The fragile X premutation: into the phenotypic fold

Premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 gene (FMR1) are known to contribute to the fragile X phenotype through genetic instability and transmission of full mutation alleles (>200 repeats). There is now mounting evidence that the premutation alleles themselves contribute to clinical involvement, including premature ovarian failure among female carriers and a new tremor/ataxia syndrome among older male carriers. Recent observations also provide direct evidence of dysregulation of the FMR1 gene in the premutation range, which may explain many of the clinical observations.     

Preliminary evidence of an effect of cerebellar volume on postural sway in FMR1 premutation males

Recent evidence suggests that early changes in postural control may be discernible among females with premutation expansions (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene at risk of developing fragile X‐associated tremor ataxia syndrome (FXTAS). Cerebellar dysfunction is well described in males and females with FXTAS, yet the interrelationships between cerebellar volume, CGG repeat length, FMR1 messenger RNA (mRNA) levels and changes in postural control remain unknown. This study examined postural sway during standing in a cohort of 22 males with the FMR1 premutation (ages 26–80) and 24 matched controls (ages 26–77). The influence of cerebellar volume, CGG repeat length and FMR1 mRNA levels on postural sway was explored using multiple linear regression. The results provide preliminary evidence that increasing CGG repeat length and decreasing cerebellar volume were associated with greater postural sway among premutation males. The relationship between CGG repeat length and postural sway was mediated by a negative association between CGG repeat size and cerebellar volume. While FMR1 mRNA levels were significantly elevated in the premutation group and correlated with CGG repeat length, FMR1 mRNA levels were not significantly associated with postural sway scores. These findings show for the first time that greater postural sway among males with the FMR1 premutation may reflect CGG repeat‐mediated disruption in vulnerable cerebellar circuits implicated in postural control. However, longitudinal studies in larger samples are required to confirm whether the relationships between cerebellar volume, CGG repeat length and postural sway indicate greater risk for neurological decline.     

Frequency of FMR1 premutation in individuals with ataxia and/or tremor and/or parkinsonism

A late onset neurological syndrome in carriers of premutation in FMR1 gene was recently described. The condition was named fragile-X-associated tremor/ataxia syndrome (FXTAS) and includes intentional tremor, cerebellar ataxia, parkinsonism, and cognitive deficit. We ascertained the contribution of FMR1 premutation to the phenotypes ataxia, tremor and/or parkinsonism. Sixty-six men over 45 years old presenting these symptoms, isolated or combined, were tested. Also, 74 normal men, randomly chosen in the population, formed the control group. In the patient group, no premutation carrier was found, which is in agreement with other observed frequencies reported elsewhere (0-5% variation). No significant differences were found when comparing gray zone allele frequencies among target and control groups. The FXTAS contribution in patients with phenotypic manifestations of FXTAS was 15/748 (2%). The presence of gray zone alleles is not correlated with FXTAS occurrence.     

Screening for FXTAS in 95 Spanish patients negative for Huntington disease

Fragile X syndrome is the most common form of hereditary mental retardation. The molecular basis of this syndrome is mainly a CGG expansion in the 5' untranslated region of the FMR1 gene. Expansions with more than 200 CGG repeats abolish gene expression causing the classical fragile X phenotype. Premutation carriers (55-200 CGG) have normal cognitive function with increased risk of developing premature ovarian failure and fragile X-associated tremor-ataxia syndrome (FXTAS). Some clinical features associated with FXTAS, such as tremor, gait ataxia, cognitive decline, and generalized brain atrophy, are also seen in other movement disorders. Ninety-five patients referred for HD, who tested negative for the expansion in the IT15 gene, were screened for FMR1 CGG-repeat expansion. One FMR1 premutation male carrier was detected, giving an FXTAS frequency of 1.6%. Our results highlight that FXTAS is still not well diagnosed; therefore, we recommend FMR1 premutation screenings in all patients with late-onset tremor, ataxia, and cognitive dysfunction.     

RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently described neurodegenerative disorder of older adult carriers of premutation alleles (60-200 CGG repeats) in the fragile X mental retardation gene (FMR1). It has been proposed that FXTAS is an RNA-mediated neurodegenerative disease caused by the titration of RNA-binding proteins by the CGG repeats. To test this hypothesis, we utilize a transgenic Drosophila model of FXTAS that expresses a premutation-length repeat (90 CGG repeats) from the 5' UTR of the human FMR1 gene and displays neuronal degeneration. Here, we show that overexpression of RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppresses the phenotype of the CGG transgenic fly. Furthermore, we show that hnRNP A2/B1 directly interacts with riboCGG repeats and that the CUGBP1 protein interacts with the riboCGG repeats via hnRNP A2/B1.     

