Cognition and lobar morphology in full mutation boys with fragile X syndrome

Meguid, Nagwa A.; Fahim, Chérine; Sami, Rasha Nabil; Nashaat, Neveen Hassan; Yoon, Uicheul; Anwar, Mona; El-Dessouky, Hosam M.; Shahine, Elham A.; Ibrahim, Ahmed S.; Mancini-Marı̈e, Adham; Evans, Alan C.

doi:10.1016/j.bandc.2011.09.005

Cited by 17 publications

(17 citation statements)

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“…When anomalies are found, these are more frequently diffuse atrophy and cortical thickness, increased whole hemispheric and lobar cortical volume, and increased cortical complexity [13, 19]. These aspects are consistent with the decreased pruning and increased spine density and length and with the presence of an immature spine, as reported in FXS patients and mice [19–21]. …”

Section: Discussionsupporting

confidence: 62%

“…A recent study by Hall et al discovered increased fractional anisotropy in patients with FXS in the left and right inferior longitudinal fasciculus, right uncinate fasciculus and left cingulum hippocampus compared with that in controls; additionally, this aspect could be attributed to the aberrant pruning and axon growth dysregulation, resulting from FMRP reduction [22]. All of these MRI anomalies in brain morphology correlate negatively with cognitive performance in FXS children [19]. …”

Section: Discussionmentioning

confidence: 99%

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Fragile X syndrome: a review of clinical and molecular diagnoses

et al. 2017

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BackgroundFragile X Syndrome (FXS) is the second cause of intellectual disability after Down syndrome and the most prevalent cause of intellectual disability in males, affecting 1:5000–7000 men and 1:4000–6000 women. It is caused by an alteration of the FMR1 gene, which maps at the Xq27.3 band: more than 99% of individuals have a CGG expansion (>200 triplets) in the 5′ UTR of the gene, and FMR1 mutations and duplication/deletion are responsible for the remaining (<1%) molecular diagnoses of FXS. The aim of this review was to gather the current clinical and molecular knowledge about FXS to provide clinicians with a tool to guide the initial assessment and follow-up of FXS and to offer to laboratory workers and researchers an update about the current diagnostic procedures.DiscussionFXS is a well-known condition; however, most of the studies thus far have focused on neuropsychiatric features. Unfortunately, some of the available studies have limitations, such as the paucity of patients enrolled or bias due to the collection of the data in a single-country population, which may be not representative of the average global FXS population. In recent years, insight into the adult presentation of the disease has progressively increased. Pharmacological treatment of FXS is essentially symptom based, but the growing understanding of the molecular and biological mechanisms of the disease are paving the way to targeted therapy, which may reverse the effects of FMRP deficiency and be a real cure for the disease itself, not just its symptoms.ConclusionsThe clinical spectrum of FXS is wide, presenting not only as an isolated intellectual disability but as a multi-systemic condition, involving predominantly the central nervous system but potentially affecting any apparatus. Given the relative high frequency of the condition and its complex clinical management, FXS appears to have an important economic and social burden.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Fragile X syndrome: a review of clinical and molecular diagnoses

et al. 2017

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“…Comparison of patients with FXS with and without autism supported the previously identified endophenotype of social withdrawal in FXS-associated autism by the finding of decrease in the left temporal gyrification index, an indicator of cortico-cortical connectivity and organization [66]. Recent significant scientific discoveries have culminated in human clinical trials targeting different aspects of the neurobiological impairments in FXS.…”

Section: Methodssupporting

confidence: 56%

Plasticity and mTOR: Towards Restoration of Impaired Synaptic Plasticity in mTOR-Related Neurogenetic Disorders

Gipson

Johnston

2012

Neural Plasticity

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Objective. To review the recent literature on the clinical features, genetic mutations, neurobiology associated with dysregulation of mTOR (mammalian target of rapamycin), and clinical trials for tuberous sclerosis complex (TSC), neurofibromatosis-1 (NF1) and fragile X syndrome (FXS), and phosphatase and tensin homolog hamartoma syndromes (PTHS), which are neurogenetic disorders associated with abnormalities in synaptic plasticity and mTOR signaling. Methods. Pubmed and Clinicaltrials.gov were searched using specific search strategies. Results/Conclusions. Although traditionally thought of as irreversible disorders, significant scientific progress has been made in both humans and preclinical models to understand how pathologic features of these neurogenetic disorders can be reduced or reversed. This paper revealed significant similarities among the conditions. Not only do they share features of impaired synaptic plasticity and dysregulation of mTOR, but they also share clinical features—autism, intellectual disability, cutaneous lesions, and tumors. Although scientific advances towards discovery of effective treatment in some disorders have outpaced others, progress in understanding the signaling pathways that connect the entire group indicates that the lesser known disorders will become treatable as well.

