Analysis of the molecular parameters that could predict the risk of manifesting premature ovarian failure in female premutation carriers of fragile X syndrome

Tejada, María-Isabel; García-Alegría, Eva; Bilbao, Amaia; Martínez-Bouzas, Cristina; Beristain, Elena; Poch, Marisa; Ramos-Arroyo, María A.; López, Blanca Elboj; Carvajal, Isabel Fernández; Ribate, María Pilar; Ramos, Feliciano J.

doi:10.1097/gme.0b013e3181647762

Cited by 54 publications

(50 citation statements)

References 21 publications

(30 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The interesting fact about this finding is that it has also been reported for ovarian insufficiency [21][22][23][24].…”

Section: Neuropsychiatric and Muscular Involvementsupporting

confidence: 63%

“…It has been found that the risk of POI and the ovarian manifestations present on a specific patient may have a non-linear association with the number of CGG repeats, with the risk of developing ovarian insufficiency increasing with the number of repeats and then reaching a plateau or even decreasing after 80-100 CGG repeats are reached [21][22][23][24]. Allen et al (2007) [24] did a study with 948 carriers with varying repeat sizes in order to get a better view of the reproductive aging milestones among these women and its relation with the number of CGG repeats present.…”

Section: Reproductive Involvementmentioning

confidence: 99%

See 1 more Smart Citation

Fragile X premutation in women: recognizing the health challenges beyond primary ovarian insufficiency

Hoyos

Thakur

2016

J Assist Reprod Genet

View full text Add to dashboard Cite

Fragile X premutation carriers have 55-200 CGG repeats in the 5' untranslated region of the FMR1 gene. Women with this premutation face many physical and emotional challenges in their life. Approximately 20% of these women will develop fragile X-associated primary ovarian insufficiency (FXPOI). In addition, they suffer from increased rates of menstrual dysfunction, diminished ovarian reserve, reduction in age of menopause, infertility, dizygotic twinning, and risk of having an offspring with a premutation or full mutation. Consequent chronic hypoestrogenism may result in impaired bone health and increased cardiovascular risk. Neuropsychiatric issues include risk of developing fragile X-associated tremor/ataxia syndrome, neuropathy, musculoskeletal problems, increased prevalence of anxiety, depression, and sleep disturbances independent of the stress of raising an offspring with fragile X syndrome and higher risk of postpartum depression. Some studies have reported a higher prevalence of thyroid abnormalities and hypertension in these women. Reproductive health providers play an important role in the health supervision of women with fragile X premutation. Awareness of these risks and correlation of the various manifestations could help in early diagnosis and coordination of care and services for these women and their families. This paper reviews current evidence regarding the possible conditions that may present in women with premutation-sized repeats beyond FXPOI.

show abstract

“…The interesting fact about this finding is that it has also been reported for ovarian insufficiency [21][22][23][24].…”

Section: Neuropsychiatric and Muscular Involvementsupporting

confidence: 63%

Section: Reproductive Involvementmentioning

confidence: 99%

Fragile X premutation in women: recognizing the health challenges beyond primary ovarian insufficiency

Hoyos

Thakur

2016

J Assist Reprod Genet

View full text Add to dashboard Cite

show abstract

“…6,7 Our earlier studies in FXS full mutation (FM: .200 CGGs) females showed that methylation of different CpG sites within FMR1 intron 1 may be more conserved between tissues, as indicated by a highly significant correlation between their methylation and cognitive status. 8,9 Interestingly, this region, also known as fragile X-related epigenetic element 2 (FREE2), is the region where RNA:DNA hybrids associated with regulation of FMRP levels in FXS have been reported to form.…”

