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The FMR1 premutation (PM:55-199 CGG) is associated with fragile X-associated tremor/ataxia syndrome (FXTAS) and when maternally transmitted is at risk of expansion to a hypermethylated full mutation (FM: ≥ 200 CGG) that causes fragile X syndrome (FXS). We describe a maternally transmitted PM (77 CGG) that was passed to a son (103 CGG), and to a daughter (220-1822 CGG), who were affected with FXTAS and FXS, respectively. The male with the PM showed low-level mosaicism for normal size of 30 and 37 CGG. This male had two offspring: one female mosaic for PM and FM (56, 157, >200 CGG) and another with only a 37 CGG allele detected in multiple tissues, neither with a clinical phenotype. The female with the 37 CGG allele showed normal levels of FMR1 methylation and mRNA and passed this 37 CGG allele to one of her daughters, who was also unaffected. These findings show that post-zygotic paternal retraction can lead to low-level mosaicism for normal size alleles, with these normal alleles being functional when passed over two generations.

Background: There is growing evidence to suggest that children with neurodevelopmental disorders may evidence differences in their sensory processing. The aim of this study was to compare sensory processing patterns in three genetic syndromes associated with sensory difference. Methods: Sensory processing in Angelman syndrome (n = 91), Cornelia de Lange syndrome (n = 28) and Fragile X syndrome (n = 40) was examined using the informant report measure the Sensory Experiences Questionnaire (SEQ). Results: All three groups were associated with a heightened prevalence of unusual sensory processing in comparison with normative data, evidenced in over 80% of all participants. Cross-syndrome comparisons highlighted syndrome-specific sensory processing profiles, with heightened hypo responsivity in Cornelia de Lange syndrome and sensory seeking in Angelman syndrome. Conclusions: The results have important implications for the understanding of sensory processing in genetic syndromes and the development of tailored behavioural interventions.

Instability of the FMR1 repeat, commonly observed in transmissions of premutation alleles (55–200 repeats), is influenced by the size of the repeat, its internal structure and the sex of the transmitting parent. We assessed these three factors in unstable transmissions of 14/3,335 normal (~5 to 44 repeats), 54/293 intermediate (45–54 repeats), and 1561/1,880 premutation alleles. While most unstable transmissions led to expansions, contractions to smaller repeats were observed in all size classes. For normal alleles, instability was more frequent in paternal transmissions and in alleles with long 3′ uninterrupted repeat lengths. For premutation alleles, contractions also occurred more often in paternal than maternal transmissions and the frequency of paternal contractions increased linearly with repeat size. All paternal premutation allele contractions were transmitted as premutation alleles, but maternal premutation allele contractions were transmitted as premutation, intermediate, or normal alleles. The eight losses of AGG interruptions in the FMR1 repeat occurred exclusively in contractions of maternal premutation alleles. We propose a refined model of FMR1 repeat progression from normal to premutation size and suggest that most normal alleles without AGG interruptions are derived from contractions of maternal premutation alleles.

Premutation carriers of the FMR1 gene (CGG repeats between 55 and 200) usually have normal intellectual abilities but approximately 20% are diagnosed with developmental problems or autism spectrum disorder. Additionally, close to 50% have psychiatric problems such as anxiety, ADHD and/or depression. The spectrum of fragile X disorders also includes Fragile-X-associated primary ovarian insufficiency (FXPOI) in female carriers and Fragile-X-associated tremor/ataxia syndrome (FXTAS) in older male and female carriers. We evaluated 25 premutation carriers in the rural community of Ricaurte Colombia and documented all behavioral problems, social deficits and clinical signs of FXPOI and FXTAS as well as reviewed the medical and obstetric history. We found an increased frequency and severity of symptoms of fragile X spectrum disorders, which might be related to the vulnerability of FMR1 premutation carriers to higher exposure to neurotoxic pesticides in this rural community.

