Optimization, validation and initial clinical implications of a Luminex-based immunoassay for the quantification of Fragile X Protein from dried blood spots

Boggs, Anna; Schmitt, Lauren; McLane, Richard; Adayev, Tatyana; LaFauci, Giuseppe; Horn, Paul S.; Dominick, Kelli C.; Groß, Christina; Erickson, Craig A.

doi:10.1038/s41598-022-09633-8

Cited by 17 publications

(14 citation statements)

References 31 publications

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“…The FMRP was detected at the level of 7.55 pm or 0.347 pg/10 3 WBC or about 19% of normal FMRP expression in males. The reference range for males with normal FMR1 allele is 1.83+/−0.28 pg/10 3 WBC (Adayev, unpublished data) or 28 pm FMRP reported for males in a typically developing control group 26 …”

Section: Resultsmentioning

confidence: 93%

“…The reference range for males with normal FMR1 allele is 1.83+/−0.28 pg/10 3 WBC (Adayev, unpublished data) or 28 pm FMRP reported for males in a typically developing control group. 26 In 2022, the original archived DNA was reanalyzed and showed 280-284 CGG repeats with no AGGs identified. 27 Methylation analysis using a PCR-based high resolution and sensitivity assay demonstrated 0% methylation.…”

Section: Genetics Evaluation and Molecular Findings (Table 1)mentioning

confidence: 99%

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High performing male with fragile X syndrome with an unmethylated FMR1 full mutation: The relevance of clinical and genetic correlations

Shieh,

Amkraut,

Spiridigliozzi

et al. 2023

Clinical Case Reports

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A high performing male with an unmethylated full mutation in the fragile X messenger ribonucleoprotein 1 (FMR1) gene surpassed our expectations into young adulthood. Although initial genetic findings helped make a correct fragile X syndrome (FXS) determination, the report was insufficient. Ten years later, we repeated and conducted additional genetic and clinical studies to determine whether more information could assist with treatment and counseling. The genetic findings were very consistent with his high functioning and would have enabled us to be more confident about a good developmental outcome had they been available previously. As FXS enters the mainstream of well-understood genetic disorders and technological advancements improve genetic tests, it should be clearer to clinical providers what a full FXS assessment could include to provide high quality information for care. For individuals with FXS who are high functioning, their families and clinical professionals would benefit from knowing more genetic findings, including, most importantly, methylation status, but also the FMR1 protein (FMRP) level and mRNA level. While we now know that obtaining only the CGG repeat number is not always adequate to inform accurate clinical care, future studies are likely to show the benefit of studying other biomarkers, such as mRNA levels.

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Section: Resultsmentioning

confidence: 93%

Section: Genetics Evaluation and Molecular Findings (Table 1)mentioning

confidence: 99%

High performing male with fragile X syndrome with an unmethylated FMR1 full mutation: The relevance of clinical and genetic correlations

Shieh,

Amkraut,

Spiridigliozzi

et al. 2023

Clinical Case Reports

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“…We first examined 5% FDR corrected Spearman’s correlations between EEG measures and clinical measures across all FXS participants. We next examined exploratory clinical correlations in males with FXS who are expected to have significantly less FXP protein expression compared to females with FXS 23 . All FXS (see Table X): The WJ3 was used to quantify selective auditory attention (including speech-sound discrimination and resistance to auditory stimulus), with higher scores indicating better performance 24 .…”

Section: Resultsmentioning

confidence: 99%

“…It is expected that the human sample is genetically more heterogeneous, including mosaic males and females (who are obligate mosaics) and increased FXP production should lead to normalization of brain signals. In addition, non-trivial amounts of peripheral FXP have been observed in a proportion of non-mosaic full mutation males 23 . Second, ignoring nomenclature, scalp potentials in mice, as in humans, represent a mixture of source activity at each electrode.…”

Section: Discussionmentioning

confidence: 99%

Temporal and frontal lobe contributions to neural synchronization dysfunction and auditory attention in Fragile X Syndrome