Fragile X-premutation tremor/ataxia syndrome (FXTAS) in a young woman: clinical, genetics, MRI and 1H-MR spectroscopy correlates

It is generally thought that fragile X-associated tremor/ataxia syndrome (FXTAS) represents a late-onset neurodegenerative disorder occuring in male carriers of a premutation expansion (55-200 CGG repeats) in the fragile X mental retardation 1 (FMR 1) gene. However, several female patients with FXTAS have also been reported recently. Here, we describe a 23-year old woman with positive family history of mental retardation and autism who presented clinically with action tremor, ataxia, emotional disturbances and cognitive dysfunction. Magnetic resonance imaging (MRI) of the brain showed diffuse cortical atrophy, while 1H-MR spectroscopy (MRS) revealed decreased levels of N-acetylaspartate (NAA) in the cerebellum, basal ganglia, and pons. Genetic testing confirmed heterozygous FMR 1 gene premutation of 100 CGG repeats in the abnormal allele and 29 CGG repeats in the normal allele. We concluded that FXTAS may be an under-recognized disorder, particularly in women.     

Fragile X premutation tremor/ataxia syndrome: molecular,clinical, and neuroimaging correlates

We present a series of 26 patients, all >50 years of age, who are carriers of the fragile X premutation and are affected by a multisystem, progressive neurological disorder. The two main clinical features of this new syndrome are cerebellar ataxia and/or intention tremor, which were chosen as clinical inclusion criteria for this series. Other documented symptoms were short-term memory loss, executive function deficits, cognitive decline, parkinsonism, peripheral neuropathy, lower limb proximal muscle weakness, and autonomic dysfunction. Symmetrical regions of increased T2 signal intensity in the middle cerebellar peduncles and adjacent cerebellar white matter are thought to be highly sensitive for this neurologic condition, and their presence is the radiological inclusion criterion for this series. Molecular findings include elevated mRNA and low-normal or mildly decreased levels of fragile X mental retardation 1 protein. The clinical presentation of these patients, coupled with a specific lesion visible on magnetic resonance imaging and with neuropathological findings, affords a more complete delineation of this fragile X premutation-associated tremor/ataxia syndrome and distinguishes it from other movement disorders.     

Fragiles-X Syndrom

Fragile X syndrome is an X-linked neurodevelopmental disorder affecting both males and females. Phenotypical characteristics include intellectual deficits, somatic symptoms and behavioural abnormalities caused by loss of the FMRP protein, which leads to destruction of synapses with metabotropic glutamate receptors. The FMR1 gene harbours a CGG repeat in the 5’-untranslated region. The vast majority of fragile-X syndrome patients have a largely expanded CGG repeat (220 or more triplets, designated “full mutation”) and an inactive gene. Full mutation alleles originate upon proliferation of oogonia in the fetal ovary of females who carry a mitotically unstable premutation (59–200 repeats). Premutation carriers have no symptoms of fragile X syndrome; they may, however, experience premature ovarian insufficiency and/or fragile X-associated tremor/ataxia syndrome. The diagnosis of both syndromes requires genetic testing to measure the number of CGG repeats. Prenatal diagnostics of fragile X syndrome is offered to females carrying a pre- or full mutation.     

Neuropathological, clinical and molecular pathology in female fragile X premutation carriers with and without FXTAS

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder associated with premutation alleles of the fragile X mental retardation 1 (FMR1) gene. Approximately 40% of older male premutation carriers, and a smaller proportion of females, are affected by FXTAS; due to the lower penetrance the characterization of the disorder in females is much less detailed. Core clinical features of FXTAS include intention tremor, cerebellar gait ataxia and frequently parkinsonism, autonomic dysfunction and cognitive deficits progressing to dementia in up to 50% of males. In this study, we report the clinical, molecular and neuropathological findings of eight female premutation carriers. Significantly, four of these women had dementia; of the four, three had FXTAS plus dementia. Post-mortem examination showed the presence of intranuclear inclusions in all eight cases, which included one asymptomatic premutation carrier who died from cancer. Among the four subjects with dementia, three had sufficient number of cortical amyloid plaques and neurofibrillary tangles to make Alzheimer's disease a highly likely cause of dementia and a fourth case had dementia with cortical Lewy bodies. Dementia appears to be more common than originally reported in females with FXTAS. Although further studies are required, our observation suggests that in a portion of FXTAS cases there is Alzheimer pathology and perhaps a synergistic effect on the progression of the disease may occur.     

