Fragile X mental retardation protein in plasticity and disease

Fragile X syndrome is the most common cause of mental retardation known to be inherited. The syndrome results from the suppressed expression of a single protein, the fragile X mental retardation protein (FMRP). Understanding the function and regulation of FMRP can, therefore, offer insights into both the pathophysiology of fragile X syndrome and the molecular mechanisms of learning and memory. We provide an overview of current concepts of how FMRP functions in the nervous system, with special emphasis on recent evidence that FMRP has a role in metabotropic glutamate receptor-activated protein translation and synaptic plasticity.     

Fragile X premutation presenting as postural tremor and ataxia (FXTAS syndrome)

We report a case of FXTAS in a 58-year-old man who presented with postural tremor, mild ataxia and dysexecutive cognitive signs. The syndrome had a slow progressive course. Brain imaging by MRI showed characteristic abnormalities with mild cerebellar atrophy, symmetric high signals in the middle cerebellar peduncles and in the subcortical white matter of cerebral hemispheres. The diagnosis was confirmed by molecular genetics showing by southern blot a 100-120 expansion repeat of the CGG trinucleotide. FXTAS is a recently described syndrome, still unknown by most neurologists and probably rather frequent in men older than 60. We emphasize the value of clinical evaluation and brain imaging by MRI in some patients presenting with non specific motor or cognitive symptoms. A diagnosis of FXTAS may have implications for genetic counselling of female relatives.     

脆性X综合征与癫痫

脆性X综合征(fragile X syndrome,FXS)是一种最常见的遗传性智力障碍.这种智力障碍疾病主要是由于脆性X智力低下蛋白(fragile X mental retardation protein,FMRP)的缺失引起.FMRP是一种RNA结合蛋白,通过调节与其结合的信使RNA的翻译而调节神经元内的信号传导.很多FXS病人表现出较高的癫痫发作易感性.癫痫是一种慢性神经系统疾病.它的主要症状是反复的癫痫发作.癫痫发作是由大脑神经元的异常高兴奋性和同步放电引起的.FMEP缺失引起的神经元形态异常和神经元内信号传导的异常均可导致癫痫发作.本文结合在FXS和癫痫病两方面上取得研究结果综合分析,探讨FXS病人癫痫高易感性的发病机理,并对其他智力障碍疾病中的癫痫高易感性的机制的研究做一展望.     

Fragile X-associated tremor/ataxia syndrome: intrafamilial variability and the size of the FMR1 premutation CGG repeat.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurological progressive disorder associated with the FMR1 gene premutation. We report on variable presentation of findings associated with FXTAS in 3 brothers aged 68, 74, and 73 years, carrying premutation alleles of (CGG)(123,) (CGG)(109), and (CGG)(91) triplets, respectively. Based on previously proposed diagnostic criteria for the syndrome, clinical and radiological data allowed establishing a "definite" diagnosis of FXTAS in the two carriers of the longest (CGG)(n). The carrier of the (CGG)(91) allele, although presenting a major radiological sign of the syndrome (symmetrical white-matter lesions in the middle cerebellar peduncles), did not have any significant neurological manifestation at 73 years of age.     

The fragile X continuum: new advances and perspectives

Fragile X syndrome is the world's most common hereditary cause of intellectual disability in men and to a lesser extent in women. The disorder is caused by the silencing of a single gene on the X chromosome, the Fragile X Mental Retardation Gene-1. A substantial body of research across the disciplines of molecular genetics, child psychiatry and developmental neuroscience bears testament to a decade of exciting and innovative science that has advanced our knowledge about the fragile X 'signature' or influence across cognitive and social development. The core aims of this review are to first discuss fragile X syndrome and premutation involvement in the context of current advances that demonstrate the dynamic nature of the genotype on phenotypic outcomes. Second, to discuss the implications of these recent advances for the development of clinical and educational interventions and resource tools that target specific phenotypic 'signatures' within the fragile X continuum.     

Atypical antipsychotic use and risk of fracture in persons with Parkinsonism

Our objective was to estimate the effect of atypical antipsychotics (AAs) on the rate of fractures in a parkinsonism population. We conducted an age‐ and state‐matched nested case‐control study in five states (CA, FL, NY, OH, IL) using the Medicaid analytic extract from 2001 to 2002. Eligible participants had a diagnosis of parkinsonism, excluding persons with secondary parkinsonism, bone cancer, bone infections, schizophrenia, schizoaffective disorder, and those who used conventional antipsychotics. The primary outcome was the occurrence of a fracture of the femur, ankle, fibula, tibia, humerus, radius, or ulna (N = 851). Risk‐set sampling defined controls (N = 4220). We used conditional‐logistic regression to derive adjusted odds ratios (AOR) and 95% confidence intervals of the association between fracture and use of quetiapine, risperidone, or olanzapine in the 60 days before the index date compared to nonuse. After adjustment for confounding, use of quetiapine (AOR 2.4; 95% CI 1.5–3.8), risperidone (AOR 1.2; 95% CI 0.9–1.7), or olanzapine (AOR 1.7; 95% CI 1.2–2.4) was associated with a higher rate of fracture. Use of an AA was associated with a higher rate of fracture in persons with parkinsonism. Prescribers must be cautious when using these agents in elderly persons with parkinsonism. © 2009 Movement Disorder Society     

Fragile X mice: reduced long-term potentiation and N-Methyl-D-Aspartate receptor-mediated neurotransmission in dentate gyrus