Objectives Expanded carrier testing is acknowledged as an acceptable strategy for carrier testing by the American College of Obstetrics and Gynecology. Limited studies have investigated positivity rates of expanded carrier panels. We describe our experience with 3 commercial laboratory panels varying in size from 3 to 218 disorders. Methods We reviewed outcomes for 3 multigene carrier screening panels: trio (3 diseases), standard (23 diseases), and global (218 diseases). All panels used targeted genotype analysis of preselected mutations via next‐generation sequencing. We calculated positivity rates for each panel. Results Positivity rates were 7.2% for Preparent Trio, 13.2% for Preparent Standard, and 35.8% for Preparent Global. The most frequent positive results in the global panel were (in descending order): abnormal hemoglobin electrophoresis, familial Mediterranean fever, cystic fibrosis, fragile X, glucose‐6‐phosphate dehydrogenase deficiency, alpha‐thalassemia, and nonsyndromic hearing loss. Conclusions While genetic diseases are individually rare, they are cumulatively common. Our experience illustrates that, with a panel of 218 diseases, the likelihood of identifying a carrier can be as high as 36%. Understanding panel positivity rates is one important factor for providers when choosing the right test for their practice, setting appropriate expectations for patients, and planning for follow‐up counseling., What's already known about this topic? Expanded carrier testing is available as an assessment option.Pan‐ethnic–based testing does not rely on ethnicity as a qualification for assessing the presence of specific genetic conditions. What does this study add? This is a report of positivity frequencies for 3 multigene carrier panels offered by a single laboratory ranging from 7.2% to 35.8%.The study includes a list of the most commonly positive conditions on a large expanded carrier panel.

Background: Catatonia‐like presentations in people with autism have been increasingly recognised within research and diagnostic guidelines. The recently developed Attenuated Behaviour Questionnaire has identified that attenuated behaviour [autistic catatonia] is very prevalent in people with autism spectrum disorders (ASDs) and associated with repetitive behaviour. In the current study, we investigated attenuated behaviour within two genetic syndromes associated with ASD and examined ASD and repetitive behaviour as longitudinal predictors of attenuated behaviour. Method: The Attenuated Behaviour Questionnaire was completed by parents/carers of 33 individuals with Cornelia de Lange syndrome (CdLS) and 69 with fragile X syndrome (FXS). Information collected from the same informants 4 years previously was utilised to examine ASD and repetitive behaviour as predictors of later attenuated behaviour, controlling for age, gender and ability. Results: Catatonia‐like attenuated behaviour was reported for individuals with CdLS (30.3%) and FXS (11.6%). Slowed movement was more prevalent in people with CdLS. No other phenotypic differences were observed. Across the two groups, repetitive behaviour predicted the presence of attenuated behaviour 4 years later, after controlling for age, gender and ability. Conclusions: Attenuated behaviour can be identified in individuals with CdLS and FXS and may have an effect on both adaptive behaviour and quality of life. Repetitive behaviours predicted subsequent risk within both groups and should be assessed by services as part of a pro‐active strategy of support.

Fragile X syndrome is the most common form of inherited mental retardation affecting approximately 1/7000 females and 1/4000 males worldwide. The syndrome is due to the silencing/dysfuntion of a single gene, the FRAGILE X MENTAL RETARDATION 1 gene, and affected patients display a variety of physical and mental abnormalities. In the last 15 years, research advances in the fragile X syndrome field have lead to a better understanding of its molecular basis as well as of the pleiotropic phenotypic effects caused by the absence of the fragile X mental retardation protein. Keywords: mental retardation; fragile X; neuron; RNA translation; RNA trafficking

Key Clinical Message This is a report of FMR1 premutation with Prader–Willi phenotype (PWP) and FXTAS. Although the PWP is common in fragile X syndrome (FXS), it has never been described in someone with the premutation. The patient presented intranuclear inclusions, severe obesity, hyperphagia, and ADHD symptoms, typical of the PWP in FXS. In addition, the autopsy revealed multiple architectural cortical abnormalities.

With widespread adoption of fragile X carrier screening in pregnant women, the number of expectant couples receiving news of an unanticipated Fragile X Mental Retardation 1 (FMR1) gene expansion has increased. The most common abnormal result from maternal FMR1 testing involves an intermediate allele, also known as a gray zone result, which requires genetic counseling but poses minimal risk for an adverse developmental outcome. By contrast, the finding of a maternal FMR1 premutation or full mutation during pregnancy has important implications for the woman herself, her unborn child, and her extended family. These multiple levels of impact, in addition to the complex inheritance pattern and variable expressivity of fragile X-associated disorders, cause significant stress for newly identified expectant couples and pose unique challenges for genetic counselors in the prenatal setting. © 2016 John Wiley & Sons, Ltd.

