Cognitive, behavioral, and neuroanatomical assessment of two unrelated male children expressingFRAXE

Abrams, Michael T.; Doheny, Kimberly F.; Mazzocco, Michèle M.M.; Knight, Samantha Jl; Baumgardner, Thomas L.; Freund, Lisa S.; Davies, Kay E.; Reiss, Allan L.

doi:10.1002/(sici)1096-8628(19970221)74:1<73::aid-ajmg16>3.0.co;2-o

Cited by 37 publications

(23 citation statements)

References 29 publications

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“…Because we were also testing for FRAXE mutations of which little is known except that they are associated with a mild phenotype,11 12 we designed our survey to be inclusive rather than exclusive; thus, our target population ranged from boys with severe mental retardation to boys in the normal IQ range who needed extra help in some areas of learning.…”

Section: Methodsmentioning

confidence: 99%

FRAXA and FRAXE: the results of a five year survey

Youings

2000

Journal of Medical Genetics

111

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We report the results of a five year survey of FRAXA and FRAXE mutations among boys aged 5 to 18 with special educational needs (SEN) related to learning disability. We tested their mothers using the X chromosome not transmitted to the son as a control chromosome, and the X chromosome inherited by the son to provide information on stability of transmission. In 1991 when the gene for fragile X was cloned, 1 2 the prevalence of fragile X was accepted as approximately 1 in 1000 to 1 in 2600.3 4 The frequency was based on population studies completed in the 1980s, when only a cytogenetic test was available for the diagnosis of fragile X. Following the discovery of the gene, some laboratories retested their families diagnosed as fragile X +ve and found a proportion of false positives. This was because (1) the test did not discriminate between FRAXA and other fragile sites in Xq27-28, and (2) a number of laboratories scored people as fragile X positive on the basis of a very small number of cells that appeared to have a fragile site, without having any suitable control data. 6Prompted by the discovery of the FMR1 gene, and before the present project, we carried out a pilot study 7 using the Southern blotting method of FRAXA detection on blood samples. Following the pilot study, we initiated a five year research programme to test boys with special educational needs (SEN) for FRAXA and FRAXE. FRAXE was at that time a newly identified fragile site, 8 shown to be the result of a polymorphic GCC repeat ∼600 kb distal to FRAXA, which appeared to have a similar expansion profile to FRAXA but was associated with a milder form of mental retardation. 9 We published preliminary results after the first two years of the study, 10 which detailed the aims of our research programme and some of our methodology. The purpose of the current paper is to report (1) the prevalence of FRAXA and FRAXE mutations in the total study population together with an estimate of the population frequency of full and premutations in both genes; (2) the distribution of allele sizes in the study population and in the control X chromosomes, with special reference to intermediate and premutation sized alleles; (3) the stability of transmission of repeat sizes from mother to son; (4) the segregation of X chromosomes among brothers in our population; and (5) the prevalence of boys with a 47,XXY constitution detected in our population. Methods THE PROTOCOLOur study was designed to test boys aged 5 to 18 years attending state schools in Wessex, a region in southern England with a population of approximately 2.3 million (table 1). The boys were selected for testing on two criteria: (1) they had SEN which were related to cognitive deficiencies with no medical diagnosis; (2) the parent/guardian was well aware that their child had SEN. The mothers of boys tested were invited to provide DNA samples to enable observation of triplet repeat stability in transmission and to use the X chromosome not transmitted to the son as our control. The samples collected were...

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Section: Methodsmentioning

confidence: 99%

FRAXA and FRAXE: the results of a five year survey

Youings

2000

Journal of Medical Genetics

111

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“…This syndrome results from the lack of fragile X mental retardation (FMR1) gene expression and the corresponding absence of its protein product, fragile X mental retardation protein (FMRP). The lack of FMRP has been correlated with mental impairment ranging from mild learning disabilities to profound mental retardation (6)(7)(8). At present, there is no cure for this syndrome, but it is extremely important to understand the consequences of the absence of FMRP to the nervous system as well as other body systems.…”

Section: -[(؎)-2-carboxypiperazin-4-yl]-propyl-1-phosphate (Cpp)mentioning

confidence: 99%

Absence of metabotropic glutamate receptor-mediated plasticity in the neocortex of fragile X mice

Wilson

Cox

2007

Proc. Natl. Acad. Sci. U.S.A.