Fragile X syndrome (FXS) is a monogenic mental retardation syndrome that frequently includes autism. The Fmr1-knockout (Fmr1-KO) mouse, like FXS-affected individuals, lacks the fragile X mental retardation protein (FMRP) and models autism as well as FXS. Limited human data and several mouse models have implicated the hippocampal dentate gyrus (DG) in autism. We therefore investigated whether the Fmr1-KO mouse exhibited functional changes in DG. We found diminished medial perforant path-granule cell long-term potentiation (LTP), complementing previous investigations of synaptic plasticity in Fmr1-KO demonstrating impaired LTP in CA1, neocortex, and amygdala and exaggerated long-term depression in CA1. We also found that peak amplitude of NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) was smaller in Fmr1-KO than control. AMPA receptor-mediated EPSCs were comparable in the two strains, yielding a lower NMDA/AMPA ratio in Fmr1-KO mice and suggesting one mechanism by which absent FMRP might contribute to diminished LTP. The clinical hallmarks of autism include both excessive adherence to patterns and impaired detection of socially important patterns. The DG has a putative role in pattern separation (for time, space, and features) that has been attributed to granule cell number, firing rates, adult neurogenesis, and even perforant path LTP. DG also contributes to pattern completion in CA3 via its mossy fiber efferents, whose terminals include abundant FMRP in "fragile X granules." Together with the present data, these observations suggest that DG is a candidate region for further investigation in autism and that the Fmr1-KO model may be particularly apt.     

Autistic Behavior, FMR1 Protein, and Developmental Trajectories in Young Males with Fragile X Syndrome

In the context of a longitudinal study, we assessed the relationship between ratings of autistic behavior, FMR1 protein expression (FMRP), and the developmental trajectories of 55 young males with fragile X syndrome. Autistic behavior, as measured by the Childhood Autism Rating Scale, was not related to FMRP expression. However, autistic behavior was a significant predictor of both developmental status and developmental change. Boys with both autistic behavior and fragile X syndrome functioned at significantly lower levels of development and grew at significantly slower rates than those without autistic behavior. FMRP expression accounted for less variance in developmental level than did autistic behavior, and was not significantly related to slope (developmental change over time). No autistic behavior × FMRP interaction was found.     

Comparison Groups in Autism Family Research: Down Syndrome, Fragile X Syndrome, and Schizophrenia

This paper examines methodological challenges inherent in conducting research on families of children with autism and in comparing these families with others who are coping with different types of disabilities or who have nondisabled children. Although most comparative research has contrasted families whose child has autism with those whose child has Down syndrome, the range of comparison groups can be expanded to offer additional points of contrast and control. We discuss both matching and statistical control procedures and point to next steps in this line of comparative autism family research.     

Axonal neuropathy in female carriers of the fragile X premutation with fragile x–associated tremor ataxia syndrome

Introduction: In this study we examined whether females with the fragile X–associated tremor ataxia syndrome (FXTAS) and non‐FXTAS premutation carriers have electrophysiological signs of underlying peripheral neuropathy. Methods: 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. Conclusions: 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     

Employment impact and financial burden for families of children with fragile X syndrome: findings from the National Fragile X Survey

Background The employment impact and financial burden experienced by families of children with fragile X syndrome (FXS) has not been quantified in the USA. Method Using a national fragile X family survey, we analysed data on 1019 families with at least one child who had a full FXS mutation. Out‐of‐pocket expenditures related to fragile X were reported. We used logistic regression to examine the role of insurance, number of affected children, and number of total co‐occurring conditions in predicting the financial burden and employment impact of FXS, while adjusting for race, education, marital status and other sociodemographic predictors. Results Almost half of families affected by FXS reported that they had experienced an increased financial burden and nearly 60% stated that they had had to change work hours or stop work because of FXS. Families with health insurance that met family needs were significantly less likely to report an excess financial burden. The type of insurance (private or public) was not associated with the reported financial burden. Affected children's mutation status, especially male children with the full mutation, was associated with employment impact. The total number of co‐occurring conditions was associated with both financial burden and employment impact. Conclusions Families affected by FXS experienced a significant employment impact and financial burden. Policies designed to help families with FXS need to take into consideration the dimension of co‐occurring conditions.     

Adaptive Skills,Behavior Problems,and Parenting Stress in Mothers of Boys With Fragile X Syndrome

The relationship of temperament, atypical behaviors, and adaptive behavior of young boys with Fragile X syndrome on mothers' parenting stress was analyzed. Twenty-six boys with Fragile X syndrome (30–88 months of age) participated. The overall development of the participants was significantly delayed with a specific profile of adaptive behaviors (i.e., strengths in domestic daily living) and behavioral challenges (i.e., high levels of detachment and hypersensitive or hyperactive behavior). Approximately 90% of the mothers reported very high levels of parenting stress. Correlational and regression analyses revealed that temperament and atypical behavior contributed significantly to the level of parenting stress. Implications for early intervention services for families with a child with Fragile X syndrome were discussed.     

A Pilot Study of Social Information Processing Skills in Girls With Fragile X Syndrome

Fragile X syndrome (FXS) is a well-described inherited cause of intellectual disability and the most common known genetic cause of autism. Social deficits in girls with FXS are not well understood. To better understand barriers to social functioning that may contribute to mental health outcomes, we administered a theoretically based social information processing (SIP) interview about challenging social situations to 11 verbal mental age-matched girls with and without FXS. We hypothesized that (a) girls with FXS have global SIP impairments and (b) less autism symptomatology is related to better SIP skills in girls with FXS. Compared to controls, girls with FXS performed significantly worse on an early SIP skill (problem identification). Scores on later SIP skills tended to be lower and exhibited moderate to strong effect sizes. Competency in goal generation was correlated with autistic-like communication skills. Systematic studies of SIP skills in larger cohorts of girls with FXS are warranted.