Several studies have demonstrated increased rates of anxiety and depressive disorders among female carriers of the fragile X premutation. However, the majority of these studies focused on mothers of children with fragile X syndrome, who experience higher rates of parenting stress that may contribute to the emergence of these disorders. The present study compared psychiatric symptom presentation (utilizing measures of current symptoms and lifetime DSM-IV Axis I disorders) in 24 female carriers without affected children (mean age = 32.1 years) to 26 non-carrier women from the community (mean age = 30.5 years). We also examined the association between CGG repeat size (adjusted for X activation ratio) and mRNA, with severity of psychiatric symptoms. Women with the premutation reported significantly elevated symptoms of anxiety, depression, interpersonal sensitivity, obsessive-compulsiveness, and somatization relative to controls during the past week. Carriers had significantly higher rates of lifetime social phobia (42.3%) compared to controls (12.5%); however, this comparison did not remain significant after multiple comparison adjustment. Rates of other psychiatric disorders were not significantly elevated relative to controls, though it should be noted that lifetime rates among controls were much higher than previously published population estimates. Although the sample is relatively small, the study of this unique cohort suggests the premutation confers risk for mood and anxiety disorders independent of the stress of parenting children with FXS. Screening for psychiatric disorders in women with the premutation, even before they become parents, is important and highly encouraged. © 2016 Wiley Periodicals, Inc.

Introduction: In this study we examined whether females with the fragile X-associated tremor ataxia syndrome (FXTAS) and non-FXTAS premutation carriers have electro- physiological signs of underlying peripheral neuropathy. Meth- ods: Nerve conduction studies (NCS) were performed on 19 women with FXTAS, 20 non-FXTAS carriers, and 26 age- matched controls. The results were compared with existing data on corresponding male carriers. Results: Women with FXTAS and non-FXTAS carriers had reduced sensory nerve action potential amplitudes. Also, there was a strong trend for reduced compound muscle action potential amplitudes in women with FXTAS, but not in non-FXTAS carriers. No significant slowing of nerve conduction velocities, prolongation of F-wave latencies, or associations with molecular measures was observed. Conclu- sions: This study suggests an underlying axonal neuropathy in women with FXTAS. However, in comparison to men with FXTAS, the NCS abnormalities in women were less severe, possibly due to the effect of a normal X chromosome. Muscle Nerve 52: 234-239, 2015

Little is known about the way in which the characteristics of autism spectrum disorder (ASD) develop and manifest across the age span in individuals with genetic syndromes. In this study we present findings from a two and a half year follow-up of the characteristics associated with ASD in three syndromes: Cornelia de Lange (CdLS), Fragile X (FXS), and Cri du Chat (CdCS). Parents and carers of 251 individuals (CdLS = 67, CdCS = 42, and FXS = 142) completed the Social Communication Questionnaire (SCQ) at Time 1 (T1) and again two and a half years later (T2). The FXS and CdLS groups were more likely to meet the cut-offs for both autism and ASD and show greater severity of ASD related behaviors, at both T1 and T2, compared to the CdCS group. Older individuals (>15yrs) with CdLS were more likely to meet the cut off for ASD than younger individuals (≤ 15yrs) with the syndrome and more likely to show greater severity of social impairments. In FXS repetitive behaviors were found to become less prominent with age and in CdCS social impairments were reported to be more severe with age. There were no significant changes between T1 and T2 in the severity of ASD characteristics in the CdCS and CdLS groups. The FXS group showed significantly fewer repetitive behaviors and less severe impairments in social interaction over this time frame. The findings suggest that while there may be similarities in overall severity and presentation of ASD characteristics in CdLS and FXS, these characteristics have divergent patterns of development within these groups. © 2015 Wiley Periodicals, Inc.

Highlights • The FMR gene is up-regulated in malignant pleural mesothelioma. • Overexpression of dFMR causes overexpression of matrix metalloprotease. • Overexpression of dFMR induces basement membrane degradation. • Overexpression of dFMR results in upregulation of the JNK pathway., Malignant pleural mesothelioma (MPM) is an aggressive form of thoracic cancer with poor prognosis. While some studies have identified the molecular alterations associated with MPM, little is known about their role in MPM. For example, fragile X mental retardation (FMR) gene is up-regulated in MPM but its role in MPM is unknown. Here, utilizing Drosophila genetics, I investigate the possible role FMR may be playing in MPM. I provide evidence which suggests that FMR may contribute to tumorigenesis by up-regulating a matrix metalloprotease (MMP) and by degrading the basement membrane (BM), both important for tumor metastasis. I also demonstrate a novel link between FMR and the JNK pathway and suggest that the effects of FMR in MPM could in part be mediated by up-regulation of the JNK pathway.

