Risk of cognitive impairment in female premutation carriers of fragile X premutation: Analysis by means of robust segmented linear regression models

Abstract

This report describes a study focused on the relationship between CGG repeat length, FMRP, mRNA levels and cognitive functioning in premutation carriers (PM) carriers of Fragile X Syndrome (FXS). We studied 60 females-43 with PM and 17 with normal (N) alleles-from 25 FXS Spanish families. The Wechsler scales were administered to all subjects and new blood samples and hair roots were taken to study mRNA and FMRP levels. Using lowess curves together with segmented models we showed that within the premutation range, IQ scores tend to decrease when the number of CGG repeats increases and the FMRP values decrease. Furthermore, we discovered cut-off points in the molecular variables that seem to change the probability of having some cognitive impairment. Specifically, for those PM females in the upper premutation range (CGG > or = 100) and with FMRP expression < 60% in hair roots, a 10% decrement of FMRP expression represents a significant decrease in IQ scores of about six points, which is more evident for Full-Scale IQ (P-value = 0.035) and Performance IQ (P-value = 0.045) than for Verbal IQ (P-value = 0.074). On the contrary, we did not find any significant correlation between FMR1 mRNA levels and the IQ scores, probably due to the fact that mRNA levels were measured in blood. In conclusion, our findings suggest that the PM can have some effect on cognitive ability in female carriers, although these effects may be subtle. In these cases, it would be advisable to carry out a hair root analysis of FMRP.

Novel methylation markers of the dysexecutive-psychiatric phenotype in FMR1 premutation women

“…While in PM women one study showed that CGG repeat size, when controlled for AR, was significantly associated with ataxia score, 7 the prognostic utility of AR in blood, when examined alone, has not been demonstrated previously. 7,22 In contrast, decrease in FMRP levels in hair root samples was significantly correlated with cognitive status of PM women. 22 Subsequently, it has been suggested that methylation of the CpG sites used to determine AR is not well conserved between blood and other tissues, and thus provides limited representation of FMRP activity in the brain.…”

“…7,22 In contrast, decrease in FMRP levels in hair root samples was significantly correlated with cognitive status of PM women. 22 Subsequently, it has been suggested that methylation of the CpG sites used to determine AR is not well conserved between blood and other tissues, and thus provides limited representation of FMRP activity in the brain. 22 Our previous studies suggest that methylation of FMR1 intron 1 CpG sites is well-conserved between different tissue types including adult and newborn blood, lymphoblasts, and amniocytes, and is stable over time in PM females.…”

“…22 Subsequently, it has been suggested that methylation of the CpG sites used to determine AR is not well conserved between blood and other tissues, and thus provides limited representation of FMRP activity in the brain. 22 Our previous studies suggest that methylation of FMR1 intron 1 CpG sites is well-conserved between different tissue types including adult and newborn blood, lymphoblasts, and amniocytes, and is stable over time in PM females. 8,15,23,24 This could explain why FMR1 intron 1 methylation was more likely than AR to correlate with severity of dysexecutive/psychiatric symptoms in the present study of PM women.…”

Cognitive Dysfunction in FMR1 Premutation Carriers

“…A combination of high CGG repeat size and low FMRP expression may further enhance vulnerability. In female carriers with over 100 CGG repeats and FMRP expression in hair roots below 60%, a 10% decrement of FMRP expression corresponded to a significant decrease in IQ scores by about six points [28]. …”

Segmented regression, a versatile tool to analyze mRNA levels in relation to DNA copy number aberrations

“…Segmented regression has previously been applied to link CGG repeats to mRNA levels in trinucleotide repeat disorders patients (Garcia-Alegria et al, 2007;Minguez et al, 2009) and gene compactness driven nonmonotonic expression levels in eukaryote cells (Carmel and Koonin, 2009).…”