<scp>FXTAS</scp> in an unmethylated mosaic male with fragile X syndrome from Chile

María, Lorena Santa; Pugin, A.; Alliende, María Angélica; Aliaga, Solange; Curotto, Bianca; Aravena, Teresa; Tang, Han; Mendoza-Morales, Guadalupe; Hagerman, Randi J.; Tassone, Flora

doi:10.1111/cge.12278

Cited by 42 publications

(43 citation statements)

References 27 publications

(60 reference statements)

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“…The primary similarity is the type of genetic mutation that leads in some cases to the early-onset developmental syndrome, and in other cases to the late-onset movement disorder. In a very small percentage of cases, both may be observed in the same individual (Santa Maria et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

The fragile X mental retardation 1 gene (FMR1): historical perspective, phenotypes, mechanism, pathology, and epidemiology

Grigsby

2016

The Clinical Neuropsychologist

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Objectives To provide an historical perspective and overview of the phenotypes, mechanism, pathology, and epidemiology of the fragile X-associated tremor/ataxia syndrome (FXTAS) for neuropsychologists. Methods Selective review of the literature on FXTAS. Results FXTAS is an X-linked neurodegenerative disorder of late onset. One of several phenotypes associated with different mutations of the fragile X mental retardation 1 gene (FMR1), FXTAS involves progressive action tremor, gait ataxia, and impaired executive functioning, among other features. It affects carriers of the FMR1 premutation, which may expand when passed from a mother to her children, in which case it is likely to cause fragile X syndrome (FXS), the most common inherited developmental disability. Conclusion This review briefly summarizes current knowledge of the mechanisms, epidemiology, and mode of transmission of FXTAS and FXS, as well as the neuropsychological, neurologic, neuropsychiatric, neuropathologic, and neuroradiologic phenotypes of FXTAS. Because it was only recently identified, FXTAS is not well known to most practitioners, and it remains largely misdiagnosed, despite the fact that its prevalence may be relatively high.

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Section: Introductionmentioning

confidence: 99%

The fragile X mental retardation 1 gene (FMR1): historical perspective, phenotypes, mechanism, pathology, and epidemiology

Grigsby

2016

The Clinical Neuropsychologist

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“…Methylation mosaicism, the presence of both fully methylated and unmethylated FM alleles, as opposed to the presence of methylated FM alone has been associated with better clinical outcomes and higher IQ levels in FXS individuals [17], and the subset of these methylation mosaics and unmethylated FM males who display moderate or normal phenotypes are referred to as high-functioning fragile X males [23,24,25]. Although the presence of an unmethylated FM could mean that FMRP is still produced, albeit at a lower amount due to the inefficient translation of the FMR1 transcripts containing a hyperexpanded CGG-repeat stretch [26], the FMR1 mRNA levels are generally higher in individuals with an unmethylated FM [25], which increases their risk of developing FXTAS [27,28,29]. The complexity in the phenotypic presentation of FXS can also be attributed to inter- and intra-tissue differences in FMR1 CGG-repeat size and its extent of methylation [17].…”

Section: Molecular Determinants Of Fxsmentioning

confidence: 99%

Molecular Correlates and Recent Advancements in the Diagnosis and Screening of FMR1-Related Disorders

Rajan‐Babu

Chong

2016

Genes

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Fragile X syndrome (FXS) is the most common monogenic cause of intellectual disability and autism. Molecular diagnostic testing of FXS and related disorders (fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS)) relies on a combination of polymerase chain reaction (PCR) and Southern blot (SB) for the fragile X mental retardation 1 (FMR1) CGG-repeat expansion and methylation analyses. Recent advancements in PCR-based technologies have enabled the characterization of the complete spectrum of CGG-repeat mutation, with or without methylation assessment, and, as a result, have reduced our reliance on the labor- and time-intensive SB, which is the gold standard FXS diagnostic test. The newer and more robust triplet-primed PCR or TP-PCR assays allow the mapping of AGG interruptions and enable the predictive analysis of the risks of unstable CGG expansion during mother-to-child transmission. In this review, we have summarized the correlation between several molecular elements, including CGG-repeat size, methylation, mosaicism and skewed X-chromosome inactivation, and the extent of clinical involvement in patients with FMR1-related disorders, and reviewed key developments in PCR-based methodologies for the molecular diagnosis of FXS, FXTAS and FXPOI, and large-scale (CGG)n expansion screening in newborns, women of reproductive age and high-risk populations.

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“…Rare individuals are seen with little or no methylation. These individuals tend to have a normal or borderline normal intelligence quotient (IQ) (Basuta et al, ; Godler et al, ; McConkie‐Rosell et al, ; Santa Maria et al, ).…”

Section: Introductionmentioning

confidence: 99%

Fragile X syndrome in a male with methylated premutation alleles and no detectable methylated full mutation alleles

Hayward

Loutaev

Ding

et al. 2019

American J of Med Genetics Pt A

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Most cases of fragile X syndrome (FXS) result from aberrant methylation of the FMR1 gene. Methylation occurs when the number of tandemly arranged cytosine guanine guanine (CGG)-repeats in the 5 0 end of the transcriptional unit of FMR1 exceeds a certain critical threshold, thought to be between 200 and 400 repeats. Such alleles are referred to as full mutation (FM) alleles. Premutation (PM) alleles, alleles with 55-200 repeats, are generally not aberrantly methylated and in fact mayhave hyperexpression of the FMR1 mRNA. We describe here a male who meets the diagnostic criteria for FXS, who is highly mosaic with a mixture of multiple PM and FM alleles and 50% methylation. However, the methylated alleles are limited to two alleles in the PM range,~165 and~175 repeats respectively, with the FM alleles being unmethylated. This finding has implications for FXS diagnosis as well as for efforts to delete the repeat in individuals with FXS using a CRISPR-Cas9 approach.

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FXTAS in an unmethylated mosaic male with fragile X syndrome from Chile

Cited by 42 publications

References 27 publications

The fragile X mental retardation 1 gene (FMR1): historical perspective, phenotypes, mechanism, pathology, and epidemiology

The fragile X mental retardation 1 gene (FMR1): historical perspective, phenotypes, mechanism, pathology, and epidemiology

Molecular Correlates and Recent Advancements in the Diagnosis and Screening of FMR1-Related Disorders

Fragile X syndrome in a male with methylated premutation alleles and no detectable methylated full mutation alleles

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