Although it is suspected that anxiety modifies the clinical presentation of autism in fragile X syndrome (FXS), neuropsychiatric co-morbidity profiles of these two disorders have not been extensively studied. The National Fragile X Survey was completed for 1,027 males with FXS, for whom yes/no information regarding the presence of several disorders is provided. Although the survey exhibited limited depth and lacked validation by standardized measures, this exploratory study was conducted to take advantage of the data as an opportunity for identifying future lines of inquiry. We addressed the following questions: (i) how do the co-morbidity profiles of FXS males with both autism and anxiety compare to those without anxiety?; (ii) do individuals with autism exhibit specific co-morbidity profiles compared to FXS males with anxiety only, or without either autism or anxiety?; (iii) how do co-morbidity profiles in children ages 3-11 differ from profiles of individuals >12 years? The group with autism and anxiety reported the highest prevalence of attention problems, hyperactivity/impulsivity, self-injurious behavior and aggressiveness. In addition, the lowest prevalence rates of these conditions were often observed in non-anxious groups regardless of autism status. Overall, this exploratory analysis generated several hypotheses for further study: (i) anxiety increases the severity of autism in FXS, particularly through additional behavioral abnormalities; (ii) some neuropsychiatric and behavioral conditions (i.e., attention problems, hyperactivity/impulsivity, aggressiveness) are primarily related to comorbid anxiety, not autism; (iii) prevalence of behavioral abnormalities increases with age. Future studies evaluating these hypotheses should incorporate validated neurobehavioral assessments, and control for cognitive level.

We utilized a sample of 299 adult females aged between 19 and 86 years, carrying fragile X mental retardation (FMR1) alleles with small CCG expansions ranging from 50 to 141 repeats to analyse the relationships between psychological symptoms as assessed by the Symptom Checklist-90-Revised (SCL-90-R) and the size of the CGG repeat in the FMR1 gene. There were highly significant (negative) correlations between the size of the CGG repeat and a great majority of SCL-90-R subscale scores and all the global indices, suggesting that carriers of premutations in the mid-size CGG repeat range may be at greatest risk for the development of psychiatric disorder.

Cognitive and behavioral correlates of molecular variations related to the FMR1 gene have been studied rather extensively, but research about the long-term outcome in individuals with fragile X spectrum disorders remains sparse. In this review, we present an overview of aging research and recent findings in regard to cellular and clinical manifestations of aging in fragile X syndrome, and the FMR1 premutation.

Recently, there has been a wealth of research into structural and functional brain connectivity, and how they change over development. While we are far from a complete understanding, these studies have yielded important insights into human brain development. There is an ever growing variety of methods for assessing connectivity, each with its own advantages. Here we review research on the development of structural and/or functional brain connectivity in both typically developing subjects and subjects with neurodevelopmental disorders. Space limitations preclude an exhaustive review of brain connectivity across all developmental disorders, so we review a representative selection of recent findings on brain connectivity in autism, Fragile X, 22q11.2 deletion syndrome, Williams syndrome, Turner syndrome, and ADHD. Major strides have been made in understanding the developmental trajectory of the human connectome, offering insight into characteristic features of brain development and biological processes involved in developmental brain disorders. We also discuss some common themes, including hemispheric specialization – or asymmetry – and sex differences. We conclude by discussing some promising future directions in connectomics, including the merger of imaging and genetics, and a deeper investigation of the relationships between structural and functional connectivity.

The grey zone (GZ; 45–54 CGG repeats in the FMR1 gene) is considered a normal allele; however, several studies have found a high frequency of GZ in movement disordered populations. Here, we describe neurological features of fragile X-associated tremor/ataxia syndrome (FXTAS) in two carriers of GZ alleles, although FXTAS has been defined as occurring only in premutation carriers (55–200 CGG repeats). Both patients had family members who had premutation and were diagnosed with FXTAS. The presence of relatively high GZ alleles with elevated fragile X mental retardation 1 mRNA (FMR1-mRNA) combined with a family history of FXTAS that may represent a facilitating genetic background for FXTAS are the factors that led to the presence of FXTAS in these individuals with a GZ allele. Further research into clinical involvement of GZ alleles is recommended and the definition of FXTAS may require revision.

Fragile X syndrome (FXS) is the leading genetic cause of autism, accounting for approximately 5% of autism cases with as many as 50% of individuals with FXS meeting DSM-IV-TR criteria for autistic disorder. Both FXS and idiopathic autism (IA) are attributed to genetic causes; however, FXS is an identified single gene disorder whereas autism is a complex disorder with multiple potential causes, some of which have been identified. Studies in IA have focused on the prospective longitudinal examination of infant siblings of children with autism as a target group due to their high risk of developing the disorder. We propose that this same model be applied to the study of infants with FXS. There is a lack of research focusing on the early development of autism within FXS and debate in the literature regarding how to best conceptualise this co-morbidity or whether it should be considered a co-morbid condition at all. Studying the emergence and stability of autism in infants with FXS has multiple benefits such as clarifying the underlying mechanisms of the development of autism in FXS and solidifying similarities and differences between co-morbid FXS with autism and IA. Infant research in both IA and FXS are discussed as well as conclusions and implications for practice and future research.

