Fragile X Mental Retardation 1 Premutation Research Articles

Syndrome tremblement-ataxie lié à une prémutation de l’X fragile

The FXTAS syndrome (Fragile X-associated tremor/ataxia syndrome) is a specific neurodegenerative syndrome affecting subjects carrying a premutation of the FMR1 (fragile X mental retardation 1) gene. It affects mainly men with the premutation and aged more than 50 years. This syndrome is separate and distinct from the fragile X syndrome. The FXTAS syndrome remains underestimated today. It should be considered in patients older than 50 years with tremors and cerebellar ataxia, especially when Parkinson disease or cognitive disorders are present or when there is a family history of infertility, early menopause, or mental retardation. In these patients, hyperintense signals of mid-cerebellar peduncle images on T2 and FLAIR MRI justify genetic testing for the FMR1 premutation.

Screening for the Presence of FMR1 Premutation Alleles in Women With Parkinsonism

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive, late-onset neurodegenerative disease that affects older carriers of premutation (CGG) repeat expansions of the fragile X mental retardation 1 (FMR1) gene. Clinical features include intention tremor, gait ataxia, memory loss, peripheral neuropathy, autonomic dysfunction, and parkinsonism. The presence of parkinsonism in FXTAS raises the possibility that some individuals who have Parkinson disease are actually carriers of a premutation FMR1 allele. To screen DNA samples from a large cohort of females with Parkinson disease for an excess of expanded alleles of the FMR1 gene. We screened a cohort of 595 women with parkinsonism, the largest screening of a parkinsonism-associated group to date, for the presence of an FMR1 premutation allele (55-200 CGG repeats). The screening protocol uses an enhanced polymerase chain reaction method capable of flagging any FMR1 expanded CGG repeat in women as well as in men. Diagnostic assessments were performed at an outpatient tertiary clinic (Parkinson Institute, Milan). Genotyping was conducted at the University of California, Davis. CGG repeat number and clinical/neuroimaging assessments of patients with Parkinson disease were conducted. Two premutation carriers were identified. Two individuals possessed an FMR1 allele in the premutation range (CGG repeats: 30 and 75; 30 and 115). This carrier frequency (2 of 595 [0.34%]) is not significantly different from estimates of the allele frequency among women in the general population (0.4%-0.8%). Clinical and radiologic features of these 2 patients were similar to those of the general Parkinson disease population; however, 1 patient (115 CGG repeats) had a family history of 2 sons with the fragile X syndrome. Screening of women within the parkinsonism clinical spectrum is unlikely to be productive in the absence of additional medical or family history suggestive of involvement of the FMR1 gene.

Very early premature ovarian failure in two sisters compound heterozygous for the FMR1 premutation

Expansion of the CGG trinucleotide repeat in the 5′ untranslated region of the fragile X mental retardation 1 ( FMR1) gene within the premutation range is one of the known genetic factors associated with premature ovarian failure and earlier age at menopause. Studies have shown that approximately 16–26% of female carriers will develop premature ovarian failure, and current research is focussed on the identification of molecular factors that predict its occurrence in female carriers. In this report we present two sisters who are compound heterozygous for a premutation, and who were referred because of very early menopause, occurring at the age of 17 years in the youngest sister. Premature ovarian failure associated with FMR1 premutation at such an early age has not been reported in the literature before.

Estrogen Receptor α Gene Polymorphisms Are Associated With Idiopathic Premature Ovarian Failure

About 1 in 100 women enter menopause before age 40; they are generally diagnosed as having premature ovarian failure (POF). The only gene that has consistently been associated with POF is FMR1 (Fragile X Mental Retardation 1), but the finding that only about 14% of women with familial POF carry an FMR1 premutation suggests that other genes may be associated with POF. This case-control study examined the role, if any, of hormone receptor or binding protein variants in genetic predisposition to POF. Fifty-five women diagnosed as having POF were compared with 107 control women from the general population and with 27 others who were proved fertile after age 37 years. Participants were from a predominantly Caucasian population in western Canada with significant Asian (mainly Chinese) admixture. Allele frequencies for repeat polymorphisms and single nucleotide polymorphisms were examined at several candidate gene sites. No significant differences were found between POF patients and control women in allele distributions of polymorphisms at the androgen receptor (AR) gene, estrogen receptor β (ESR2) gene, sex hormone-binding globulin (SHBG) gene, or follicle-stimulating hormone (FSH) receptor (FSHR) gene. In contrast, at a repeat in a promoter of the estrogen receptor a (ESR1) gene, women with POF had fewer (less than 18) short repeat alleles than control women (P = 0.004 versus the combined control groups). A genotype consisting of 2 short alleles was identified in 36.4% of control women but only 5.5% of those with POF (P < 0.0001 versus combined controls). Calculations showed that the ESR1 repeat may create a risk of POF in a simple dominant manner in which carriers of a long repeat have a relative risk of POF of 9.7, with a 95% confidence interval of 2.6-35.6.

