ISSN:1080-4013    

DOI:10.1002/mrdd.20001

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:2004

数据来源: WILEY

摘要:

AbstractNewborn screening for fragile X syndrome (FXS) is technically possible, and in the relatively near future accurate and inexpensive screening technologies are likely to be available. When that happens, will America's public health system adopt newborn screening for fragile X syndrome? This article addresses this issue by first placing screening for FXS in the context of the history and current status of newborn screening policy and practice. Lack of a proven medical treatment may stand as a barrier to newborn screening, but strong arguments can be made that early intervention provides important services for identified newborns and their families. Furthermore, other arguments could be used to justify newborn screening, including informed reproductive risk, medically necessary information, and consumer demand. Fragile X syndrome is offered as a prototype for many of the issues that will face society as more genetic disorders are discovered and new technologies for screening are developed. MRDD Research Reviews 2004;10:3–10. © 2004 Wiley‐Liss,

ISSN:1080-4013    

DOI:10.1002/mrdd.20002

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:2004

数据来源: WILEY

摘要:

AbstractFragile X syndrome (FXS) is a well‐recognized cause of mental retardation and developmental delay in males. Alongside the well‐documented clinical characteristics of the condition, recent advances in technology and methodology have begun to define FXS at a number of different levels: genetic, brain structure and function, cognition, and behavior. This article suggests that the FXS phenotype is not merely a juxtaposition of spared and impaired functions but rather may be characterized by an inhibitory control deficit that interferes with the individual's ability to modulate output causing perseverative responding across various skill areas. It is further suggested that an inability to modulate arousal may be at least one cause for the inhibitory control deficit that typifies the FXS phenotype. The approach to understanding atypical development outlined here holds exciting promise for future research in FXS and other developmental disorders. MRDD Research Reviews 2004;10:11–16. © 2004 Wiley‐L

ISSN:1080-4013    

DOI:10.1002/mrdd.20003

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:2004

数据来源: WILEY

摘要:

AbstractFragile X syndrome (FXS), caused by a single gene mutation on the X chromosome, offers a unique opportunity for investigation of gene–brain–behavior relationships. Recent advances in molecular genetics, human brain imaging, and behavioral studies have started to unravel the complex pathways leading to the cognitive, psychiatric, and physical features that are unique to this syndrome. In this article, we summarize studies focused on the neuroanatomy and neuroendocrinology of FXS. A review of structural imaging studies of individuals with the full mutation shows that several brain regions are enlarged, including the hippocampus, amygdala, caudate nucleus, and thalamus, even after controlling for overall brain volume. These regions mediate several cognitive and behavioral functions known to be aberrant in FXS such as memory and learning, information and sensory processing, and social and emotional behavior. Two regions, the cerebellar vermis, important for a variety of cognitive tasks and regulation of motor behavior, and the superior temporal gyrus, involved in processing complex auditory stimuli, are reported to be reduced in size relative to controls. Functional imaging, typically limited to females, has emphasized that individuals with FXS do not adequately recruit brain regions that are normally utilized by unaffected individuals to carry out various cognitive tasks, such as arithmetic processing or visual memory tasks. Finally, we review a number of neuroendocrine studies implicating hypothalamic dysfunction in FXS, including abnormal activation of the hypothalamic–pituitary–adrenal (HPA) axis. These studies may help to explain the abnormal stress responses, sleep abnormalities, and physical growth patterns commonly seen in affected individuals. In the future, innovative longitudinal studies to investigate development of neurobiologic and behavioral features over time, and ultimately empirical testing of pharmacological, behavioral, and even molecular genetic interventions using MRI are likely to yield significant positive changes in the lives of persons with FXS, as well as increase our understanding of the development of psychiatric and learning problems in the general population. MRDD Research Reviews 2004;10:17–24. © 2004 Wiley

ISSN:1080-4013    

DOI:10.1002/mrdd.20004

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:2004

数据来源: WILEY

摘要:

AbstractCarriers of fragile X mental retardation 1 (FMR1) premutation alleles (55 to 200 CGG repeats) are generally spared the more serious neurodevelopmental problems associated with the full‐mutation carriers (>200 repeats) of fragile X syndrome. However, some adult male premutation carriers (55–200 repeats) develop a neurological syndrome involving intention tremor, ataxia, dementia, parkinsonism, and autonomic dysfunction. In excess of one‐third of male premutation carriers over 50 years of age develop thefragileX‐associatedtremor/ataxiasyndrome (FXTAS). FXTAS also represents a new form of inclusion disease, with eosinophilic intranuclear inclusions found throughout the brain in both neurons and astrocytes. Because FXTAS appears to be relatively specific to male premutation carriers, who are known to possess elevated levels ofFMR1mRNA, the neuropathology may arise as a consequence of a toxic gain‐of‐function of the mRNA itself, although this proposal requires additional direct testing. One of the critical needs at present is a better estimate for the prevalence of this disorder, because FXTAS is likely to be underdiagnosed in the adult movement disorders clinics. MRDD Research Reviews 2004;10:25–30. © 2004 W

ISSN:1080-4013    

DOI:10.1002/mrdd.20005

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:2004

数据来源: WILEY

摘要:

