This X-linked syndrome is characterized by moderate to severe mental retardation in affected males, while 60% of carrier females present mild to moderate mental retardation. Affected boys often manifest hyperactive and/or autistic behaviour (1,2). In addition to cognitive and behavioural defects, fragile-X male patients are characterized by facial dysmorphism, post pubertal macroorchidism and mild connective tissue dysplasia.

Randi J. Hagerman, M.D., F.A.A.P. discusses advances at the molecular and behavioral levels and features that they have in common as well as differences in regards to Fragile X gene and autism.

Randi J. Hagerman, M.D., F.A.A.P. discusses advances at the molecular and behavioral levels and features that they have in common as well as differences in regards to Fragile X gene and autism.

We believe that the single most important trait of the fra(x) syndrome is a difficulty in modulating arousal, and that this inability to normally modulate arousal is directly responsible for many of the distinctive behaviors found in fra(x].

We have reported that the diagnosis of autism spectrum disorder (ASD) in boys with Fragile X (FraX) is associated with distinctive abnormalities in adaptive socialization and aberrant social behavior (AJMG 004;126A:9). We also demonstrated that impairment in adaptive socialization is a better predictor of Autism Diagnostic Interview-Revised (ADI-R) scores and ASD diagnosis than communication parameters. This study examined the stability of ASD diagnosis, and associated factors, over a 1-year period in FraX boys. We evaluated 39 subjects with standardized measures of cognition, language, and adaptive, aberrant, and autistic (ADI-R) behaviors. Diagnosis was stable, across a spectrum of ASD severity (none, PDD-NOS, autism), for 72% of subjects. Of the approximately same proportion of subjects with more (13%) or less (15%) severe discrepant diagnosis, only two (5% sample) had changed from none to autism or vice versa. Adaptive socialization was still the greatest predictor of ADI-R scores and diagnoses, and other socialization-related measures were once more associated with ASD diagnosis. These data further support the presence of a distinctive ASD subphenotype in FraX, which represents a wide-ranging disturbance in social behavior.

Children with fragile X syndrome exhibited several typical neurodevelopmental patterns. Aberrations in volumes of subcortical nuclei, gender differences in rates of cortical grey matter reduction and an absence of correlation between grey matter and cognitive performance provided indices of the deleterious effects of the fragile X mutation on the brain's structural organization.

Autism is a behavioral disorder with impaired social interaction, communication, and repetitive and stereotypic behaviors. About 5�10 % of individuals with autism have 'secondary' autism in which an environmental agent, chromosome abnormality, or single gene disorder can be identified. Ninety percent have idiopathic autism and a major gene has not yet been identified. We have assessed the incidence of chromosome abnormalities and Fragile X syndrome in a population of autistic patients referred to our laboratory.... Twenty-eight percent of chromosome abnormalities detected in our study were subtle; therefore a high resolution cytogenetic study with a scrutiny of 15q11.2q13, 2q37 and Xp23.3 region should be standard practice when the indication is autism. The higher incidence of mosaic fragile-X mutations with partial methylation compared to FRAXA positive population [50% vs 15�40%] suggests that faint bands and variations in the Southern band pattern may occur in autistic patients.

Fragile-X syndrome is the most common single-gene inherited form of mental retardation. Morphological studies suggest a possible failure of the synapse maturation process. Cerebral cortical spine morphology in fragile-X syndrome and in a knockout mouse model of it appears immature, with long, thin spines much more common than the stubby and mushroom-shaped spines more characteristic of normal development. In human fragile-X syndrome there is also a higher density of spines along dendrites, suggesting a possible failure of synapse elimination. While variously misshapen spines are characteristic of a number of mental retardation syndromes, the overabundance of spines seen in fragile-X syndrome is unusual. Taken with evidence of neurotransmitter activation of the synthesis of the fragile-X protein (FMRP) at synapses in vitro and evidence for behaviorally induced FMRP expression in vivo, and with evidence compatible with a role for FMRP in regulating the synthesis of other proteins, it is possible that FMRP serves as an 'immediate early protein' at the synapse that orchestrates aspects of synaptic development and plasticity.

