Rapid antibody test for diagnosing fragile X syndrome:  a validation of the technique

Willemsen, Rob; Smits, A.P.T.; Mohkamsing, S.; Beerendonk, H van; Haan, Anton de; Vries, Bert de; Ouweland, Ans van den; Sistermans, Erik A.; Galjaard, H.; Oostra, Ben A.

doi:10.1007/s004390050363

Cited by 95 publications

(98 citation statements)

References 12 publications

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“…In individuals carrying the full mutation, the severity of the physical and behavioral phenotypes correlates with lower levels of FMRP (36). To be noted, there are limitations in FMRP quantification, as many techniques utilize immunohistochemistry to label peripheral white blood cells (37,38) or hair roots (39,40) with monoclonal antibodies to indirectly measure FMRP levels. These methods cannot quantify FMRP protein levels, which is essential for understanding how the degree of FMRP loss relates to FXS clinical phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Modeling fragile X syndrome in the <i>Fmr1</i> knockout mouse

Kazdoba

Leach

Silverman

et al. 2014

IRDR

201

156

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Section: Introductionmentioning

confidence: 99%

Modeling fragile X syndrome in the <i>Fmr1</i> knockout mouse

Kazdoba

Leach

Silverman

et al. 2014

IRDR

201

156

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“…A rapid immunohistochemical test of blood smears, using a mouse monoclonal antibody, was developed by Willemsen et al 15,16 In that approach, measurement of FMRP was assessed by counting positively stained lymphocytes, with the fraction of positively staining lymphocytes representing a measure of protein level. Microscopic evaluation of smears is necessary to distinguish positively stained lymphocytes from non-specifically stained monocytes.…”

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confidence: 99%

A Quantitative ELISA Assay for the Fragile X Mental Retardation 1 Protein

Iwahashi

Tassone

Hagerman

et al. 2009

The Journal of Molecular Diagnostics

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Non-coding (CGG-repeat) expansions in the fragile X mental retardation 1 (FMR1) gene result in a spectrum of disorders involving altered neurodevelopment (fragile X syndrome) , neurodegeneration (lateonset fragile X-associated tremor/ataxia syndrome), or primary ovarian insufficiency. Most individuals with a premutation allele have IQs that fall within the normal range, although some children experience attention deficit hyperactivity disorder and autism spectrum disorders. 8,9 Moreover, in adults, there is an increased risk of primary ovarian insufficiency, 10,11 emotional problems including depression and anxiety, 12 and the late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome. 13,14 Although reduction or loss of FMRP is generally believed to be the basis for fragile X syndrome, as well as many of the neurodevelopmental problems in the upper premutation range, quantitative comparisons of molecular (FMRP) and clinical phenotypes are generally lacking due to the absence of a quantitative measure of the protein.Thus far, the main approaches for measuring protein levels have been indirect, involving immunohistochemical staining of peripheral blood lymphocytes or hair roots. A rapid immunohistochemical test of blood smears, using a mouse monoclonal antibody, was developed by Willemsen et al 15,16 In that approach, measurement of FMRP was assessed by counting positively stained lymphocytes, with the fraction of positively staining lymphocytes representing a measure of protein level. Microscopic evaluation of smears is necessary to distinguish positively stained lymphocytes from non-specifically stained monocytes. Moreover, as there is no weighting

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“…Blood draws were performed by a local physician or lab and samples were mailed directly to Kimball Genetics using overnight mail. FMRP immunostaining, an indirect alkaline phosphatase technique, was used (Willemsen et al 1997 …”

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confidence: 99%

Longitudinal Changes in Intellectual Development in Children with Fragile X Syndrome

Hall

Burns

Lightbody

et al. 2008

J Abnorm Child Psychol

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Structural equation modeling (SEM) was used to examine the development of intellectual functioning in 145 school-age pairs of siblings. Each pair included one child with Fragile X syndrome (FXS) and one unaffected sibling. All pairs of children were evaluated on the Wechsler Intelligence Scale for Children-Third Edition (WISC-III) at time 1 and 80 pairs of children received a second evaluation at time 2 approximately 4 years later. Compared to their unaffected siblings, children with FXS obtained significantly lower percentage correct scores on all subtests of the WISC at both time points. During the time between the first and second assessments, the annual rate of intellectual development was approximately 2.2 times faster in the unaffected children compared to the children with FXS. Levels of the fragile X mental retardation protein (FMRP) were highly associated with intellectual ability scores of the children with FXS at both time points (r=0.55 and 0.64 respectively). However, when gender, age, and the time between assessments were included as covariates in the structural equation model, FMRP accounted for only 5% of the variance in intellectual ability scores at time 1 and 13% of the variance at time 2. The results of this study suggest that slower learning contributes to the low and declining standardized IQ scores observed in children with FXS. KeywordsFragile X syndrome; Structural equation modeling; Intellectual functioning; IQ; FMRP Fragile X syndrome occurs in approximately 1 in every 4,000 live births and is the most common inherited form of cognitive and behavioral disability. In 1991, Verkerk and colleagues reported that a single gene on the X chromosome (locus Xq27.3), FMR1, was associated with the symptoms of FXS (Verkerk et al. 1991). Subsequent research revealed that persons with FXS had increased numbers of triplet (CGG) repeats within FMR1. In normal alleles, the CGG repeats vary from 6 to 50, whereas expansions of ~50-200 repeats are associated with the "premutation" form of the gene seen in carrier females and males. The probability of having a child with the full mutation increases as the length of the mothers' CGG repeat length increases-a phenomenon known as genetic anticipation. Larger expansions (200 to thousands) of CGG repeats are considered "full mutations" and are typically associated with excessive methylation of cytosines in the FMR1 promoter. This hallss@stanford.edu. HHS Public AccessAuthor manuscript J Abnorm Child Psychol. Author manuscript; available in PMC 2016 April 04. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript modification extinguishes transcription of the FMR1 gene into mRNA, thus stopping translation of the fragile X mental retardation protein (FMRP). FMRP plays an important role in the development of synaptic function, maturation, and plasticity during development, and possibly, on an ongoing basis throughout adult life as well (Reiss et al. 1995).Investigators have reported that individuals with FXS experience weaknesses in executi...

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Rapid antibody test for diagnosing fragile X syndrome: a validation of the technique

Cited by 95 publications

References 12 publications

Modeling fragile X syndrome in the <i>Fmr1</i> knockout mouse

Modeling fragile X syndrome in the <i>Fmr1</i> knockout mouse

A Quantitative ELISA Assay for the Fragile X Mental Retardation 1 Protein

Longitudinal Changes in Intellectual Development in Children with Fragile X Syndrome

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