AbstractData on the relationships between cognitive and physical phenotypes, and a deficit of fragile X mental retardation 1 (FMR1) gene‐specific protein product, FMRP, are presented and discussed in context with earlier findings. The previously unpublished results obtained, using standard procedures of regression and correlations, showed highly significant associations in males between FMRP levels and the Wechsler summary and subtest scores and in females between these levels and the full‐scale intelligence quotient (FSIQ), verbal and performance IQ, and some Wechsler subtest scores. The published results based on data from 144 extended families with fragile X, recruited from Australia and the United States within a collaborative NIH‐supported project, were obtained using robust modification of maximum likelihood in pedigrees. The results indicated that processing speed, short‐term memory, and the ability to control attention, especially in the context of regulating goal‐directed behavior, may be primarily affected by the FMRP depletion. The effect of this depletion on physical phenotype was also demonstrated, especially on body and head height and extensibility of finger joints. It is recommended that further studies should rely on more accurate measures of FMRP levels, and use of larger samples, to overcome extensive variability in the data. MRDD Research Reviews 2004;10:31–41. © 2004 Wil

ISSN:1080-4013    

DOI:10.1002/mrdd.20006

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:2004

数据来源: WILEY

摘要:

AbstractIn addition to cognitive disability, fragile X syndrome (FXS) is associated with behavioral problems that are often functionally limiting. There are few controlled trials to guide treatment; however, available information does suggest that medications can be quite helpful for a number of categories of behavioral disturbance in FXS. Specifically, stimulants appear to be quite useful for management of distractibility, hyperactivity, and impulsive behavior; antidepressants help with anxiety, obsessive‐compulsive behaviors and mood dysregulation; and antipsychotics can reduce aggression. These medications are supportive and help minimize dysfunctional behaviors and maximize functioning. As more is learned about the neural functions of FMRP, medications in the future will be expected to target specific synaptic mechanisms dysregulated in FXS brain and thus ameliorate the cognitive deficit with resultant behavioral improvements. This article summarizes knowledge about effectiveness and approaches to management of currently available psychopharmacology for behavior in FXS and discusses early leads to future treatments for cognition. MRDD Research Reviews 2004;10:42–48. © 2004 Wiley‐Lis

ISSN:1080-4013    

DOI:10.1002/mrdd.20007

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:2004

数据来源: WILEY

摘要:

AbstractFragile X mental retardation is a disease caused by the loss of function of a single RNA‐binding protein, FMRP. Identifying the RNA targets recognized by FMRP is likely to reveal much about its functions in controlling some aspects of memory and behavior. Recent evidence suggests that one of the predominant RNA motifs recognized by the FMRP protein is an intramolecular G‐quartet and that the RGG box of FMRP mediates this interaction. Searching databases of mRNA sequence information, as well as compiled sequences of predicted FMRP targets based on biochemical identification, has revealed that many of these predicted FMRP targets contain intramolecular G‐quartets. Interestingly, many of the G‐quartet containing RNA targets encode proteins involved in neuronal development and synaptic function. Defects in the metabolism of this set of RNAs, presumably in the translation of their protein products, is likely to underlie the behavioral and cognitive changes seen in the disease. MRDD Research Reviews 2004;10:49–52. © 2004 Wiley

ISSN:1080-4013    

DOI:10.1002/mrdd.20008

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:2004

数据来源: WILEY

摘要:

AbstractFragile X syndrome (FXS) is characterized by a pattern of morphological, functional, and molecular characteristics with, in at least some cases, apparent relationships among phenotypic features at different levels. Gross morphology differences in the sizes of some human brain regions are accompanied by fine structural alterations in the shapes and in the numbers of dendritic spines in both humans and the knockout mouse model. The excess number of spines, their immature appearance, and the impaired withdrawal of inappropriately oriented dendrites in FXS or the mouse model suggest impairment of neuronal maturation, including dendritic and spine pruning. It is not clear how these differences arise, although regionally or globally impaired translation of the mRNAs that interact with theFmr1protein product, FMRP, in the vicinity of the synapse, including genes involved in synapse development and plasticity and dendritic retraction, is certainly plausible. FMRP binds mRNA and may be involved in both transport and translation of the mRNAs it binds. The mRNAs it binds belong to multiple functional classes, apparently indicating that FMRP may impact multiple cellular processes. In one example, the glucocorticoid receptor, whose mRNA binds FMRP, regulates the stress‐sensitive glucocorticosteroids. Both human FXS and the mouse model exhibit a protracted elevation in glucocorticosteroids after stress. Possible relationships of other genes to morphological and functional characteristics of FXS are also discussed. MRDD Research Reviews 2004;10:53–59. © 2004 Wiley‐Lis

ISSN:1080-4013    

DOI:10.1002/mrdd.20009

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:2004

数据来源: WILEY

摘要:

AbstractSince the identification of the FMR1 gene basic research has been focused on the molecular characterization of the FMR1 gene product, the fragile X mental retardation protein (FMRP). Recent developments in fragile X research have provided new insights and knowledge about the physiological function of FMRP in the cell and the nerve cell in particular. Currently, compelling evidence suggests a role for FMRP in the transport/translation of dendritically localized mRNAs. In addition, the identification of some of the target mRNAs of FMRP have led to an increased interest in the neurobiology of the syndrome. This review highlights the role of FMRP in dendritic mRNA transport/translation in relation to synaptic plasticity, a molecular mechanism implicated in learning and memory. MRDD Research Reviews 2004;10:60–67. © 2004 Wiley‐Liss,

ISSN:1080-4013    

DOI:10.1002/mrdd.20010

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:2004

数据来源: WILEY