Associated Clinical Disorders Diagnosed by Medical Specialists in 188 FMR1 Premutation Carriers Found in the Last 25 Years in the Spanish Basque Country: A Retrospective Study

Sonia Merino,Maria-Isabel Tejada,Maria-Asunción López-Aríztegui,Begoña Prieto,Nekane Ibarluzea,Hiart Maortua,Idoia Rouco

doi:10.3390/genes7100090

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI) are definitely related to the fragile X mental retardation 1 (FMR1) premutation (PM). Additional medical problems have also been associated with the PM, such as fibromyalgia, endocrine, and psychiatric disorders. To improve our understanding in the field, we reviewed all PM carriers and their reasons for any medical referrals from 104 fragile X families molecularly diagnosed in our laboratory and living in the Spanish Basque Country. After signing the written informed consent, we studied their electronic medical records in order to identify the disorders associated with the PM and their frequencies. We obtained clinical data in 188 PM carriers (147 women and 41 men). In women, the frequency of FXPOI (22.61%) was similar to that previously reported in PM carriers. In men, the frequency of definite FXTAS (28.57%) was lower than reported elsewhere. Furthermore, thyroid pathology was associated with the PM, the frequency of hypothyroidism being much higher in the studied region than in the general population (8.84% vs. 0.93%). Finally, we found no association with fibromyalgia or psychiatric problems. These findings represent another population contribution in this field and may be useful for the clinical management of PM carriers.

Highlights

Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability and autism spectrum disorder (ASD) [1,2,3]
In order to improve our understanding in the field, we undertook this work to determine how many PM carriers we studied in our region, the reasons for any medical referrals, and the frequency of clinical pathologies associated with the PM
The clinical reasons for the molecular testing of the 205 PM carriers were the following: 44 were mothers of children with FXS; 5 were probands for Fragile X-associated tremor/ataxia syndrome (FXTAS); 5 were probands for fragile X-associated primary ovarian insufficiency (FXPOI); 6 PMs were found in children probands tested due to global developmental delay; 133 were relatives studied in cascade testing from a proband; 4 were prenatal diagnosis in pregnant carriers; 8 were tested for other reasons

Summary

Introduction

Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability and autism spectrum disorder (ASD) [1,2,3]. The fragile X mental retardation 1 (FMR1) gene, discovered in. 1991, encodes the fragile X mental retardation protein (FMRP), which is absent and leads to FXS when a triplet repeat expansion (CGG)—located in the 50 untranslated region of the first exon of the FMR1gene—expands to more than 200 copies and the promoter region becomes hypermethylated (full mutation or FM). Individuals with alleles that range from 55 to 200 repeats are considered. FMR1 premutation (PM) carriers because women with alleles in this range may expand to more than 200 copies in the generation [4]. Individuals with PM do not have FXS The alleles in this range produce slightly lower levels of FMRP, but enough for patients not to develop the FXS phenotype. Among the molecular mechanisms underlying the fact that some of the carriers have clinical signs and symptoms, the first theory postulated was that of the mRNA toxicity due to an increase in FMR1 transcription [6,7]

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Conclusion