Transmission of double <Emphasis Type="Italic">FMR1</Emphasis> allelic premutations in a family

The fragile X mental retardation 1 (FMR1) gene is the only gene known responsible for fragile X related disorders, including fragile X syndrome (FXS), fragile X-associated primary ovarian insufficiency, and fragile X-associated tremor/ataxia. Although FMR1 premutation carriers are common, double mutations of the FMR1 gene is very rare. To our knowledge, only twelve such reports including twenty-three cases from fourteen families have been documented. We report here another family with a FXS family history in which the proband’s maternal grandmother had compound FMR1 gene premutations and we review twelve published papers associated with double allelic mutations. Our study and literature review indicated that compound premutations may have influences regarding the early onset of fragile X-associated primary ovarian insufficiency and severity of psychiatric issues, and less likely aggravate the cognitive deficits compared with one allele mutant patients. Further detailed studies of similar cases are needed to clarify the profile of double FMR1 premutaions.     

Recent research in fragile X-associated tremor/ataxia syndrome

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a cytosine–guanine–guanine repeat expansion neurological disease that occurs in a subset of aging carriers of the premutation (55–200 cytosine–guanine–guanine repeats) in the FMR1 gene located on the X chromosome. The clinical core involves intention tremor and gait ataxia. Current research seeks to clarify the pathophysiology and neuropathology of FXTAS, as well as the development of useful biomarkers to track the progression of FXTAS. Efforts to implement quantitative measures of clinical features, such as kinematics and cognitive measures, are of special interest, in addition to characterize the differences in progression in males compared with females and the efficacy of new treatments.     

The fragile-X premutation: a maturing perspective

Carriers of premutation alleles (55-200 CGG repeats) of the fragile-X mental retardation 1 (FMR1) gene are often regarded as being clinically uninvolved. However, it is now apparent that such individuals can present with one (or more) of three distinct clinical disorders: mild cognitive and/or behavioral deficits on the fragile-X spectrum; premature ovarian failure; and a newly described, neurodegenerative disorder of older adult carriers, fragile-X-associated tremor/ataxia syndrome (FXTAS). Awareness of these clinical presentations is important for proper diagnosis and therapeutic intervention, not only among families with known cases of fragile-X syndrome but also more broadly for adults with tremor, gait ataxia, and parkinsonism who are seen in movement-disorders clinics.     

A female compound heterozygote (pre- and full mutation) for the CGG FMR1 expansion

Fragile X syndrome is the most common cause of inherited mental retardation. The incidence has been estimated to be 1 in 1250 males and 1 in 2000 females. Molecular studies have shown that 95% of fragile X syndrome cases are caused by the expansion of a CGG triplet in the FMR1 gene with hypermethylation of the adjacent CpG island. In spite of the high incidence of this syndrome, a female with both FMR1 genes in the expanded form has never been reported. We present here a female from the Canary Islands presenting mental retardation and attention problems. Molecular analysis has revealed that both of her FMR1 genes have the CGG expansion, one with a premutation and the other with a full mutation. We have studied the CGG repeat in the FMR1 gene in 64 members of her family and detected 33 normal individuals, 14 carriers with the premutation (1 male and 13 females), and 18 individuals with full mutations (8 males and 10 females). The index case illustrates that the possibility of both parents being carriers of the fragile X syndrome premutation should be considered in consanguineous families or in small communities. Received: 4 April 1996 / Revised: 3 May 1996     

FMR1: A gene with three faces

The FMR1 gene is involved in three different syndromes, the fragile X syndrome (FXS), premature ovarian insufficiency (POI) and the fragile X-associated tremor/ataxia syndrome (FXTAS) at older age. Fragile X syndrome is caused by an expansion of a CGG repeat above 200 units in the FMR1 gene resulting in the absence of the FMR1 mRNA and protein. The FMR1 protein is proposed to act as a regulator of mRNA transport and of translation of target mRNAs at the synapse. FXS is seen as a loss of function disorder. POI and FXTAS are found in individuals with an expanded repeat between 50 and 200 CGGs and are associated with increased FMR1 mRNA levels. The presence of elevated FMR1 mRNA in FXTAS suggests that FXTAS may represent a toxic RNA gain-of-function effect. The molecular basis of POI is yet unknown. The role of the FMR1 gene in these disorders is discussed.