A cerebellar tremor/ataxia syndrome among fragile X premutation carriers

Fragile X syndrome is a neurodevelopmental disorder that is not known to have any progressive neurological sequelae in adulthood. However, a neurological condition involving intention tremor, ataxia, and cognitive decline has recently been identified among older male carriers of premutation alleles of the FMR1 gene. This condition is clinically distinct from fragile X syndrome and arises through a different molecular mechanism involving the same gene (FMR1). Characteristic findings on magnetic resonance imaging include cerebral and cerebellar volume loss and altered signal intensities of the middle cerebellar peduncles. A striking feature of this fragile X-associated tremor/ataxia syndrome is the presence of ubiquitin-positive neuronal and astroglial intranuclear inclusions. Unlike the CAG repeat expansion diseases, which lead to altered protein products, there is no known protein abnormality among FMR1 premutation carriers. Thus, inclusion formation may reflect a gain-of-function effect of the FMR1 mRNA or the CGG repeat itself. Finally, since this syndrome may represent one of the more common single-gene causes of tremor, ataxia, and dementia among older males, FMR1 DNA testing should be considered when evaluating adult patients with tremor/ataxia.     

Neurobehavioral effects of the fragile X premutation in adult women: a controlled study.

Although previous studies have suggested that the fragile X premutation (fra [X] pM) does not cause deleterious effects, methodological constraints have prevented more definitive conclusions from being reached. In this report, we describe the neuropsychiatric and cognitive-neuropsychological status of 34 adult women with the fra (X) pM, as compared with a well-matched control group of 41 mothers of fra (X)-negative children with developmental disability. The results indicate that there are no meaningful differences between adult women with the fra (X) pM and control subjects with respect to cognitive abilities or profile, neuropsychological function, psychiatric diagnoses or symptoms, and self-rated personality profile. No measure for either group showed evidence of functioning outside the normal range except for a high lifetime prevalence of major depression in both groups. Additional exploratory analyses within the fra (X) group showed no significant effect of either the size of the fra (X) insert or X chromosome inactivation pattern in leukocytes, on any measure of neurobehavioral function. These findings provide additional information to professionals providing genetic counseling to, and assessment of, fra (X) families.     

The fragile X premutation in carriers and its effect on mutation size in offspring.

The pattern of inheritance in the fragile X (fra(X)) mutation follows a multistage intergenerational process in which the premutation evolves into the full mutation and the characteristic phenotype of the fra(X) syndrome after passing through oogenesis or a postzygotic event. Findings from our multicenter study confirm a strong direct relationship between fra(X) premutation size in the mother and probability of a full mutation in offspring with the mutation. Remarkably, the best-fitting equations are nonlinear asymptotic functions. The close approximation to both the logistic model and Gompertz suggests a process of accumulation of errors in DNA synthesis, as has been proposed previously. We also note that a larger-than-expected number of daughters of transmitting males have premutations that are smaller than their fathers', and that proportion is significantly higher than the proportion of daughters whose premutations are smaller than their mothers'. Intergenerational decreases in premutation size have been reported in other trinucleotide-repeat disorders and also appear to be parent-of-origin specific. Thus, while intergenerational expansion to the full mutation in fra(X) may manifest a postzygotic event, decreases in mutation size may occur during or prior to meiosis.     

Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles

The CGG repeat in the 5' untranslated region of the fragile X mental retardation 1 gene (FMR1) exhibits remarkable instability upon transmission from mothers with premutation alleles. A collaboration of 13 laboratories in eight countries was established to examine four issues concerning FMR1 CGG-repeat instability among females with premutation (approximately 55-200 repeats) and intermediate (approximately 46-60 repeats) alleles. Our central findings were as follows: (1) The smallest premutation alleles that expanded to a full mutation (>200 repeats) in one generation contained 59 repeats; sequence analysis of the 59-repeat alleles from these two females revealed no AGG interruptions within the FMR1 CGG repeat. (2) When we corrected for ascertainment and recalculated the risks of expansion to a full mutation, we found that the risks for premutation alleles with <100 repeats were lower than those previously published. (3) When we examined the possible influence of sex of offspring on transmission of a full mutation-by analysis of 567 prenatal fragile X studies of 448 mothers with premutation and full-mutation alleles-we found no significant differences in the proportion of full-mutation alleles in male or female fetuses. (4) When we examined 136 transmissions of intermediate alleles from 92 mothers with no family history of fragile X, we found that, in contrast to the instability observed in families with fragile X, most (99/136 [72.8%]) transmissions of intermediate alleles were stable. The unstable transmissions (37/136 [27.2%]) in these families included both expansions and contractions in repeat size. The instability increased with the larger intermediate alleles (19% for 49-54 repeats, 30.9% for 55-59, and 80% for 60-65 repeats). These studies should allow improved risk assessments for genetic counseling of women with premutation or intermediate-size alleles.     

