pathogenesis of neuropsychiatric diseases such as schizophrenia although further independent replication studies are needed in the future. 相似文献
20.
Expression of the autosomal folate-sensitive fragile sites in ten kindreds with Martin-Bell syndrome
V Ventruto M Stabile G Gentile G de Tollis M Colantuoni P Sirone L Perone F Lonardo M Della Monica M Fiore 《Annales de génétique》1986,29(1):59-61
The authors analyse the expression of all the folate-sensitive fra sites in a sample of 24 male patients with Martin-Bell syndrome (MBS) and their 12 mothers distributed in 10 kindreds. The cytogenetic results are compared with that of a control group, constituted by 8 unrelated normal subjects. Except for the fra Xq27, there was no autosomal folate-sensitive fra site significantly more expressed in patients with MBS than in the control group. On the basis of the present cytogenetic sample of about 6 500 R-banded mitoses, a list of all the in vitro folate-sensitive fra sites and their relative frequencies is given. 相似文献