Psychiatric disability in female carriers of the fragile X chromosome

Fragile X syndrome, an X-linked genetic condition, is an important genetic cause of mental retardation in males. In addition to mental retardation, hemizygous males with fragile X syndrome appear to have a greater likelihood of displaying behaviors classified under the diagnostic category of pervasive developmental disorder than would be expected on the basis of mental retardation alone. Although the majority of female heterozygotes with the fragile X genetic defect are of normal intelligence, our clinical work with this population and a recent case report have suggested that females with fragile X syndrome have an increased rate of schizophrenia spectrum and affective disorders. In this study, the relationship of the fragile X genetic defect to psychopathology in female heterozygotes is investigated by psychiatric evaluation of 35 obligate female carriers of the fragile X chromosome and a comparison group of 24 fragile X-negative controls. Female fragile X carriers were found to have a greater frequency of psychopathology associated with schizophrenia spectrum diagnoses, particularly schizotypal features. A weaker association between the fragile X genetic defect and chronic affective disorders was detected. The specificity of the neuropsychiatric phenotype occurring in particular genetic conditions such as the fragile X syndrome adds a potentially valuable tool to the study of psychopathology in the general population.     

Fragile X syndrome associated with tic disorders

Movement disorders other than late onset tremor‐ataxia in association with fragile X syndrome, the most common identifiable cause of inherited mental retardation, seem to be rare. Here we describe five male patients from three unrelated families with fragile X syndrome that presented with motor and phonic tics. Clinically, 4 patients fulfilled diagnostic criteria for Gilles de la Tourette syndrome (GTS) while 1 patient would have been diagnosed with an adult onset tic disorder. However, in all patients onset of tics was considerably later than in typical GTS. Three patients had atypical tics and two patients reported waxing and waning of tic intensity over time. Four of the 5 patients showed clinical signs typical of fragile X syndrome, in particular dysmorphic features, learning difficulties and speech and language problems that required special treatment. All patients had co‐morbidities common to both GTS and fragile X syndrome. We suggest considering fragile X syndrome in GTS complicated by co‐morbidity with late onset of atypical tics, in particular when learning disability and dysmorphic features are present. © 2008 Movement Disorder Society     

Autism in association with fragile X syndrome in females: implications for diagnosis and treatment in children

Fragile X syndrome is the second most common chromosomal cause of mental retardation (MR). The calculated incidence is 1/1000, making accurate and early diagnosis important for specific preventive, pharmacologic, and cognitive treatment. The timely diagnosis in males is facilitated by the characteristic phenotype and an association with autism. In contrast, in females heterozygous for fragile X, the characteristic phenotype and infantile autism are rarely reported. We present two females with cytogenetic expression of the fragile X chromosome for whom the studies were performed because of the presence of autism or prominent autistic features and a behavioral and physical phenotype consistent with fragile X syndrome. The first female, age three years, has autism, hyperactivity, echolalia, language delay, hand stereotypies, and mild MR. The characteristic phenotype was not present nor was there a family history of X-linked MR. Fragile X expression was 6% in the proband, 3% in the mother and 1% (normal) in the father. The second child, seven years old, has prominent autistic features, hyperactivity, mild MR, mild language disorder, and a family history consistent with X-linked MR. Fragile X expression was 3% in the proband and 0% in the mother. These cases support the occurrence of fragile X in autistic females and emphasize the importance of cytogenetic screening for fragile X in this high risk population. Early diagnosis of fragile X allows precise genetic counseling and more specific cognitive and pharmacologic treatment.     

Clinical and cytogenetic survey of institutionalized mentally retarded patients with emphasis on the fragile-X syndrome

A detailed clinical and cytogenetic survey for the fragile-X syndrome was undertaken on 201 institutionalized mentally retarded males with no previously recognized cause of retardation, and the causes of mental retardation were summarized from a total of 595 institutionalized male and female patients after the review of their medical records including clinical and cytogenetic data. Among the 201 males clinically and cytogenetically examined, five (2.5%) had abnormal chromosome findings with four (2%) having the fragile-X syndrome. Twelve of the males (60%) were diagnosed with a single gene disorder. In the present study, mental retardation was classified as possibly due to multifactorial causes when a genetic syndrome, chromosome abnormality or environmental insult was not identified, but mental retardation was present in one or more first and/or second degree relatives, but did not follow a recognizable inheritance pattern. Hence, mental retardation was recorded in other family members and may indicate possible multifactorial causes in 45 males (22.4%). An environmental insult was noted in 25 males (12.4%); unexplained birth defects in three males (1.5%); a specific condition or diagnosis identified, but cause unknown (e.g. Rubinstein-Taybi syndrome) in 10 males (5%); and no diagnosis made in the remaining 101 males (50.2%). Of all 595 patients (334 males and 261 females), including the 201 males who had undergone a detailed clinical and cytogenetic evaluation, 39 (6.6%) had abnormal chromosome findings, with Down's syndrome noted in 31 of the patients. Twenty-five patients (4.2%) were diagnosed with a single gene disorder while mental retardation was noted in other family members and may indicate possible multifactorial causes in 64 patients (10.8%). An environmental insult was noted in 170 patients (28.6%); unexplained birth defects in 17 patients (2.9%); a specific condition or diagnosis but cause unknown in 27 patients (4.5%); and no diagnosis made in 253 patients (42.5%). Clinical and cytogenetic screening of mentally retarded patients for the fragile-X syndrome and other causes of mental retardation is helpful in identifying individuals and their families who may benefit from genetic services such as counseling and treatment. This study was performed over an approximate 2 year period from 1987 to 1989.     

