Noninvasive Test for Fragile X Syndrome, Using Hair Root Analysis

Willemsen, Rob; Anar, Burçu; Otero, Yolanda de Diego; Vries, Bert B.A. de; Hilhorst‐Hofstee, Yvonne; Smits, A.P.T.; Looveren, Eddy van; Willems, Patrick J.; Galjaard, H.; Oostra, Ben A.

doi:10.1086/302462

Cited by 56 publications

(55 citation statements)

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“…In this paper, we have assumed that the direction of Tassone et al 1999a;Willemsen et al 1999). In addition, we measured the effects of FMRP at 11 and 15 years of age, when intellectual functioning was already rather severely impaired.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, several investigators have pointed out that FMRP in the blood is synthesized in leukocytes, a tissue of mesodermal origin. In contrast, brain FMRP is of ectodermal origin (Abrams et al 1999;Tassone et al 1999a;Willemsen et al 1999). In addition, we measured the effects of FMRP at 11 and 15 years of age, when intellectual functioning was already rather severely impaired.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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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“…[95][96][97] Typically, fewer than 40% of the lymphocytes from males with the fragile X syndrome have detectable amounts of FMRP. 96 This protein-based test has recently been adapted for hair root 98,99 and prenatal 100,101 samples. Although promising, this technique cannot accurately identify affected females.…”

Section: Laboratory Testsmentioning

confidence: 99%

FMR1 and the fragile X syndrome: Human genome epidemiology review

Crawford

Acuña

Sherman

2001

Genetics in Medicine

578

391

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The fragile X syndrome, an X-linked dominant disorder with reduced penetrance, is one of the most common forms of inherited mental retardation. The cognitive, behavioral, and physical phenotype varies by sex, with males being more severely affected because of the X-linked inheritance of the mutation. The disorder-causing mutation is the amplification of a CGG repeat in the 5' untranslated region of FMR1 located at Xq27.3. The fragile X CGG repeat has four forms: common (6 -40 repeats), intermediate (41-60 repeats), premutation (61-200 repeats), and full mutation (Ͼ200 -230 repeats). Population-based studies suggest that the prevalence of the full mutation, the disorder-causing form of the repeat, ranges from 1/3,717 to 1/8,918 Caucasian males in the general population.The full mutation is also found in other racial/ethnic populations; however, few population-based studies exist for these populations. No population-based studies exist for the full mutation in a general female population. In contrast, several large, population-based studies exist for the premutation or carrier form of the disorder, with prevalence estimates ranging from 1/246 to 1/468 Caucasian females in the general population. For Caucasian males, the prevalence of the premutation is~1/1,000. Like the full mutation, little information exists for the premutation in other populations. Although no effective cure or treatment exists for the fragile X syndrome, all persons affected with the syndrome are eligible for early intervention services. The relatively high prevalence of the premutation and full mutation genotypes coupled with technological advances in genetic testing make the fragile X syndrome amenable to screening. The timing as well as benefits and harms associated with the different screening strategies are the subject of current research and discussion. Genet Med 2001:3(5):359 -371.

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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%