Pedapati

Ethridge

DeStefano

et al. 2022

Preprint

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Fragile X syndrome (FXS) is a trinucleotide repeat disorder and the most common hereditary form of intellectual disability. Patients with FXS are commonly impaired by sensory hypersensitivity. Compared to cognition, neural correlates of sensory responses can be studied more objectively and across species. Alterations in auditory processing in FXS measured by scalp electroencephalography (EEG) are well documented. However, the orientation of the auditory cortex in humans introduces significant confounding between temporal and frontal sources. Herein, we conducted EEG source analysis in 36 participants with FXS and 39 matched controls to localize known alterations to the auditory chirp stimulus. The key findings in participants with FXS include 1) distinct contributions of frontal and temporal sources to the onset and intrastimulus neural synchronization, 2) moderation of abnormal neural responses in females with FXS, 3) evidence of deep brain sources contributing to impairments in synchronization, and 4) presence of robust region-specific clinical correlations. The synchronous and asynchronous gamma activity (SA ratio) ratio may further represent a clinically relevant biomarker of the efficiency of auditory processing in FXS. Findings from this study have implications for back translation and relevance for signal-to-noise conceptual frameworks in understanding neural activity in neurodevelopmental disorders.

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“…It would be interesting in future studies to correlate FMRP expression levels with individual mouse behaviors, particularly considering the variability in FMRP expression seen among mice in this study. In humans, FMRP expression is reported to vary among clinically normal and FXS subjects [ 49 , 50 , 51 , 52 ]. Investigating other genetic markers of FXS in these FXS-like mice would also help to further characterize this model.…”

Section: Discussionmentioning

confidence: 99%

Maternal Microbiota Modulate a Fragile X-like Syndrome in Offspring Mice

Varian

Weber

Kim

et al. 2022

Genes

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Maternal microbial dysbiosis has been implicated in adverse postnatal health conditions in offspring, such as obesity, cancer, and neurological disorders. We observed that the progeny of mice fed a Westernized diet (WD) with low fiber and extra fat exhibited higher frequencies of stereotypy, hyperactivity, cranial features and lower FMRP protein expression, similar to what is typically observed in Fragile X Syndrome (FXS) in humans. We hypothesized that gut dysbiosis and inflammation during pregnancy influenced the prenatal uterine environment, leading to abnormal phenotypes in offspring. We found that oral in utero supplementation with a beneficial anti-inflammatory probiotic microbe, Lactobacillus reuteri, was sufficient to inhibit FXS-like phenotypes in offspring mice. Cytokine profiles in the pregnant WD females showed that their circulating levels of pro-inflammatory cytokine interleukin (Il)-17 were increased relative to matched gravid mice and to those given supplementary L. reuteri probiotic. To test our hypothesis of prenatal contributions to this neurodevelopmental phenotype, we performed Caesarian (C-section) births using dissimilar foster mothers to eliminate effects of maternal microbiota transferred during vaginal delivery or nursing after birth. We found that foster-reared offspring still displayed a high frequency of these FXS-like features, indicating significant in utero contributions. In contrast, matched foster-reared progeny of L. reuteri-treated mothers did not exhibit the FXS-like typical features, supporting a key role for microbiota during pregnancy. Our findings suggest that diet-induced dysbiosis in the prenatal uterine environment is strongly associated with the incidence of this neurological phenotype in progeny but can be alleviated by addressing gut dysbiosis through probiotic supplementation.

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Optimization, validation and initial clinical implications of a Luminex-based immunoassay for the quantification of Fragile X Protein from dried blood spots

Cited by 17 publications

References 31 publications

High performing male with fragile X syndrome with an unmethylated FMR1 full mutation: The relevance of clinical and genetic correlations

High performing male with fragile X syndrome with an unmethylated FMR1 full mutation: The relevance of clinical and genetic correlations

Temporal and frontal lobe contributions to neural synchronization dysfunction and auditory attention in Fragile X Syndrome

Maternal Microbiota Modulate a Fragile X-like Syndrome in Offspring Mice

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