mentioning

confidence: 99%

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

et al. 2015

View full text Add to dashboard Cite

Objective: To examine the epigenetic basis of psychiatric symptoms and dysexecutive impairments in FMR1 premutation (PM: 55 to 199 CGG repeats) women.Methods: A total of 35 FMR1 PM women aged between 22 and 55 years and 35 age-and IQmatched women controls (CGG ,45) participated in this study. All participants completed a range of executive function tests and self-reported symptoms of psychiatric disorders. The molecular measures included DNA methylation of the FMR1 CpG island in blood, presented as FMR1 activation ratio (AR), and 9 CpG sites located at the FMR1 exon1/intron 1 boundary, CGG size, and FMR1 mRNA levels. Results:We show that FMR1 intron 1 methylation levels could be used to dichotomize PM women into greater and lower risk categories (p 5 0.006 to 0.037; odds ratio 5 14-24.8), with only FMR1 intron 1 methylation, and to a lesser extent AR, being significantly correlated with the likelihood of probable dysexecutive or psychiatric symptoms (p , 0.05). Furthermore, the significant relationships between methylation and social anxiety were found to be mediated by executive function performance, but only in PM women. FMR1 exon 1 methylation, CGG size, and FMR1 mRNA could not predict probable dysexecutive/psychiatric disorders in PM women.Conclusions: This is the first study supporting presence of specific epigenetic etiology associated with increased risk of developing comorbid dysexecutive and social anxiety symptoms in PM women. These findings could have implications for early intervention and risk estimate recommendations aimed at improving the outcomes for PM women and their families. Neurology ® 2015;84:1631-1638 GLOSSARY 5-hmC 5 5-hydroxymethylacytosine; ADHD-PI 5 attention-deficit/hyperactivity disorder-predominantly inattentive; AR 5 FMR1 activation ratio; DASS 5 Depression Anxiety Stress Scale; ELVF 5 Excluded Letter Verbal Fluency; FM 5 full mutation; FMR1 5 fragile X mental retardation 1 gene; FMRP 5 fragile X mental retardation protein; FREE 5 fragile X-related epigenetic element; FXS 5 fragile X syndrome; GEE 5 generalized estimating equation; IQR 5 interquartile range; LNS 5 Letter-Number Sequencing; OR 5 odds ratio; PM 5 premutation; ROC 5 receiver operating characteristic.The common premutation (PM) CGG expansion (55-199 repeats) in the 59 UTR of the fragile X mental retardation 1 (FMR1) gene (;1 in 450 males and ;1 in 150 females) 1 leads to a number of late-onset disorders 2 and high rates of dysexecutive and psychiatric symptoms, all with incomplete penetrance. 3 The RNA gain-of-function toxicity 4 and deficient FMR1 protein (FMRP) translation 5 are primary molecular features of PM-related disorders and are directly related to the CGG size. However, their effects on the phenotype are diluted in PM females through methylation-related silencing as part of X-inactivation.

show abstract

“…La sintomatología más característica, en el 16-30 % de mujeres premutadas, es el riesgo de presentar Insuficiencia Ovárica Primaria (FXPOI), en la que los ovarios dejan de funcionar antes de los 40 años y aparece amenorrea (Fernández-Carvajal, 2014;Mallolas et al, 2000;Rodríguez-Revenga et al, 2009;Tejada et al, 2008).…”

Section: Cuadro 1 Manifestaciones Clínicas Y Fenotipo Físicounclassified

El síndrome X frágil: identificación del fenotipo y propuestas educativas

Gómez

2014

Redis

View full text Add to dashboard Cite

Las investigaciones confirman que el síndrome X frágil es la primera causa de discapacidad intelectual de tipo hereditario, pero aún es muy desconocido por profesionales de la educación, de la salud y de los servicios sociales. Una detección precoz evitaría la transmisión de la alteración genética y permitiría el establecimiento de las intervenciones más adecuadas para cada persona. En los últimos años se han dado grandes avances en la comprensión de este trastorno del neurodesarrollo. En este artículo se ha realizado una exhaustiva revisión de los estudios y contribuciones más significativas que existen hasta el momento acerca de este síndrome, de su interacción molecular, cerebral, cognitiva y conductual, de herramientas para hacer un primer cribado para la detección de posibles afectados y de sugerencias para la intervención, pero se necesita seguir avanzando para mejorar la evaluación e intervención en cada caso concreto.

show abstract

Analysis of the molecular parameters that could predict the risk of manifesting premature ovarian failure in female premutation carriers of fragile X syndrome

Cited by 54 publications

References 21 publications

Fragile X premutation in women: recognizing the health challenges beyond primary ovarian insufficiency

Fragile X premutation in women: recognizing the health challenges beyond primary ovarian insufficiency

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

El síndrome X frágil: identificación del fenotipo y propuestas educativas

Contact Info

Product

Resources

About