106

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Fragile X syndrome is a common heritable form of mental retardation in humans. Recent neuroanatomical studies indicate an apparent immature appearance of neurons in fragile X syndrome patients and fragile X mental retardation protein (FMRP)-knockout mice, an animal model of this condition. In this work, we investigated possible alterations in synaptic plasticity in the neocortex of FMRP-knockout mice. Extracellular field potentials were recorded from the deep-layer visual neocortex. Long-term potentiation (LTP) was severely attenuated in brain slices from knockout mice relative to that observed in slices from wild-type mice. Considering that neocortical LTP can involve both NMDA receptor-dependent and -independent mechanisms, we attempted to distinguish the nature of LTP attenuated in the knockout condition. In slices from wildtype mice, LTP was partially attenuated by the NMDA receptor antagonist 3-[(؎)-2-carboxypiperazin-4-yl]-propyl-1-phosphate (CPP); however, the general metabotropic glutamate receptor (mGluR) antagonist ␣-methyl-4-carboxyphenylglycine (MCPG) strongly attenuated LTP, resulting in a response indistinguishable from that observed in slices from knockout mice. The selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) attenuated LTP to a similar degree as did MCPG in wild-type slices, but MPEP did not alter the reduced potentiation in knockout slices. Our results suggest that LTP in layer V visual neocortex depends primarily on mGluR5 activation. Our data also indicate that mGluR5-mediated synaptic plasticity is absent in the neocortex of FMRPknockout mice. Such an alteration may contribute to the cognitive and learning deficits exhibited in these mice as well as in fragile X syndrome.fragile X mental retardation protein ͉ long-term potentiation ͉ synaptic plasticity ͉ visual cortex F ragile X syndrome is the most frequent cause of familial mental retardation and is a prevalent cause of mental disability second only to Down's syndrome, affecting Ϸ1 in 4,000 males and 1 in 8,000 females (1-3). Fragile X syndrome is linked to a large variety of phenotypic characteristics, including increased incidence of autistic behavior, attention-deficit disorder, anxiety disorder, sensory-processing problems, epilepsy, delays in speech and language development, and macroorchidism (4, 5). This syndrome results from the lack of fragile X mental retardation (FMR1) gene expression and the corresponding absence of its protein product, fragile X mental retardation protein (FMRP). The lack of FMRP has been correlated with mental impairment ranging from mild learning disabilities to profound mental retardation (6-8). At present, there is no cure for this syndrome, but it is extremely important to understand the consequences of the absence of FMRP to the nervous system as well as other body systems.FMRP is expressed most abundantly in neurons and is concentrated within dendritic spines, and at the subcellular level the protein is primarily found associated with both cytoplasmic and endoplasmic reticulum...

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“…The children are less severely affected and less likely to be stigmatized than those with fragile X. A rare patient with high-functioning autism has been reported (Abrams et al 1997).…”

Section: The X Chromosomementioning

confidence: 99%

The Neurology of Autism - Edited by Mary Coleman

Ravet¹

2010

Journal of Research in Special Educational Needs

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Cognitive, behavioral, and neuroanatomical assessment of two unrelated male children expressingFRAXE

Cited by 37 publications

References 29 publications

FRAXA and FRAXE: the results of a five year survey

FRAXA and FRAXE: the results of a five year survey

Absence of metabotropic glutamate receptor-mediated plasticity in the neocortex of fragile X mice

The Neurology of Autism - Edited by Mary Coleman

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