Understanding the biological underpinnings of fragile X syndrome

PURPOSE OF REVIEW: The purpose of this review is to present the latest findings on fragile X syndrome and to put them into perspective. Fragile X syndrome is a relatively common form of inherited mental retardation, caused by loss of function of the FMR1 gene on the long arm of the X chromosome. The molecular mechanisms underlying the syndrome are complex and continue to surprise researchers more than 12 years after the cloning of the gene. RECENT FINDINGS: We will specifically discuss the various aspects of the clinical phenotype, reassessed with the employment of functional imaging and electrophysiological techniques. The unexpected finding of a pathologic phenotype in premutation carriers is highlighted, as it represents a new and distinct condition with a different presentation in males and females. The third section deals briefly with the various functions of the FMRP protein, an RNA-binding protein interacting with multiple RNA molecules as well as proteins. It is important to realize that FMRP is probably changing partners several times, depending on its localization, on posttranslational modifications and on the available interacting proteins. In the following section, we present in short recent discoveries on the defective neuronal circuits in the fragile X syndrome. Most of these new data were made available by the study of animal models, mostly the Fmr1 knockout mouse, but also Drosophila. SUMMARY: We briefly discuss the alternative options for treating fragile X syndrome. Presently, a neuropharmacological approach acting on either critical receptors or aimed at reactivating the silenced FMR1 gene appears promising.     

Language use in females with fragile X or Turner syndrome during brief initial social interactions

Fragile X and Turner syndromes are associated with risk of atypical social function. We examined language use, including normal and atypical speech, during initial social interactions among participants engaged in a brief social role play with an unfamiliar adult. There were 27 participants with Turner syndrome, 20 with fragile X syndrome and 28 in an age-matched comparison group. Females with fragile X did not exhibit more abnormal language, but exhibited less of what is typical during initial interactions. Overall rates of dysfluencies did not differ, although females with fragile X made more phrase repetitions. Females with Turner syndrome had no language use abnormalities. Our findings suggest that language use may influence social function in females with fragile X syndrome and that such language characteristics may be observed in the context of brief encounters with an unfamiliar adult.     

Lessons from fragile X regarding neurobiology, autism, and neurodegeneration

The fragile X mental retardation 1 gene (FMR1) mutation causes two disorders: fragile X syndrome (FXS) in those with the full mutation and the fragile X-associated tremor/ataxia syndrome (FXTAS) in some older individuals with the premutation. FXS is caused by a deficiency of the FMR1 protein (FMRP) leading to dysregulation of many genes that create a phenotype with ADHD, anxiety, and autism. FXTAS is caused by the elevation of FMR1-mRNA to levels 2 to 8 times normal in the premutation. This causes an RNA gain of function toxicity leading to brain atrophy, white matter disease, neuronal and astrocytic inclusion formation, and subsequent ataxia, intention tremor, peripheral neuropathy, and cognitive decline. The neurobiology and pathophysiology of FXS and FXTAS are described in detail.     

Learning disabilities and attentional problems in boys with the fragile X syndrome

The fragile X syndrome is a relatively common form of mental retardation that tends to affect boys more severely than girls. The syndrome is associated with a fragile site at q27 on the X chromosome and with physical features including large or prominent ears and macro-orchidism. Four boys had physical and cytogenetic features of the fragile X syndrome. However, the IQ scores of these patients extended into the normal range. All four patients demonstrated similar learning difficulties that included hyperactivity, visuomotor incoordination, language deficits, and academic delays in mathematics. The fragile X syndrome should be considered in the differential diagnosis of learning disabled children.     

Fragile X syndrome among children with mental retardation

Prospective screening for fragile X syndrome was carried out among 1,111 patients with mental retardation who attended the Genetic clinic. Using defined clinical criteria, 55 patients were selected for cytogenetic studies to detect folate sensitive fragile sites. Twenty patients were diagnosed to have the fragile X syndrome. The prevalence of fragile X (A) syndrome was 18 per 1,000 patients of both sexes with mental retardation, 2.8% among male patients with mental retardation, and 5.8% among subjects with nonspecific mental retardation.     

Fragile X syndrome and very early onset schizophrenia: a female case study.]