The major objectives of this project were to develop and evaluate a brochure to help parents make an informed decision about participation in a fragile X newborn screening study. We used an iterative development process that drew on principles of Informed Decision Making (IDM), stakeholder input, design expertise, and expert evaluation. A simulation study with 118 women examined response to the brochure. An independent review rated the brochure high on informational content, guidance, and values. Mothers took an average of 6.5 min to read it and scored an average of 91.1 % correct on a knowledge test. Most women rated the brochure as high quality and trustworthy. When asked to make a hypothetical decision about study participation, 61.9 % would agree to screening. Structural equation modeling showed that agreement to screening and decisional confidence were associated with perceived quality and trust in the brochure. Minority and white mothers did not differ in perceptions of quality or trust. We demonstrate the application of IDM in developing a study brochure. The brochure was highly rated by experts and consumers, met high standards for IDM, and achieved stated goals in a simulation study. The IDM provides a model for consent in research disclosing complicated genetic information of uncertain value.

Objective To determine risks of expansion for normal, intermediate, and premutation FMR1 CGG repeats. Methods PCR was used to compare the FMR1 alleles in prenatal (chorionic villi and amniocytes) and parental samples collected from 1991 to 2010. Prenatal diagnoses were confirmed by Southern analysis. Results Fragile X analysis of 1112 pregnancies identified 558 normal, 106 intermediate, 216 premutation, and 232 full mutation fetuses. Of 509 maternal, intermediate, and premutation alleles, 350 (68.7%) were unstable on transmission with expansions ranging from one repeat to the full mutation. The smallest premutation alleles expanding to the full mutation were in mothers with 65 and 66 repeats. Transmissions from women with or without a family history of fragile X suggested greater instability in women from families that included full mutation expansions. Conclusions The maternal transmissions of alleles with 55 to 59 CGG repeats summarized here indicate that the risk for expansion to full mutation is substantially less than previous estimates for this size category. Most premutation alleles with no family history of fragile X exhibited less instability than those with a history of fragile X. Thus, lower risk estimates for full mutation expansion may be appropriate for women newly identified as premutation carriers through routine screening. Copyright © 2011 John Wiley & Sons, Ltd.

The quest to understand how the brain is able to store information for later retrieval has been pursued by many scientists through the years. Although many have made very significant contributions to the field and our current understanding of the process, few have played as pivotal a role in advancing our understanding as William T. Greenough. The current report will utilize associative learning, a training paradigm that has greatly assisted in our understanding of memory consolidation, to demonstrate how findings emerging from the Greenough laboratory helped to not only shape our current understanding of learning induced anatomical plasticity, but to also launch future analyses into the molecular players involved in this process, especially the Fragile X Mental Retardation Protein.

Neuroimaging methods represent a critical tool in efforts to join the study of the neurobiology of genes with the neurobiology of behaviour, and to understand the neurodevelopmental pathways that give rise to cognitive and behavioural impairments. This article reviews the clinical features and highlights studies with a focus on the relevant gene–brain–behaviour connections observed in neurogenetic syndromes, such as Williams, Rett, Fragile X, Prader-Willi, Angelman, Down and velocardiofacial (22q11.2 deletion) syndromes. The relationship of altered brain regions and activation patterns are discussed for each syndrome, as well as the clinical, cognitive and behavioural correlates of these neuroimaging findings.

Contains fulltext : 87444.pdf (Publisher’s version ) (Closed access) Since only 20% of female fragile X premutation carriers develop premature ovarian failure (POF, i.e., amenorrhea before age of 40 years), and since X chromosome inactivation (XCI) determines the phenotypic severity of full mutation women, we reasoned that the development of POF in fragile X premutation carriers could be due to skewed XCI (XCI ratio >80:20). To determine inactivation ratios and activities of the premutations, inactivation patterns were assessed in peripheral blood samples from 101 fragile X premutation carriers (mean age 47.1 years, range 12-72) through analysis of the AR and FMR1 loci, respectively. In addition, AR inactivation patterns were assessed in peripheral blood samples from 25 women with idiopathic POF (mean age 31.7 years, range 19-48). We addressed the association between age and skewed XCI because older women are prone to XCI skewness. The median XCI ratios were 68% for premutation carriers with POF (N = 37), 67% for premutation carriers without POF (N = 64) and 61% for women with idiopathic POF (N = 25). The incidence of skewing was similar in all groups, that is, 7 of 37 (18.9%) in premutation carriers with POF, 11 of 64 (17.2%) in premutation carriers without POF, and 3 of 25 (12%) in women with idiopathic POF. There was good concordance between inactivation ratios at the two loci tested in 62 premutation carriers (intraclass correlation coefficient = 0.86; P < 0.01). No age-specific skewing was observed. Skewed XCI and activity of the premutation are not associated with POF in fragile X premutation carriers. 01 februari 2010