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“…Children with FXS and seizures (47) as well as additional medical problems that affect the CNS, such as birth asphyxia or additional gene mutations, are at greater risk of having autism in addition to FXS (48). Very recent studies on patients with FXS and FXS plus ASD supported the endophenotype of social withdrawal via decrease of cortico-cortical connectivity and organization (49). Thus initiating established behavioral interventions for patients with FXS and ASD is important, including Applied Behavioral Analysis and the Early Start Denver Model (50, 51), alongside the "symptomatic" pharmacological approaches discussed below.…”

Section: Figurementioning

confidence: 99%

Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics

Bagni¹,

Tassone²,

Neri³

et al. 2012

J. Clin. Invest.

297

289

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Genetics of fragile XFragile X syndrome (FXS), an X-linked condition first described by Martin and Bell (1), is the leading cause of inherited intellectual disability (ID). Estimates report that FXS affects approximately 1 in 2,500 to 5,000 men and 1 in 4,000 to 6,000 women (2, 3). FXS is caused by mutations in the FMR1 gene, which is located on the X chromosome and whose locus at Xq27.3 coincides with the folate-sensitive fragile site (4, 5). Cytogenetic methods (6) used in the past to diagnose FXS have been replaced by molecular diagnostic of FMR1 DNA using Southern blot analysis and, more recently, PCR.Affected men display varying degrees of symptoms ranging from mild to severe. Due to compensation by the unaffected X chromosome, only one-third of female carriers with a full mutation (FM) have ID; the majority have normal IQ, although learning difficulties and emotional problems are common (7).Identified in 1991 by positional cloning (8), the FMR1 gene is characterized by the presence of a polymorphic CGG triplet sequence in the 5′ UTR (8, 9). Expansion in this triplet sequence gives rise to FXS, which is the prototype of unstable triplet expansion disorders. The triplet variability defines four types of alleles (Figure 1). Normal alleles have a number of CGG repeats, ranging from 5 to 54, with a mode of 30. Premutation (PM) alleles have a number of CGG repeats, ranging from 55 to 200. PM alleles are unstable and have a strong tendency to expand to FM alleles upon maternal transmission. Expansion from a PM to FM can occur with alleles as small as 56 CGGs (10). Alleles possessing between 45 and 54 CGG repeats, referred to as gray-zone or intermediate alleles, are proposed to be precursors of PM alleles, potentially due to paternal and maternal meiotic instability (11). The risk of a PM to FM transition depends on the CGG repeat size, such that the expansion risk is nearly 100% for alleles of >99 CGG repeats (11). A recent study (12) showed that the number of AGG interruptions present in the CGG repeats correlates inversely with the risk of expansion to a FM in the next generation. The presence of AGG interruptions, in addition to the CGG length, may thus better define the risk for transmission from a maternal PM to FM in the offspring.FMR1 silencing is the consequence of rather complex epigenetic modifications (13). In FXS, cytosines located approximately up to 1-kb upstream of the CGG repeat sequences, including the FMR1 promoter, are methylated (14, 15). Normal alleles are also methylated in the FMR1 promoter region but not in close proximity to the CGG repeat, which seems to be a "boundary" in the normal allele that prevents methylation from spreading. This boundary is missing in FM alleles, and the cytosines upstream of the CGG repeat become methylated around the thirteenth week of embryonic development (16). As a consequence, gene transcription is inhibited, leading to the absence of its protein product FMRP (17). Of note, some alleles remain partially or even fully unmethylated (UFM), despite containing ...

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Cognition and lobar morphology in full mutation boys with fragile X syndrome

Cited by 17 publications

References 99 publications

Fragile X syndrome: a review of clinical and molecular diagnoses

Fragile X syndrome: a review of clinical and molecular diagnoses

Plasticity and mTOR: Towards Restoration of Impaired Synaptic Plasticity in mTOR-Related Neurogenetic Disorders

Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics

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