Genotype-phenotype relationship studies for psychiatric disorders in females carrying fragile X syndrome full mutation and premutation underline association with schizo-affective disorders. In female children with X fragile full mutation, only behavioural symptoms and no standardised psychiatric disorders have been systematically explored. Therefore, we report the case of a nine-year-old girl carrying the fragile X syndrome full mutation with a comorbid childhood onset schizophrenia (COS), and of her mother carrying the fragile X syndrome premutation and a comorbid schizotypal personality disorder. The impact of these associations is discussed regarding the recent literature in chromosome anomalies in COS.     

DNA testing for fragile X syndrome in schools for learning difficulties

Fragile X syndrome is the most common inherited cause of mental retardation. Early diagnosis is important not only for appropriate management of individuals but also to identify carriers who are unaware of their high risk of having an affected child. The disorder is associated with a cytogenetically visible fragile site (FRAXA) at Xq27.3, caused by amplification of a (CGG)n repeat sequence within the gene at this locus designated FMR1. Clinical and molecular studies have been undertaken to screen for fragile X syndrome in 154 children with moderate and severe learning difficulties of previously unknown origin. Southern blot analysis of peripheral blood showed the characteristic abnormally large (CGG)n repeat sequence associated with fragile X syndrome in four of the 154 children. The findings were confirmed by cytogenetic observation of the fragile site and by further molecular studies. The families of the affected children were offered genetic counselling and DNA tests to determine their carrier status. These findings show that there are still unrecognised cases of fragile X syndrome. Given the difficulty of making a clinical diagnosis and the implications for families when the diagnosis is missed, screening in high risk populations may be justified. The issues involved in screening all children in special schools for fragile X syndrome are discussed.     

DNA testing for fragile X syndrome in schools for learning difficulties.

Fragile X syndrome is the most common inherited cause of mental retardation. Early diagnosis is important not only for appropriate management of individuals but also to identify carriers who are unaware of their high risk of having an affected child. The disorder is associated with a cytogenetically visible fragile site (FRAXA) at Xq27.3, caused by amplification of a (CGG)n repeat sequence within the gene at this locus designated FMR1. Clinical and molecular studies have been undertaken to screen for fragile X syndrome in 154 children with moderate and severe learning difficulties of previously unknown origin. Southern blot analysis of peripheral blood showed the characteristic abnormally large (CGG)n repeat sequence associated with fragile X syndrome in four of the 154 children. The findings were confirmed by cytogenetic observation of the fragile site and by further molecular studies. The families of the affected children were offered genetic counselling and DNA tests to determine their carrier status. These findings show that there are still unrecognised cases of fragile X syndrome. Given the difficulty of making a clinical diagnosis and the implications for families when the diagnosis is missed, screening in high risk populations may be justified. The issues involved in screening all children in special schools for fragile X syndrome are discussed.     

Fragile X syndrome

Fragile X syndrome is the most common familial form of mental retardation. This X-linked disorder affects one in every 1000 males and one in every 2000 females. The female carrier rate in the general population is estimated to be 1/600. A fragile site at the distal long arm of the X chromosome (Xq 27.3) is the hallmark cytogenetic feature of the syndrome. Clinical features include physical as well as cognitive and neuropsychological deficits. Although fragile X syndrome follows an X-linked pattern of inherltance (which explains the predominance of affected males), females can also beaffected,Many inconsistencies exist between the genetic inheritance pattern of fragile X and traditional Mendelian inheritance tenets of most X-linked diseases. Due to recent molecular advances, our understanding of the perplexing genetic issues surrounding fragile X syndrome has grown and diagnostic techniques have become both reliable and readily available.     

The fragile X syndrome (Martin-Bell syndrome). Clinical and cytogenetic findings in 16 prepubertal boys and in 4 of their 5 families

Clinical and cytogenetic findings from 16 prepubertal males with the fragile X syndrome (X-linked mental retardation with postpubertal macro-orchidism and fragile site at Xq27/8, or Martin-Bell syndrome) and from their families are reported. During the first postnatal years, protruding, large ears, full periorbital tissue, and thick septum and alae nasi were the most characteristic phenotypic findings, while after approximately 6 years of age a longish face with full lips and prominent maxilla and mandible became more distinct. It was estimated that a clinical suspicion of the fragile X syndrome could be made in most of the 16 boys from phenotypic findings in combination with the characteristic developmental profile described in our previous paper. The marker X chromosome was demonstrated in each of the 16 patients; the incidence of fra(X)-positive cells did not correlate with either age or the degree of mental retardation. 13 boys stemmed from 2 families, the other 3 were sporadic cases. In one family with 11 affected boys, the gene was transmitted by 4 brothers, grandfathers to the probands, who were intellectually normal; three of them did not show the clinical picture of the fragile X syndrome and did not express the marker. All mentally subnormal heterozygote females and one half of daughters of heterozygotes revealed the marker, but this was present only in a minority of non-retarded adult heterozygotes. In contrast to the overall incidence of about 1/4 to 1/3 mentally retarded heterozygotes, all 15 daughters of the four normal obligatory hemizygous brothers were of normal intelligence.     