SUMMARY An investigation of children in schools for the moderately mentally handicapped in Coventry demonstrated that 29 of 259 children had a significant chromosomal abnormality. 10 of 155 boys (6 per cent) and 10 of 104 girls (10 per cent) had the fragile X syndrome. The clinical features which suggested this syndrome in males were IQ in the 50 to 70 range, head circumference greater than the 50th centile and post-pubertal testicular volume greater than the 50th centile. For both males and females, large ears were a useful sign. All children with fragile X had a carrier parent. The occurrence of mental retardation among sibs was one in two for brothers and one in four sisters. Considering all the males with fragile X syndrome resident in Coventry (this and previous studies), there were twice as many in schools for the moderately mentally handicapped as there were in schools for the severely mentally handicapped. There were as many females as males in the schools for the moderately mentally handicapped. RESUME Enfants avec syndrome de chromosome X fragile dans les ecoles pour retardes mentaux legers Une exploration des enfants des ecoles pour retard mental modere a Coventry a montre que 29 parmi 259 enfants presentaient une anomalie chromosomique significative. 10 parmi 155 garcons (6 pour cent) at 10 parmi 104 filles (10 pour cent) presentaient un syndrome d'X fragile. Les caracteristiques cliniques suggerant le syndrome chez les garcons etaient un QI compris entre 50 et 70, un tour de tete superieur au 50eme centile et un volume testiculaire post-pubertaire superieur au 50eme centile. Chez les garcons comme chez les filles, de grandes oreilles etaient un signe d'orientation. Tous les enfants avec X fragile avaient un parent porteur. L'occurence du retard mental dans la fratrie etait d'un pour deux chez les freres et d'un pour quatre chez les soeurs. Considerant tous les garcons avec un syndrome d'X fragile residant a Coventry (Etude actuelle et etude precedente), ceux-ci sont deux fois plus nombreux dans les ecoles pour retard mental modere qu'ils ne le sont dans les ecoles pour arrieration mentale severe. On notait autant de filles que de garcons dans les ecoles pour retard mental leger. ZUSAMMENFASSUNG Kinder mit fragilem X-Syndrom an Schulen fur Kinder mit leichter geigstiger Behinderung Eine Untersuchung von Kindern in Schulen fur Kinder mit leichter geistiger Behinderung in Coventry zeigte, das 29 von 259 Kindern eine eindeutige Chromosomenanomalie aufwiesen. 10 von 155 Jungen (6 Prozent) und 10 von 104 Madchen (10 Prozent) hatten ein fragiles X-Syndrom. Die klinischen Markmale, die dieses Syndrom bei den Jungen vermuten liesen, waren ein IQ zwischen 50 und 70, ein Kopfumfang uber der 50sten Perzentile und eine postpubertare Hodengrose uber der 50sten Perzentile. Sowohl bei den Jungen als auch bei den Madchen waren die grosen Ohren ein hilfreicher Hinweis. Alle Kinder mit fragilem X-Syndrom hatten einen Elternteil mit dieser Erbanlage. Das Auftreten von geistiger Retardierung bei Geschwistern war eins von zweien bei Brudern und eins von vieren bei Schwestern. Berucksichtigt man alle Jungen mit fragilem X-Syndrom in Coventry (aus dieser und fruheren Studien), so fand man zweimal soviele in den Schulen fur Kinder mit leichter geistiger Behinderung als in den Schulen fur geistig schwer Behinderte. Es waren gleich viele Madchen wie Jungen in den Schulen fur Kinder mit leichter geistiger Behinderung. RESUMEN Ninos con cromosoma X fragil en escuelas para ninos moderadamente retardados mentales Una investigacion en ninos de escuelas para moderadamente retrasados mentales en Coventry demostro que 29 de 259 ninos tenian una anomalia cromosomica significativa. 10 de 155 chicos (6 por ciento) y de 104 ninas (10 por ciento) tenian el sindrome de la fragilidad del chromosoma X. Las caracteristicas clinicas que sugerian este sindrome en varones eran un CI entre 50 y 70 una perimetria craneal mayor del 50 centil y un volumen testicular postpubertal mayor que el centil 50. Tanto para ninos como para ninas unas orejas grandes eran un signo util. Todos los ninos con un X fragil tenian un progenitor portador. La existencia de un retraso mental entre los hermanos era de uno cada dos para los hermanos y una cada cuatro en hermanas. Considerando todos los varones con sindrome de fragil X residentes en Coventry (segun el presente estudio y otros previos) habia el doble de ellos en escuelas para moderadamente retrasados que en escuelas para profundos. En las primeras habia tantos chicos como chicas.