Reproductive Health of Adolescent Girls Who Carry the FMR1 Premutation

The fragile X mental retardation 1 (FMR1) gene, located on the X chromosome, is characterized by a dynamic CGG repeat expansion in the 5' untranslated region. It has long been known that female carriers of the FMR1 premutation allele (55-199 CGG) are at risk for passing the FMR1 full mutation (> or =200 repeats) to their offspring, which results in a common form of mental retardation known as fragile X syndrome. The FMR1 premutation allele, however, also places female carriers at significantly increased risk for prematurely diminished ovarian function, which we refer to as fragile X-associated primary ovarian insufficiency (FXPOI). Although of particular concern for younger women, to date, studies of FXPOI have been restricted to women > or =18 years of age and have not specifically addressed ovarian reserve and menstrual cycle characteristics among adolescent carriers. We discuss the expected reproductive phenotype among FMR1 premutation carriers during adolescence, the associated health considerations based on our current understanding of FXPOI, and the directions for future studies.

Developmental Study of Fragile X Syndrome Using Human Embryonic Stem Cells Derived from Preimplantation Genetically Diagnosed Embryos

We report on the establishment of a human embryonic stem cell (HESC) line from a preimplantation fragile X-affected embryo and demonstrate its value as an appropriate model to study developmentally regulated events that are involved in the pathogenesis of this disorder. Fragile X syndrome results from FMR1 gene inactivation due to a CGG expansion at the 5'UTR region of the gene. Early events in FMR1 silencing have not been fully characterized due to the lack of appropriate animal or cellular models. Here we show that, despite the presence of a full mutation, affected undifferentiated HESCs express FMR1 and are DNA unmethylated. However, epigenetic silencing by DNA methylation and histone modification occurs upon differentiation. Our unique cell system allows the dissection of the sequence by which these epigenetic changes are acquired and illustrates the importance of HESCs in unraveling developmentally regulated mechanisms associated with human genetic disorders.

Screen for Excess FMR1 Premutation Alleles Among Males With Parkinsonism

Individuals with fragile X-associated tremor/ataxia syndrome frequently have associated features of parkinsonism, often leading to an initial diagnosis of Parkinson disease or other parkinsonism spectrum disorders. Parkinson disease populations may thus include individuals who harbor premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. To screen DNA samples (male) from an Italian Parkinson disease clinic for an excess of premutation expansions of the FMR1 gene. DNA samples obtained from 903 unrelated males through consecutive clinic visits were analyzed by an enhanced polymerase chain reaction method for detecting expanded CGG repeats. Diagnostic assessments were performed at the Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy. Genotyping was conducted at the University of California Davis School of Medicine. A cohort of unrelated males with clinical features of parkinsonism. All but 12 males were of Italian origin, and all reported Caucasian ethnicity. CGG repeat number. Three premutation carriers (61, 69, and 80 CGG repeats) were identified (0.33%), which is not significantly higher than the frequency of premutation alleles in the general population. The outcome of the current study, the largest screen of individuals with parkinsonism to date, supports previous screens of smaller parkinsonism cohorts. Broad screening for premutation alleles in Parkinson disease populations is unlikely to be productive in the absence of additional clinical or family history data that suggest involvement of the FMR1 gene.

Amygdala dysfunction in men with the fragile X premutation

Premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene are associated with autism spectrum disorder in childhood, premature ovarian failure, and the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS, and perhaps the other clinical presentations among carriers, are thought to be due to toxic gain-of-function of elevated levels of the expanded-repeat FMR1 mRNA. Previous structural MRI studies have implicated the amygdala as a potential site of dysfunction underlying social deficits and/or risk for FXTAS. As a preliminary investigation of this possible association, adult males with the premutation, and male controls matched for IQ, age and education, completed three protocols that probe amygdala and sympathetic function: (i) a functional MRI paradigm that measures brain response to fearful faces; (ii) a fear-potentiated startle paradigm that differentiates responses to fearful faces and fearful non-social images and (iii) measurement of skin conductance level during a brief social encounter. Compared with controls, men with the FMR1 premutation demonstrated diminished brain activation in the amygdala and several brain areas that mediate social cognition while viewing fearful faces. The reduced amygdala activation in the premutation group was significantly associated with self-report of psychological symptoms on the Symptom Checklist-90--Revised. These men also displayed a lack of startle potentiation while viewing fearful faces and showed reduced skin conductance response when greeting an unfamiliar experimenter in comparison with the control group. The current findings may be related to social cognition deficits reported previously in children and adults with the premutation. The aetiology for this dysfunction may be elevated FMR1 mRNA or reduced FMR1 protein that occurs in carriers with higher premutation CGG repeat alleles.