Is it possible to make a clinical diagnosis of the fragile X syndrome in a boy?

Clinical observations were made on a series of 156 boys with severe mental retardation, before cytogenetic results were known. The clinical features that helped to distinguish the 14 boys with the fragile X chromosome from those without were: head circumference over the 50th centile, postpubertal testicular volume over the 50th centile, and an IQ between 35 and 70. If the above clinical features were all present, then the chance of finding the fragile X chromosome was 1 in 3.6, whereas the chance of finding this abnormality in any boy with severe idiopathic mental retardation, regardless of his clinical features, was 1 in 9. Two boys with fragile X syndrome did not, however, possess any of the above clinical features. Moreover, some of the other retarded boys had clinical features of the syndrome, or an X linked pedigree, but lacked the chromosome abnormality.     

Family experiences and factors associated with the diagnosis of fragile X syndrome

The authors interviewed 41 mothers of young boys with fragile X syndrome to determine the process by which they learned their child had fragile X syndrome. The average family had concerns about the child's development at 9 months of age. Developmental delay was determined at an average age of 24 months, and fragile X syndrome was diagnosed at a mean age of 35 months. Considerable variability was found in age of first concern, determination of delay, and diagnosis of fragile X syndrome. Three child variables (severity of delay, autistic behavior, temperament style) and four family variables (mother's age, mother's education, sibling status, social support) did not account for this variability, although birth year did (children born more recently were somewhat more likely to be identified earlier). Families often encountered physicians who initially discounted concerns or said that it was too early to determine whether a problem did indeed exist. Given current knowledge and practice, improving the early identification (under 3 years of age) of children with fragile X syndrome is likely to remain difficult if based solely on behavioral and clinical observations.     

Screening for fragile X syndrome: results from a school for mentally retarded children

Fragile X syndrome is the most common inherited form of familial mental retardation. The purpose of this study was to identify yet unrecognized fragile X individuals and to estimate the frequency of both the FRAXA and FRAXE forms of the disease in a population of mentally retarded children attending a special school in Croatia. The results are reported of molecular screening of 114 children with mild to severe mental retardation. Three individuals (2.6%) with the FRAXA form of the fragile X syndrome and one boy (0.9%) with FRAXE mental retardation were detected; a total of four newly diagnosed fragile X families were identified. Closer clinical examination revealed that behavioural and speech disturbances were clearly present among all fragile X cases (both FRAXA and FRAXE), indicating that these features could be additional diagnostic criteria for the preselection of individuals at risk.

Conclusion: Fragile X screening among mentally retarded children attending a special school should be highly encouraged to reveal the cause of mental retardation and to detect yet unrecognized fragile X individuals. The frequency of fragile X syndrome in a such population in Croatia was found to correlate with similar results from previous studies. However, since at the time of diagnosis all affected families had a second or even a third child born, earlier diagnosis should be considered to provide greater benefit to fragile X families.     

GABAA受体与脆性X综合征

脆性X综合征(fragile X syndrome,FXS)是引起先天性智力低下的常见疾病,GABAA受体是哺乳动物中枢神经系统内最主要的抑制性神经递质受体,与焦虑、抑郁、癫癎、睡眠、认知等相关.多项研究证明GABA能神经系统特别是GABAA受体的变化与FXS的遗传表型有关.GABAA受体某些亚基的表达变化是FXS患者神经行为学改变的原因之一,可为FXS的治疗提供一个新的方向.     