The genetic counseling needs of 32 women of normal intelligence at-risk for having children with the fragile-X syndrome (FXS) were determined by a questionnaire study which included assessment of their attitudes toward prenatal diagnosis and the option of pregnancy termination. Eighteen (56%) of the women had one or more children with the FXS and 14 (44%) had no affected children. Twenty-six (81%) of the subjects stated that they would choose to have prenatal diagnosis and 9 (28%) indicated they would terminate an affected pregnancy. There was no significant difference between women who had affected children and those who did not have affected children, nor between Catholics and non-Catholics regarding acceptance of prenatal diagnosis. Catholic women were less likely to consider pregnancy termination than non-Catholics, but the majority of subjects (56%) were unsure what they would do if a fetus they were carrying was found to be affected. Issues the subjects considered most important for discussion with a genetic counselor included: 1) availability of treatment, 2) risk for having an affected grand child, 3) expectations for future functioning of affected children, and 4) availability of prenatal diagnosis.

Apparent reduction in the size of the CGG repeat is reported from seven fragile-X mothers to nine offspring in seven extended families. The overall frequency of the reduction amongst 121 fragile-X mother-fragile-X child transmissions was 7.4%, compared with an 18% reduction in fragile-X father-fragile-X daughter transmissions, but ascertainment bias may account for some underestimation of the frequency of reductions, especially between mothers and their offspring. In one mother-son transmission, a premutation present in the son (with a full mutation present in the mother) was unmethylated. This may be the result of either demethylation with reduction, or undetected mosaicism in the mother. There was no obvious increase in the level of intellectual performance in female offspring who received a reduced fragment from their mothers. Several mechanisms leading to apparent reduction, such as germline mosaicism, deletion or replication slippage, should be considered.

The fragile X [fra(X)] syndrome is the most common inherited form of X-linked mental retardation and is associated with a rare folate sensitive fragile site on the X chromosome at band Xq27.3. Recently, a common fragile site located at chromosome band Xq27.2 was delineated (Sutherland & Baker 1990). In order to confirm the previous findings and to further investigate the conditions required for induction of both types of fragile sites, we studied the use of four experimental protocols. Samples from a control male, two fra(X) males and a fra(X) carrier female were studied. Both common and rare fragile sites were seen in the samples from the fra(X) subjects. Up to 4% of cells showed both common and rare fragile sites on the same X chromosome at the 500 band level. The rare and common fragile sites on the X chromosome could be clearly distinguished. From 1 to 3% of the control cells exhibited the common fragile site, while none exhibited the rare fragile site. These protocols should be useful in resolving questionable fra(X) syndrome diagnoses.

The common fragile site on the end of the long arm of the human X chromosome has been shown to be at a different location from the rare fragile site which produces the fragile X syndrome of intellectual handicap. The different locations can be clearly seen in chromosomes at about the 550 band level of resolution. This finding should help resolve difficulties in fragile X cytogenetics where expression of the common fragile site can lead to false positive diagnoses.

Two hundred and eight fragile X subjects (92 males and 116 females) and matched Australian (60 males and 32 females) and British (122 males and 118 females) normal samples were used to calculate 4 discriminant functions, based on dermatoglyphic measurements. The most efficient discriminating variables between fragile X and normal males, selected by means of the Wilk's stepwise method, included: ridge counts on fingers 1–3, the hallucal (f) count on soles, the atd angle, and pattern intensities in palmar areas 2, 4 and 5 as well as on fingers 4 and 5. In females, the ridge breadth, the hallucal (e) count, the atd angle and pattern intensities in palmar areas 3–5 as well as on fingers 1, 3 and 5 comprised the final discriminant. The misclassification rate based on distributions of individual discriminant scores in each pair of samples, and on prior probabilities, was lowest (16.8%) in fragile X males compared with the Australian normal subjects. In both female comparisons, this rate approached 44%. A bias to misclassification rates resulting from various analytical procedures and some properties of the data are discussed. We conclude that the discriminant function based on dermatoglyphic measured variables alone is not good enough for assessing carrier probabilities for fragile X, especially in females. However, we have been able to select the best discriminators which may be used, together with other measured body characteristics, to obtain a more powerful discriminant function. Moreover, a consideration of discriminant scores based on dermatoglyphic traits only may help in estimating carrier probabilities. We propose that the discriminant function based on such scores is most appropriate for use as a dermatoglyphic diagnostic index, since indices which are derived from frequencies of binary traits tend to understimate misclassification rates.