The risk of fragile X premutation expansion is lower in carriers detected by general prenatal screening than in carriers from known fragile X families

The Fragile X syndrome is the most common cause of inherited mental retardation. For a female premutation carrier, the risk of having a child with a full mutation is positively correlated with the size of the premutation. The current study was performed to evaluate the risk of premutation expansion in the offspring of average-risk carriers detected by general prenatal screening. Over a 4-year period, 9,660 women underwent DNA screening for FMR1 mutation/premutation at the Tel Aviv Sourasky Medical Center. A premutation was defined as a CGG repeat number >50 in the 5' untranslated region (UTR) of exon 1 in the FMR1 gene. The study included only individuals with no family history of X-linked mental retardation or known FMR1 mutations. A premutation was found in 85 women (1 in 114), 68 of whom consented to have prenatal diagnoses in 74 pregnancies. The abnormal allele was transmitted to the offspring in 44 pregnancies. Of these, no change in allele size was noted in 35 pregnancies (79.6%), and expansion within premutation range was evident in 4 pregnancies (9%). In 5 pregnancies (11.4%), expansion to the full mutation was noted. This occurred only in carriers having more than 90 repeats. We conclude that the likelihood of Fragile X premutation expansion to full mutation is significantly lower in individuals ascertained by general prenatal carrier testing than in those from known Fragile X families.     

Population genetics implications of the premutation hypothesis for the generation of the fragile X mental retardation gene

Summary The population genetics implications of the premutation hypothesis for the generation of the fragile X mental retardation gene are explored. With some broad assumptions, the consequences of the model are that (a) 50% of mothers of probands carry the premutation; (b) 6.5% of mothers of probands receive the premutation from their mothers, 18.9% from their fathers, and 24.6% as a new mutation; (c) the incidence of carriers for the full mutation equals the incidence of affected males, whereas the incidence of carriers for the premutation is 1.35 times the incidence of affected males; (d) assuming mutation rates are equal in eggs and sperm, the mutation rate from normal to premutation alleles is 1.67x10^-4; (e) the expected segregation ratio in sibs of probands is 0.44, which corresponds to observed values. In addition, predictions using the premutation hypothesis of the expected segregation ratio in sibs of mothers of probands fits well with the data of Vogel and coworkers.     

The fragile X syndromes

Fragile X syndrome is a leading cause of mental retardation worldwide, with an incidence of approximately one case in 2000 live births. It is amongst the most common of human genetic diseases, and was the first to be associated with an unstable trinucleotide (CGG) repeat sequence. It is also characterized by a chromosomal fragile site which was the first of (now) four such sites to be identified at the molecular level. Each shows very similar features suggesting that other representatives of this type of fragile site will likely involve similar sequences. As with the other unstable trinucleotide repeats, the sequence at the fragile X locus is found to be remarkably unstable upon genetic transmission, however many features differ from the other repeats. As repeat expansion at the fragile X locus results in loss of expression of the co-resident FMR1 gene, the basis for clinical features is best understood in this disorder. Two additional fragile sites in the vicinity have been identified, and at least one of these is associated with mental retardation.     

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.     

Review: The fragile X syndrome: Isolation of the FMR-1 gene and characterization of the fragile X mutation

Fragile X syndrome, associated with the fragile X chromosome, is the most common cause of familial mental retardation. A breakthrough has been made in molecular biological research into the fragile X site. In this review we describe the molecular investigations that have led to the isolation of the FMR-1 gene. The nature of the fragile X mutation as well as the implications of the DNA test for the mutation are discussed.     

New insights into fragile X syndrome: from molecules to neurobehaviors

Fragile X syndrome - a common form of inherited mental retardation - is caused by the loss of the fragile X mental retardation 1 protein (FMRP). FMRP is an RNA-binding protein which forms a messenger ribonucleoprotein (mRNP) complex that associates with translating polyribosomes. It has been proposed that FMRP is involved in synaptic plasticity through the regulation of mRNA transportation and translation. Recent advances in the identification of the mRNA ligands that are bound by FMRP, the RNA sequence and structure required for FMRP-RNA interaction, and the physiological consequences of FMRP deficiency in the brain are important steps towards understanding the molecular pathogenesis of fragile X syndrome, and learning and memory in general.     