GABAA受体与脆性X综合征

脆性X综合征(fragile X syndrome,FXS)是引起先天性智力低下的常见疾病,GABAA受体是哺乳动物中枢神经系统内最主要的抑制性神经递质受体,与焦虑、抑郁、癫癎、睡眠、认知等相关.多项研究证明GABA能神经系统特别是GABAA受体的变化与FXS的遗传表型有关.GABAA受体某些亚基的表达变化是FXS患者神经行为学改变的原因之一,可为FXS的治疗提供一个新的方向.     

NASOPHARYNGEAL CARCINOMA IN A BOY WITH FRAGILE X SYNDROME

The authors report on what they believe to be the first case of nasopharyngeal carcinoma in a patient with fragile X syndrome. In the literature, a few cases of fragile X syndrome associated with malignancies are described. Although this association seems more than coincidental, the molecular correlation between this syndrome and cancer is yet unclear.     

Nasopharyngeal carcinoma in a boy with fragile X syndrome

The authors report on what they believe to be the first case of nasopharyngeal carcinoma in a patient with fragile X syndrome. In the literature, a few cases of fragile X syndrome associated with malignancies are described. Although this association seems more than coincidental, the molecular correlation between this syndrome and cancer is yet unclear.     

Ethical, legal, and social concerns about expanded newborn screening: fragile X syndrome as a prototype for emerging issues

Technology will make it possible to screen for fragile X syndrome and other conditions that do not meet current guidelines for routine newborn screening. This possibility evokes at least 8 broad ethical, legal, and social concerns: (1) early identification of fragile X syndrome, an "untreatable" condition, could lead to heightened anxiety about parenting, oversensitivity to development, alterations in parenting, or disrupted bonding; (2) because fragile X syndrome screening should be voluntary, informed consent could overwhelm parents with information, significantly burden hospitals, and reduce participation in the core screening program; (3) screening will identify some children who are or appear to be phenotypically normal; (4) screening might identify children with other conditions not originally targeted for screening; (5) screening could overwhelm an already limited capacity for genetic counseling and comprehensive care; (6) screening for fragile X syndrome, especially if carrier status is disclosed, increases the likelihood of negative self-concept, societal stigmatization, and insurance or employment discrimination; (7) screening will suggest risk in extended family members, raising ethical and legal issues (because they never consented to screening) and creating a communication burden for parents or expanding the scope of physician responsibility; and (8) screening for fragile X syndrome could heighten discrepancies in how men and women experience genetic risk or decide about testing. To address these concerns we recommend a national newborn screening research network; the development of models for informed decision-making; materials and approaches for helping families understand genetic information and communicating it to others; a national forum to address carrier testing and the disclosure of secondary or incidental findings; and public engagement of scientists, policy makers, ethicists, practitioners, and other citizens to discuss the desired aims of newborn screening and the characteristics of a system needed to achieve those aims.     

Fragile X syndrome: recognition in young children

In recent years, a number of articles have appeared in the literature concerning the fragile X syndrome; however, in few cases was the diagnosis of the syndrome in young children discussed. A review of 20 children younger than 7 1/2 years of age who had the fragile X syndrome seen at the Cincinnati Center of Developmental Disorders was undertaken in an attempt to establish guidelines that would aid the practicing physician in determining which children should have a chromosomal analysis. All children were developmentally delayed; 95% had speech delays. Short attention span with hyperactivity, temper tantrums, mouthing of objects persisting at an age beyond when it would be expected, autistic behaviors, and poor gross motor coordination were seen in 50% or more of the children. Mental retardation was present in the family history of 65%, and 90% had a family history of at least one of the following: mental retardation, learning disabilities, or hyperactivity. The most common physical findings were long and/or wide and/or protruding ears, prominent jaw and/or long face, high arched palate, and a flattened nasal bridge. The fragile X syndrome can be recognized by noting key aspects of the behavioral and family histories as well as the physical findings.     

脆性X综合征患儿细胞内环磷酸腺苷降低的机制

目的 探讨脆性X综合征细胞内环磷酸腺苷(cAMP)降低的机制。方法 通过基因封闭方法，建立Fra(X)细胞模型，研究cAMP代谢途径中的两个关键酶腺苷酸环化酶(AC)及磷酸二酯酶(PDE)的活性变化。结果 试验组AC的比活力明显低于对照组(P＝0．000)，而PDE比活力则无显著改变(P＝0．983)。结论 Fra—(X)细胞内cAMP水平的降低可能与AC活性的抑制有关，而与PDE活性无明显关系。