Movement disorders other than late onset tremor-ataxia in association with fragile X syndrome, the most common identifiable cause of inherited mental retardation, seem to be rare. Here we describe five male patients from three unrelated families with fragile X syndrome that presented with motor and phonic tics. Clinically, 4 patients fulfilled diagnostic criteria for Gilles de la Tourette syndrome (GTS) while 1 patient would have been diagnosed with an adult onset tic disorder. However, in all patients onset of tics was considerably later than in typical GTS. Three patients had atypical tics and two patients reported waxing and waning of tic intensity over time. Four of the 5 patients showed clinical signs typical of fragile X syndrome, in particular dysmorphic features, learning difficulties and speech and language problems that required special treatment. All patients had co-morbidities common to both GTS and fragile X syndrome. We suggest considering fragile X syndrome in GTS complicated by co-morbidity with late onset of atypical tics, in particular when learning disability and dysmorphic features are present.

The effect of folic acid intake on the frequency of fragile X positive cells and some behavioural characteristics were evaluated in 5 boys and 4 adult males with the fragile X syndrome. The expression of fragile X was nullified in 6 and decreased in 3 of the 9 patients. Behavioural and motor ability were considered to have improved in 4 of the 5 boys but not in the 4 adults with fragile X syndrome.

Co-cultivation studies in different combinations have been carried out between cells which have been found to be positive for the fragile (X) (q27) and control cells. As no increase or decrease was discernible in the level of Fra(X) detected in 'positive' cells, and no fragility was introduced into the 'negative' cells, it was concluded that there had been no intercellular co-operation, and a diffusible expression or suppression factor was not involved.

Fragile X syndrome, the most common genetic disorder associated with mental retardation is caused by an expansion of the unstable CGG repeat within the FMR1 gene. Although overgrowth is not the main hallmark of this condition, the fragile X syndrome is usually included in the differential diagnosis of children with mental retardation and excess growth. This review highlights the most recent advances in the field of fragile X research.

The distribution of fragile X mental retardation-1 (FMR1) allele categories, classified by the number of CGG repeats, in the population of Tasmania was investigated in 1253 males with special educational needs (SEN). The frequencies of these FMR1 categories were compared with those seen in controls as represented by 578 consecutive male births. The initial screening was based on polymerase chain reaction analysis of dried blood spots. Inconclusive results were verified by Southern analysis of a venous blood sample. The frequencies of common FMR1 alleles in both samples, and of grey zone alleles in the controls, were similar to those in other Caucasian populations. Consistent with earlier reports, we found some (although insignificant) increase of grey zone alleles in SEN subjects compared with controls. The frequencies of predisposing flanking haplotypes among grey zone males FMR1 alleles were similar to those seen in other Caucasian SEN samples. Contrary to expectation, given the normal frequency of grey zone alleles, no premutation (PM) or full mutation (FM) allele was detected in either sample, with only 15 fragile X families diagnosed through routine clinical admissions registered in Tasmania up to 2002. An explanation of this discrepancy could be that the C19th founders of Tasmania carried few PM or FM alleles. The eight to ten generations since white settlement of Tasmania has been insufficient time for susceptible grey zone alleles to evolve into the larger expansions.

The Fragile X syndrome is the most common cause of inherited mental retardation. Clinical features are neither specific nor constant and molecular diagnosis is thus widely used since the characterization of the causal mutation in 1991. The aim of this project was to study the evolution of Fragile X diagnosis in France. A preliminary study of the efficiency of screening for the Fragile X mutation in mentally retarded probands with no previous familial diagnosis was done in the Strasbourg's laboratory with a comparison between data from 1991–1994 and 1997–2000 (Biancalana et al. [2002: 1ieres Assises de Genetique Humaine et Medicale: 95p]). This study showed an improvement in the use of the Fragile X testing regarding the probands' age at diagnosis and the recruitment of sporadic and female cases. To avoid possible bias in clinical referrals and to evaluate the situation nation wide, this study was enlarged to 28 of the 30 laboratories involved in the Fragile X diagnosis in France from 1997 to 2001 (20,816 probands tested, data representative of 95% of the national screening activity). Median age at diagnosis decreased from 9.2 to 5.8 (average 16–11.6y) between the 1991–1994 and the 1997–2001 studies. Over this period, 477 new families were diagnosed with Fragile X, representing 2.8% of tested male probands (417/14,867) and 1.0% of tested female probands (60/5,949). Forty one percent of positive cases corresponded to probands with a familial history of mental retardation, compared to 66% in the initial (1991–1994) study. We also discuss issues concerning premutations discovered in affected individuals and in females with premature ovarian failure (POF). © 2004 Wiley-Liss, Inc.