This study shows that parents perceive the discovery of FXS as a process that takes too long, primarily as a result of their perception that the pediatrician or family physician is reluctant to acknowledge a developmental problem or is not knowledgeable enough about the various causes of disability to know when to refer children for specific genetic tests.

The 1991 discovery of the genetic error that underlies fragile X and a series of new studies is leading to treatments that can target the biomedical malfunctions, specifically.

We aim to provide support and information for Fragile X families from those who share and understand their concerns and needs; educate, inform and advise the public and professionals; and encourage research into all aspects of the syndrome.

Fragile X syndrome is an X chromosome defect that causes mental retardation and a wide range of associated signs and symptoms.

Although fragile X is an X-linked disorder, both females and males with a full mutation can be affected. Males typically are more severely affected than females, with most boys showing mental retardation and only about one third to one half of girls having significant intellectual impairment. The rest of the girls have either normal IQ or learning disabilities. Emotional and behavioral problems are common in both males and females. In addition, individuals with fragile X syndrome may have attention deficit and hyperactivity, anxiety and unstable mood, and autistic-like behaviors. About 20% of boys with fragile X syndrome meet full criteria for autism. The classic phenotype of fragile X syndrome includes a long face with prominent forehead, large ears, and prominent jaw and macro-orchidism. There is a growing understanding of the implications for some premutation carriers, including mild developmental delay, premature ovarian failure, or fragile X-associated tremor/ataxia syndrome

Autism, an entirely behavioral diagnosis with no largely understood etiologies and no population-wide biomarkers, contrasts with fragile X syndrome (FXS), a single-gene disorder with definite alterations of gene expression and neuronal morphology. Nevertheless, the behavioral overlap between autism and FXS suggests some overlapping mechanisms. Understanding how the single-gene alteration in FXS plays out within complex genetic and neural network processes may suggest targets for autism research and illustrate strategies for relating autism to more singular genetic syndromes.

Carriers of premutation alleles (55ndash200 CGG repeats) of the fragile-X mental retardation 1 (FMR1) gene are often regarded as being clinically uninvolved. However, it is now apparent that such individuals can present with one (or more) of three distinct clinical disorders: mild cognitive and/or behavioral deficits on the fragile-X spectrum; premature ovarian failure; and a newly described, neurodegenerative disorder of older adult carriers, fragile-Xndashassociated tremor/ataxia syndrome (FXTAS). Awareness of these clinical presentations is important for proper diagnosis and therapeutic intervention, not only among families with known cases of fragile-X syndrome but also more broadly for adults with tremor, gait ataxia, and parkinsonism who are seen in movement-disorders clinics.

Fragile X Syndrome support

Although fragile X syndrome is the most commonly occurring known inherited cause of mental retardation, it accounts for only a small portion of all the cases of mental retardation.

Individuals with fragile X syndrome manifest neurodevelopmental abnormalities that include varying levels of cognitive dysfunction, particularly in the domains of executive, visual-spatial, and visual motor abilities.

First, the basic pattern of neuronal organization appears to be largely intrinsic to the developing brain. A second concept is that neuronal activity strengthens immature synaptic connections between neurons, whereas inactive synapses weaken and die away.

For boys with fragile X, effectiveness of educational and therapeutic services and parental psychological problems predicted internalizing and externalizing types of problems, while the quality of the home environment predicted autistic behavior.

Results of multiple regression analyses showed that for boys with fragile X, effectiveness of educational and therapeutic services and parental psychological problems predicted internalizing and externalizing types of problems, while the quality of the home environment predicted autistic behavior. For girls with fragile X, the results emphasized significant effects of FMRP on behavior, in particular social withdrawal and anxious/depressed behavior.