The X chromosome and fragile X mental retardation

Fragile X syndrome represents the most common inherited cause of mental retardation. It is caused by a stretch of CGG repeats within the fragile X gene, which increases in length as it is transmitted from generation to generation. Once the repeat exceeds a threshold length, no protein is produced, resulting in the fragile X phenotype. Both X chromosome inactivation and inactivation of the FMR1 gene are the result of methylation. X inactivation occurs earlier than inactivation of the FMR1 gene. The instability to a full mutation is dependent on the sex of the transmitting parent and occurs only from mother to child. For most X-chromosomal diseases, female carriers do not express the phenotype. A clear exception is fragile X syndrome. It is clear that more than 50% of the neurons have to express the protein to ensure a normal phenotype in females. This means that a normal phenotype in female carriers of a full mutation is accompanied by a distortion of the normal distribution of X inactivation.     

Physical mapping across the fragile X: hypermethylation and clinical expression of the fragile X syndrome

The most common genetic cause of mental retardation after Down's syndrome, the fragile X syndrome, is associated with the occurrence of a fragile site at Xq27.3. This X-linked disease is intriguing because transmission can occur through phenotypically normal males. Theories to explain this unusual phenomenon include genomic rearrangements and methylation changes associated with a local block of reactivation of the X chromosome. Using microdissected markers close to the fragile site, we have been able to test these hypotheses. We present evidence for the association of methylation with the expression of the disease. However, there is no simple relationship between the degree of methylation and either the level of expression of the fragile site or the severity of the clinical phenotype.     

A phenotypic and molecular characterization of the fmr1-tm1Cgr fragile X mouse

Fragile X Syndrome is the most common form of inherited mental retardation. It is also known for having a substantial behavioral morbidity, including autistic features. In humans, Fragile X Syndrome is almost always caused by inactivation of the X-linked FMR1 gene. A single knockout mouse model, fmr1-tm1Cgr, exists. In this report we further characterize the cognitive and behavioral phenotype of the fmr1-tm1Cgr Fragile X mouse through the use of F1 hybrid mice derived from two inbred strains (FVB/NJ and C57BL/6J). Use of F1 hybrids allows focus on the effects of the fmr1-tm1Cgr allele with reduced influence from recessive alleles present in the parental inbred strains. We find that the cognitive phenotype of fmr1-tm1Cgr mice, including measures of working memory and learning set formation that are known to be seriously impacted in humans with Fragile X Syndrome, are essentially normal. Further testing of inbred strains supports this conclusion. Thus, any fmr1-tm1Cgr cognitive deficit is surprisingly mild or absent. There is, however, clear support presented for a robust audiogenic seizure phenotype in all strains tested, as well as increased entries into the center of an open field. Finally, a molecular examination of the fmr1-tm1Cgr mouse shows that, contrary to common belief, it is not a molecular null. Implications of this finding for interpretation of the phenotype are discussed.     

Autoimmune disease in mothers with the FMR1 premutation is associated with seizures in their children with fragile X syndrome

An increased prevalence of autoimmune diseases in family members of children with autism spectrum disorders (ASD) has been previously reported. ASD is also a common problem co-occurring in children with fragile X syndrome (FXS). Why ASD occurs in some individuals with FXS, but not all, is largely unknown. Furthermore, in premutation carrier mothers, there is an increased risk for autoimmune diseases. This study compared the rate of ASD and other neurodevelopmental/behavioral problems in 61 children with FXS born to 41 carrier mothers who had autoimmune disease and in 97 children with FXS of 78 carrier mothers who did not have autoimmune disease. There were no significant differences in the mean age (9.61 ± 5.59 vs. 9.41 ± 6.31, P = 0.836), cognitive and adaptive functioning in children of mothers with and without autoimmune disease. Among children whose mothers had autoimmune disease, the odds ratio (OR) for ASD was 1.27 (95% CI 0.62–2.61, P = 0.5115). Interestingly, the OR for seizures and tics was 3.81 (95% CI 1.13–12.86, P = 0.031) and 2.94 (95% CI 1.19–7.24, P = 0.019), respectively, in children of mothers with autoimmune disease compared to children of mothers without autoimmune disease. In conclusion, autoimmune disease in carrier mothers was not associated with the presence of ASD in their children. However, seizures and tics were significantly increased in children of mothers with autoimmune disease. This suggests a potential new mechanism of seizure and tic exacerbation in FXS related to an intergenerational influence from autoimmunity in the carrier mother.