Dementia With Mood Symptoms in a Fragile X Premutation Carrier With the Fragile X-Associated Tremor/Ataxia Syndrome: Clinical Intervention With Donepezil and Venlafaxine

Dementia With Mood Symptoms in a Fragile X Premutation Carrier With the Fragile X-Associated Tremor/Ataxia Syndrome: Clinical Intervention With Donepezil and Venlafaxine

Parkinsonism, dysautonomia, and intranuclear inclusions in a fragile X carrier: A clinical–pathological study

A new tremor-ataxia syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS), has been described among carriers of premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. The prevalence of FMR1 premutation alleles has been reported to be 1 in 813 among men. Patients with FXTAS may also have features of parkinsonism. Postmortem findings have been described in eight patients with FXTAS and detailed descriptions of the pathological features of this syndrome have been published in two of these. We present a detailed description of the postmortem findings in a third patient. The patient had parkinsonism and was a carrier of a premutation expansion in the FMR1 gene. As in previous reports, the most prominent finding was the presence of eosinophilic nuclear inclusions in neurons and astrocytes, loss of Purkinje cells, and regional vacuolation of the cerebral white matter. As in one previous report, nuclear inclusions were also present in ependymal and choroid plexus cells. A new finding is that of nuclear inclusions in both the adeno- and neurohypophysis. These findings confirm the diffuse nature of this pathology. Further studies of clinical-pathological correlation in a larger sample of brains would provide additional insight into the mechanisms of the tremor, ataxia, and parkinsonism in these patients.

Psychiatric Phenotype of the Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) in Males

The authors describe and quantify the neuropsychiatric symptoms present in a cohort of males with the fragile X mental retardation 1 (FMR1) premutation allele who have developed fragile X-associated tremor/ataxia syndrome (FXTAS). Fourteen male carriers of the FMR1 premutation who had clinical manifestations of the FXTAS syndrome and 14 age- and education-matched controls were assessed with the Neuropsychiatric Inventory (NPI), formal cognitive testing, and genetic analysis. Males with FXTAS had significantly higher total NPI scores (p < .004) and significantly higher scores on the agitation/aggression (p < .004), depression (p < .004), apathy (p < .004), disinhibition (p < .004), and irritability (p < .004) scales, compared with controls. Cognitive performances on the Mini-Mental State Examination did not correlate with severity of symptoms on the NPI. The neuropsychiatric manifestations of FXTAS, based on this preliminary report, appear to cluster as a fronto-subcortical dementia. Clinicians encountering patients with clinical dementia with motor symptoms suggesting FXTAS should consider genetic testing to determine whether the patient's dementia syndrome is secondary to a fragile X premutation carrier status.

Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation

Until recently, individuals with premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene were believed to be psychologically unaffected. However, the recent documentation of abnormal elevation of FMR1 mRNA, discovery of fragile X-associated tremor/ataxia syndrome (FXTAS), and reports of psychiatric disorders in children and adults with the premutation have suggested a pathogenic gene-brain-behavior mechanism. In a large collaborative study, 68 men and 144 women with the FMR1 premutation completed a psychological symptoms checklist and FMR1 genetic testing, including determination of CGG repeat size, percentage of FMR1 protein (FMRP)-positive lymphocytes, and FMR1 mRNA levels. Relative to published norms, men and women with FXTAS symptoms reported higher levels of several types of psychological symptoms. In addition, men and women with the premutation and no overt evidence of FXTAS reported higher levels of obsessive-compulsive symptoms. Elevated FMR1 mRNA, but not CGG repeat size or reduced FMRP (as measured by immunocytochemistry), was significantly associated with increased psychological symptoms, predominantly obsessive-compulsive symptoms and psychoticism, in premutation men with and without FXTAS symptoms. There was no relationship between CGG repeat size, FMR1 mRNA or FMRP and psychological symptoms in premutation women unless the sample was restricted to those with skewed X-activation ratio toward >50% active premutation alleles. The results of this study support the hypothesis that FMR1 function is associated with psychological difficulties in individuals with the premutation, and provide evidence concordant with an RNA toxic gain-of-function model in a neuropsychiatric phenotype.

The fragile X premutation presenting as postprandial hypotension

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder consisting of progressive intention tremor and cerebellar ataxia recently described in men with the premutation (55 to 200 CGG repeats) in the promoter region of the fragile X mental retardation 1 ( FMR1 ) gene1 and with grandchildren with fragile X syndrome (FXS).2 We describe here a patient with postprandial hypotension and intention tremor carrying an FMR1 premutation allele and without a family history for FXS. A 73-year-old man was referred to our clinic for episodes of blurred vision, dizziness, and weakness appearing after meals and associated with low blood pressure (BP) values. These episodes began 1 year before our visit, but the patient also had bilateral hand tremor with onset at age 71 years, mostly pronounced with posture and action. His family history was unremarkable for peculiar neurologic disorders: he had two healthy sons aged 42 and 39 years and two healthy grandchildren. Moreover, he had only two sisters: one died at age 38 years …