Following the recent discovery that the methyl-CpG binding protein 2 (MECP2) gene located on Xq28 is involved in Rett syndrome (RTT), a wild spectrum of phenotypes, including mental handicap, has been shown to be associated with mutations in MECP2. These findings, with the compelling genetic evidence suggesting the presence in Xq28 of additional genes besides RabGDI1 and FMR2 involved in non-specific X-linked mental retardation (MRX), prompted us to investigate MECP2 in MRX families. Two novel mutations, not found in RTT, were identified. The first mutation, an E137G, was identified in the MRX16 family, and the second, R167W, was identified in a new mental retardation (MR) family shown to be linked to Xq28. In view of these data, we screened MECP2 in a cohort of 185 patients found negative for the expansions across the FRAXA CGG repeat and reported the identification of mutations in four sporadic cases of MR. One of the mutations, A140V, which we found in two patients, has been described previously, whereas the two others, P399L and R453Q, are novel mutations. In addition to the results demonstrating the involvement of MECP2 in MRX, this study shows that the frequency of mutations in MECP2 in the mentally retarded population screened for the fragile X syndrome is comparable to the frequency of the CGG expansions in FMR1. Therefore, implementation of systematic screening of MECP2 in MR patients should result in significant progress in the field of molecular diagnosis and genetic counseling of mental handicap.

The distributions of scores for autistic behaviours obtained from the Autism Diagnostic Observation Scale-Generic (ADOS-G) were investigated in 147 males and females affected with the full mutation in the fragile X mental retardation 1 (FMR1) gene, in 59 individuals with the premutation, and in 42 non-fragile X relatives, aged 4-70 years. The scores representing communication and social interaction were continuously distributed across the two fragile X groups, and they were significantly elevated compared with the non-fragile X controls. Strong relationships were found between both these scores and FMRP deficits, but they became insignificant for social interaction, and the sum of social interaction and communication scores, when FSIQ was included as another predictor of autism scores. Other significant predictors of these scores in both sexes were those executive skills which related to verbal fluency, and to the regulation and control of motor behaviour. Overall, our data have shown that cognitive impairment, especially of verbal skills, best explains the comorbidity of autism and fragile X. This implies some more fundamental perturbations of specific neural connections which are essential for both specific behaviours and cognition. We also emphasize that FXS offers a unique molecular model for autism since FMRP regulates the translation of many other genes involved in synaptic formation and plasticity which should be natural targets for further exploration.

The clinical diagnosis of fragile X mental retardation (FXMR) is not possible as dysmorphic features are subtle. Molecular diagnosis by Southern Blot is the confirmatory test that makes carrier detection and prenatal diagnosis possible.

The aim of management is to help the children and adults with FXMR learn to function in the household environment and be employed in constructive occupations in sheltered atmospheres.

Currently, there is no adequate animal model to study the detailed molecular biochemistry of fragile X syndrome, the leading heritable form of mental impairment. In this study, we sought to establish the use of immature neural cells derived from adult tissues as a novel model of fragile X syndrome that could be used to more fully understand the pathology of this neurogenetic disease... The successful production of neural cells from an individual with fragile X syndrome opens a new avenue for the scientific study of the molecular basis of this disorder, as well as an approach for studying the efficacy of new therapeutic agents.

Fragile X syndrome is the most common inherited form of learning disabilities and mental retardation known. It is characterized by a host of symptoms ranging from impaired learning abilities to severe retardation and autistic behaviors.

Fragile X boys display an attention deficit at higher levels of attention function/executive functioning, a profile different from Down's syndrome boys and more extreme than the profile identified in the poor attention control group.

There is an association with autism in that fragile X syndrome accounts for 2-3 per cent of cases of autism. Conversely autism can be diagnosed in a substantial minority of children with fragile X syndrome.

