Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families

Abstract

Within the past few years, there has been a significant change in identifying and characterizing the FMR1 premutation associated phenotypes. The premutation has been associated with elevated FMR1 mRNA levels and slight to moderate reductions in FMRP levels. Furthermore, it has been established that B20% of female premutation carriers present primary ovarian insufficiency (POI) and that fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in one-third of all male premutation carriers older than 50 years. Besides POI and FXTAS, new disorders have recently been described among individuals (especially females) with the FMR1 premutation. Those pathologies include thyroid disease, hypertension, seizures, peripheral neuropathy, and fibromyalgia. However there are few reports related to FXTAS penetrance among female premutation carriers or regarding these disorders recently associated to the FMR1 premutation. Therefore, we have evaluated 398 fragile X syndrome (FXS) families in an attempt to provide an estimation of the premutation associated phenotypes penetrance. Our results show that signs of FXTAS are detected in 16.5% of female premutation carriers and in 45.5% of premutated males older than 50 years. Furthermore, among females with the FMR1 premutation, penetrance of POI, thyroid disease and chronic muscle pain is 18.6, 15.9 and 24.4%, respectively. The knowledge of this data might be useful for accurate genetic counselling as well as for a better characterization of the clinical phenotypes of FMR1 premutation carriers.

Enhanced Asynchronous Ca2+ Oscillations Associated with Impaired Glutamate Transport in Cortical Astrocytes Expressing Fmr1 Gene Premutation Expansion

“…Premutation alleles of the FMR1 gene have estimated frequencies of 1:130 -250 females and 1:250 -810 males (1,2). These premutation carriers can display clinical features including behavioral and cognitive abnormalities in children (3)(4)(5)(6), primary ovarian insufficiency in ϳ20% of women (7), and FXTAS (7)(8)(9) in ϳ40% of male carriers.…”

Evidence of an age-related correlation of ovarian reserve and FMR1 repeat number among women with “normal” CGG repeat status

“…If indicated, Southern blot was performed by hybridizing the probe StB12.3 to EcoRI-and EagI digested DNA. The sensitivity of both the PCR and Southern blot analyses was 99 % [16][17][18][19].…”

Fragile X Syndrome in a Colombian Family

“…In addition, patients present a variable degree of ID and behavioral symptoms such as shyness, auto and hetero aggression, poor eye contact, anxiety, attention deficit hyperactivity among others (21,22). Women with full mutation, depending on the activation rate which represents the activity of the mutated allele, may present the physical phenotype and severe ID or may not present any suggestive finding (4).…”