Rare Intranuclear Inclusions in the Brains of 3 Older Adult Males With Fragile X Syndrome

NeuroTherapeutics Research Institute and Department of Neurological Surgery, University of California, Davis School of Medicine, USA.
Journal of Neuropathology and Experimental Neurology (Impact Factor: 3.8). 06/2011; 70(6):462-9. DOI: 10.1097/NEN.0b013e31821d3194
Source: PubMed


The FMR1 gene is polymorphic for the length of CGG trinucleotide repeat expansions in the 5' untranslated region. Premutation (55-200 CGG repeats) and full-mutation (>200 CGG repeats) alleles give rise to their respective disorders by different pathogenic mechanisms: RNA gain-of-function toxicity leads to fragile X-associated tremor/ataxia syndrome in the premutation range, and transcriptional silencing and absence of fragile X mental retardation protein (FMRP) lead to fragile X syndrome in the full-mutation range. However, for the latter, incomplete silencing and/or size-mosaicism might result in some contribution to the disease process from residual messenger RNA production. To address this possibility, we examined the brains of 3 cases of fragile X syndrome for the presence of intranuclear inclusions in the hippocampal dentate gyrus. We identified low levels (0.1%-1.3%) of intranuclear inclusions in all 3 cases. Quantitative reverse transcription-polymerase chain reaction for FMR1 messenger RNA and immunofluorescence for FMRP revealed low but detectable levels of both RNA and protein in the 3 cases, consistent with the presence of small numbers of inclusions. The intranuclear inclusions were only present in FMRP-immunoreactive cells. The small numbers of inclusions and very low levels of both FMR1 RNA and protein suggest that the clinical course in these 3 subjects would not have been influenced by contributions from RNA toxicity.

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    • "Another mosaic male was reported with a fully unmethylated full mutation (297–480 CGG repeats) and a threefold increased FMR1 mRNA levels [Loesch et al., 2011]. Finally, very rare intranuclear inclusions, the neuropathological hallmark of FXTAS, were observed in three males with a full mutation [Hunsaker et al., 2011]. "
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    ABSTRACT: Fragile X syndrome (FXS) affects individuals with more than 200 CGG repeats (full mutation) in the fragile X mental retardation 1 (FMR1) gene. Those born with FXS experience cognitive and social impairments, developmental delays, and some features of autism spectrum disorders. Carriers of a premutation (55-200 CGG repeats) are generally not severely affected early in life; however, are at high risk of developing the late onset neurodegenerative disorder, Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), or Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and may have other medical conditions such as developmental delay, autism spectrum disorders, hypertension, anxiety, and immune-mediated disorders. Here we present a case of a 58-year-old man with a borderline IQ, average memory skills, and executive function deficits. He met criteria for multiple psychiatric diagnoses and presented with tremor and ataxia, meeting criteria for FXTAS. Molecular testing unveiled a completely unmethylated FMR1 full mutation in peripheral blood mononucleated cells with elevated FMR1 mRNA and premutation alleles of different sizes in two other tissues (primary fibroblasts and sperm), indicating the presence of allele instability based on both inter- and intra-tissue mosaicism. The observation of FXTAS in this case of a full mutation mosaic man suggests that the pathogenic mechanism underlying this disorder is not observed exclusively in premutation carriers as it was originally thought. The concomitant presence of features of FXS and late onset neurological deterioration with probable FXTAS likely result from a combined molecular pathology of elevated FMR1 mRNA levels, a molecular hallmark of FXTAS and low FMRP expression that leads to FXS. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 04/2015; 167(9). DOI:10.1002/ajmg.a.37125 · 2.16 Impact Factor
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    • "The gyrus and sulci on either side were completely sampled and all neurons and astroglia were counted, as well as the number of intranuclear inclusions in each cell type (Temporal cortex: 2.12% of neurons (4 of 189 cells) and 8.03% of astroglial cells (25 of 311 cells); Frontal cortex: 3.40% of neurons (7 of 206 cells) and 4.51% of astroglial cells (19 of 421 cells). The temporal cortex and frontal cortex were chosen for comparison with previous studies of inclusions in male and female subjects with FXTAS [8,34], as well as a report in FXS [26]. "
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    ABSTRACT: Lack of the fragile X mental retardation protein leads to Fragile X syndrome (FXS) while increased levels of FMR1 mRNA, as those observed in premutation carriers can lead to Fragile X- associated tremor ataxia syndrome (FXTAS). Until recently, FXTAS had been observed only in carriers of an FMR1 premutation (55–200 CGG repeats); however the disorder has now been described in individuals carriers of an intermediate allele (45–54 CGG repeats) as well as in a subject with a full mutation with mosaicism. Here, we report on molecular and clinical data of a male FMR1 mosaic individual with full and premutation alleles. Molecular analysis of FMR1 and FMRP expression in this subject is consistent with a FXS phenotype. We observed reduced expression of FMRP in both peripheral blood and brain leading to the FXS diagnosis. In addition, a dramatic 90% depletion of both FMR1 mRNA and FMRP levels was observed in the blood, as normally observed in FXS cases, and an even greater depletion in the brain. A clinical report of this patient, at age 71, described neurodegenerative signs of parkinsonism that were likely, in retrospect, part of a FXTAS scenario as post-mortem examination shows the presence of intranuclear inclusions, the hallmark pathology of FXTAS. The findings presented in this study indicate co-morbidity for both FXS and FXTAS in this individual carrying both full and premutation FMR1 alleles. In addition, based on symptoms and pathological and molecular evidence, this report suggests the need to redefine the diagnostic criteria of FXTAS.
    Translational Neurodegeneration 05/2013; 2(1):10. DOI:10.1186/2047-9158-2-10
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    • "Less ambiguous is the report of a male with clinical and radiological features (middle cerebellar peduncle sign) of FXTAS, but who was a carrier of an unmethylated, full mutation allele.31 The recent observation of (rare) intranuclear inclusions in three older adult males with methylated, or methylation-mosaic full mutation alleles, and fragile X syndrome,59 suggests that residual RNA expression from full mutation alleles can lead to neuropathologic features normally associated with FXTAS; but, in these three cases, typical clinical features of FXTAS were not evident. However, parkinsonism is common in aging patients with fragile X syndrome60 with no difference between those with a full mutation and those with (pre/full mutation) mosaicism. "
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    ABSTRACT: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder with defining clinical features that include kinetic tremor, gait ataxia, and parkinsonism, with associated features spanning medical, cognitive, and psychiatric clinical domains. The emerging model for the pathogenesis of FXTAS is that of RNA toxicity as a consequence of the sequestration of RNA binding proteins by the expanded CGG-repeat element within the FMR1 message, thus compromising the normal functions of those proteins. A principal challenge at this point is to determine precisely which proteins are involved in FXTAS pathogenesis and how to prevent or reverse this process. A second challenge is to determine why there is incomplete penetrance of FXTAS among premutation carriers with identical CGG-repeat lengths, and what the protective factors are in some carriers. Finally, the discovery in premutation mice of early neurodevelopmental abnormalities, some occurring even during late embryogenesis, raises the question of whether FXTAS is the end-stage of a life-long process of neuronal dysregulation. If an extended pre-clinical phase precedes the development of FXTAS, there is great potential for therapeutic intervention, years or even decades before its clinical features are manifest.
    05/2012; 2.
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