Background Research on parental well-being has focused largely on Down syndrome and autism; however, fragile X syndrome is likely to pose different challenges for parents compared with these other diagnostic conditions. Moreover, there is considerable variability among youth with fragile X syndrome; for example, 25% to 33% of affected youth meet criteria for a co-morbid diagnosis of autism. It is likely that parents of youth with fragile X syndrome will experience different degrees and patterns of stress, depending on whether their offspring do or do not have a co-morbid diagnosis of autism. In the present study, we compared mothers of three groups of young males on measures of psychological well-being and stress: those with fragile X syndrome and a co-morbid diagnosis of autism; those with fragile X syndrome alone; and those with Down syndrome. Method The sample consisted of mothers of adolescent and young adult males with fragile X syndrome and co-morbid autism (n = 9), fragile X syndrome alone (n = 19), and Down syndrome (n = 19). We screened all youth for autism using the Autism Behavior Checklist, which was completed by mothers, fathers and teachers, and the youth who scored above the suggested cut-off were evaluated by a licensed psychologist to determine autism status. The three groups of youth did not differ in chronological age (16.4, 15.8 and 16.0 years, respectively) or non-verbal mental age (3.8, 3.9 and 3.8 years, respectively). Several self-report measures were completed by mothers. These measures assessed current mental health status (e.g. the Center for Epidemiological Studies Depression Scale), perceptions of their son's and family's functioning (e.g. the Positive Affect Index, which measures closeness felt by the mother to her son and also reciprocated closeness felt by the son towards the mother, as perceived by the mother), and approach to coping with their son's disability [e.g. the Multidimensional Coping Inventory (COPE), which measures emotion-focused and problem-solving focused coping]. Results The results suggest that fragile X syndrome creates more challenges to maternal psychological well-being than Down syndrome, and that the combination of fragile X syndrome and autism can be particularly challenging. Differences among groups, however, were manifested mainly as concerns about the affected son and about relationships within the family rather than as lower levels of mental health. Thus, mothers of sons with fragile X syndrome, regardless of the son's autism status, reported more pessimism about the son's future and more conflict within the family than mothers of sons with Down syndrome. Additionally, mothers of sons with fragile X syndrome and co-morbid autism reported lower levels of reciprocated closeness than the other two groups of mothers. Conclusion We consider possible causes of these maternal differences, the implications for clinical practice, needs for future research, and the importance of understanding child and contextual factors as well as the dynamics leading to these differences.

Using a highly sensitive quantification assay, we demonstrate significantly diminished FMRP levels in carriers, negatively correlated with repeat number. Despite reduced FMRP, these carrier alleles overexpress FMR1, resulting in a positive correlation between repeat number and FMR1 message level. These biochemical deviations associated with intermediate and premutation FMR1 alleles, found in ~4% of the population, suggest that the phenotypic spectrum of fragile X syndrome may need to be revisited.

Even if people with FraX do not fully meet the diagnostic criteria for autism they are very likely to have some typically autistic behaviours such as hand stereotypies, communication abnormalities, and a lack of direct eye contact with others.

these data show that mutations of the FMR1 gene impact equivalent processes in both humans and mice. However, since these phenotypic changes are opposite in direction, they also suggest that murine compensatory mechanisms following loss of FMR1 function differ from those in humans.

We discuss here the recent progress made towards understanding the molecular mechanism of CGG repeat expansion and physiological function(s) of FMRP. These studies will not only help to illuminate the molecular basis of the general class of human diseases with trinucleotide repeat expansion but also provide an avenue to understand aspects of human cognition and intelligence.

A large French family including members affected by nonspecific X-linked mental retardation, with or without autism or pervasive developmental disorder in affected male patients, has been found to have a 2ndashbase-pair deletion in the Neuroligin 4 gene (NLGN4) located at Xp22.33. This mutation leads to a premature stop codon in the middle of the sequence of the normal protein and is thought to suppress the transmembrane domain and sequences important for the dimerization of neuroligins that are required for proper cell-cell interaction through binding to beta-neurexins. As the neuroligins are mostly enriched at excitatory synapses, these results suggest that a defect in synaptogenesis may lead to deficits in cognitive development and communication processes. The fact that the deletion was present in both autistic and nonautistic mentally retarded males suggests that the NLGN4 gene is not only involved in autism, as previously described, but also in mental retardation, indicating that some types of autistic disorder and mental retardation may have common genetic origins.