Fragile X Screening by Quantification of FMRP in Dried Blood Spots by a Luminex Immunoassay

LaFauci, Giuseppe; Adayev, Tatyana; Kascsak, Richard J.; Nolin, Sarah L.; Mehta, Pankaj; Brown, W. Ted; Dobkin, Carl

doi:10.1016/j.jmoldx.2013.02.006

Cited by 52 publications

(88 citation statements)

References 55 publications

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“…Together, their results provide further evidence that proteins involved in the FMRPmGluR5 signaling pathway are altered in Sch and mood disorders. These findings support the potential use of the qFMRP test for much broader clinical applications other than just fragile X disorders [19].…”

Section: Neurobiological Features and Targeted Treatments In Fragile supporting

confidence: 73%

“…Furthermore, by quantifying FMRP (qFMRP) − the functional endpoint of FMR1 gene expression − a more comprehensive understanding of FXS biology may help improve the diagnosis, prognosis, and treatment options for affected individuals. To demonstrate the potential of the qFMRP assay, Asuragen recently collaborated with the LaFauci and colleagues [19], who methodologically advanced an effort in the field of using dried blood spots (DBS) aimed to reliably quantify FMRP [19]. It is noteworthy that after they screened 2000 individuals of all ages, they found that qFMRP test can identify PM females with low FMRP (methylated).…”

Section: Introductionmentioning

confidence: 99%

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Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

Budimirović¹,

Duy²

2015

Engrami

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SummaryFragile X syndrome (FXS) is the leading known monogenetic cause of autism spectrum disorder (ASD) and inherited form of intellectual disability (ID). As the major and growing public health problem worldwide, ASD is purely behaviorally defined whereas FXS is a medical/genetic disorder characterized by ID and ASD in males and learning and behavioral/emotional problems (social anxiety, attention network) in both genders. FXS is caused by a mutation in the Fragile X Mental Retardation 1 gene (FMR1) that leads to the epigenetic silencing of the gene and absence of its encoded protein, the fragile X mental retardation protein (FMRP). FMRP selectively targets approximately 4% of the transcribed mRNAs in the brain. Namely, to date, 842 such target mRNAs in mammalian brains have been identified and many of them converge on the same pathway as nonsyndromic ASD. Thus, FXS is the most studied 'disorder of synapse' model for syndromic ASD in the field of neuroscience. There are currently no effective treatments for either FXS or ASD.In this review article, we discuss recent progress and future directions in translating breakthrough preclinical findings that reveal potential therapeutic targets into clinical trials for humans with FXS of potential relevance for ASD. To date, a total of 20 double-blinded, randomized, placebo-controlled clinical trials in FXS have been identified through the FDA ClinicalTrial.gov website. The majority of these trials were completed between 2008−2015. These mostly phase II trials in adults and adolescents tested 13 compounds and have primarily targeted excitatory/inhibitory imbalance theory of FXS and ASD, namely a reversal of social/behavioral symptoms that are part of the core FXS phenotype but not the core synaptic dysfunction in FXS. Despite much progress in the field propelled by the preclinical advances, these clinical studies illustrate the gaps and challenges of translating therapies from animal models to humans with FXS and ASD ('building a bridge and walking on it'). Specifically, recent challenges in the clinical trials demonstrate the need to study for longer period of time (6−12 months), prepubertal age group(s), develop more objective clinical outcome measures (i.e., clinician-based, relevant learning paradigms, and desired biomarkers), and longer placebo run-ins to minimize the placebo impact for both FXS and ASD. Ultimately, a truly satisfactory FXS, and ASD, therapy may likely involve a combination of drugs (and learning paradigms), each targeting a different aspect of the core synaptic, cognitive and behavioral impairments in FXS.

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Section: Neurobiological Features and Targeted Treatments In Fragile supporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

Budimirović¹,

Duy²

2015

Engrami

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“…This variation has been demonstrated by ELISA technology but the technique is difficult to replicate in subsequent samples (155). Newer techniques including the immunoassay utilizing timeresolved Forster's resonance energy transfer (156) and also the Luminex immunoassay (157). These techniques will lead to a new understanding of FMRP deficits not only in FXSD, but also in other neurodevelopmental/ neuropsychiatric disorders.…”

Section: Resultsmentioning

confidence: 99%

“…These techniques will lead to a new understanding of FMRP deficits not only in FXSD, but also in other neurodevelopmental/ neuropsychiatric disorders. The recent publication of FMRP deficits in the brains of individuals with bipolar disorder, schizophrenia, depression and autism (156)(157)(158) has opened our eyes to the importance of FMRP outside of the FXSD population. Even more remarkable is the finding that the age of onset and overall IQ in those with schizophrenia is correlated with FMRP deficits in peripheral blood (159).…”

Section: Resultsmentioning

confidence: 99%

Fragile X spectrum disorders

Lozano

Rosero²,

Hagerman

2014

IRDR

156

110

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“…Another is the incorporation of an immunoassay which quantifies the amount of FMRP present in DBS samples, such as the method described by Reference [43].…”

Section: Discussionmentioning

confidence: 99%

Are We Ready for Fragile X Newborn Screening Testing?—Lessons Learnt from a Feasibility Study

Wotton

Wiley

Bennetts

et al. 2018

IJNS

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Fragile X syndrome (FXS) is the most prevalent heritable cause of cognitive impairment but is not yet included in a newborn screening (NBS) program within Australia. This paper aims to assess the feasibility and reliability of population screening for FXS using a pilot study in one hospital. A total of 1971 mothers consented for 2000 newborns to be tested using routine NBS dried blood spot samples. DNA was extracted and a modified PCR assay with a chimeric CGG primer was used to detect fragile X alleles in both males and females in the normal, premutation, and full mutation ranges. A routine PCR-based fragile X assay was run in parallel to validate the chimeric primer assay. Babies with CGG repeat number ≥59 were referred for family studies. One thousand nine hundred and ninety NBS samples had a CGG repeat number less than 55 (1986 < 50); 10 had premutation alleles >54 CGG repeats (1/123 females and 1/507 males). There was complete concordance between the two PCR-based assays. A recent review revealed no clinically identified cases in the cohort up to 5 years later. The cost per test was $AUD19. Fragile X status can be determined on routine NBS samples using the chimeric primer assay. However, whilst this assay may not be considered cost-effective for population screening, it could be considered as a second-tier assay to a developed immunoassay for fragile X mental retardation protein (FMRP).

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Fragile X Screening by Quantification of FMRP in Dried Blood Spots by a Luminex Immunoassay

Cited by 52 publications

References 55 publications

Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

Fragile X spectrum disorders

Are We Ready for Fragile X Newborn Screening Testing?—Lessons Learnt from a Feasibility Study

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