Atypical neurological symptoms associated with CGG expansions of the FMR1 gene

More than 40 CGG expansions in the 5’ noncoding region of the fragile X mental retardation 1 (FMR1) gene of the X chromosome give rise to several distinct clinical phenotypes, depending on the size of the expansion. First, more than 200 CGG expansions (full mutation) cause an inherited mental retardation called fragile X syndrome. Second, CGG expansions between 55 and 199 (premutation) cause a disorder called fragile X-associated tremor/ataxia syndrome (FXTAS) which typically includes intention tremor, ataxia and specific magnetic resonance imaging (MRI) findings. Indeed, it could develop parkinsonism although it usually shows features of postsynaptic parkinsonism. Finally, CGG expansions between 41 and 54 CGG (gray zone) are not consider normal but rarely develops abnormal neurological conditions. In this sense, the aim of this study is to report two atypical cases associated with CGG expansions of the FMR1 gene. First, a FMR1 premutation alleles carrier with an unusual phenotype, such as a presynaptic parkinsonism indistinguishable from Parkinson disease (PD) and a FMR1 gray zone alleles carrier presented with neurological features, namely hand tremor, parkinsonism and ataxia, usually described in FXTAS, as well as orthostatic tremor. We conclude that, on the one hand, FMR1 premutation alleles might cause two phenotypes of parkinsonism, such as a presynaptic phenotype, indistinguishable from PD, and a postsynaptic phenotype, associated with clinical features of FXTAS. On the other hand, although FMR1 gray zone alleles carriers were believed to have no abnormal neurological conditions, our study supports that they could develop FXTAS and other neurological disorders such as orthostatic tremor which has not been reported before associated with the FMR1 gene.     

FMR1 gray‐zone alleles: Association with Parkinson's disease in women?

Carriers of fragile X mental retardation 1 repeat expansions in the premutation range (55–200 CGG repeats), especially males, often develop tremor, ataxia, and parkinsonism. These neurological signs are believed to be a result of elevated levels of expanded CGG‐repeat fragile X mental retardation 1 mRNA. The purpose of this study was to determine the prevalence of fragile X mental retardation 1 repeat expansions in a movement disorder population comprising subjects with all types of tremor, ataxia, and parkinsonism. We screened 335 consecutive patients with tremor, ataxia, or parkinsonism and 273 controls confirmed to have no movement disorders. There was no difference in fragile X mental retardation 1 premutation size expansions in the cases compared with controls. Eleven percent of the women with Parkinson's disease had fragile X mental retardation 1 gray‐zone expansions compared with 4.4% of female controls (odds ratio of 3.2; 95% confidence interval, 1.2–8.7). Gray‐zone expansions in patients with other phenotypes were not overrepresented in comparison with controls. Fragile X mental retardation 1 premutation range expansions are not more common in a mixed movement disorder population compared with controls. Our results, however, suggest that fragile X mental retardation 1 gray‐zone alleles may be associated with Parkinson's disease in women. © 2011 Movement Disorder Society     

Amyotrophic lateral sclerosis in a patient with fragile X syndrome

Fragile X syndrome is a common cause of mental retardation. We report the clinical and pathologic features of a patient with fragile X syndrome who developed amyotrophic lateral sclerosis (ALS) at a relatively young age. Although the occurrence of these 2 diseases could be a mere coincidence, the development of ALS in this patient might be related to the chromosomal aberration of fragile X syndrome.     

Fragile X syndrome and cerebral perfusion abnormalities: single-photon emission computed tomographic study

Fragile X syndrome is an inherited disorder caused by a defective gene on the X chromosome. It is associated with developmental or behavioral symptoms and various degrees of mental retardation. Morphologic abnormalities and altered perfusion of various brain areas can underlie these functional disturbances. The aim of this study was to investigate the cerebral perfusion state in patients with fragile X syndrome using single-photon emission computed tomography (SPECT). Structural and functional assessment was also performed by magnetic resonance imaging (MRI) and electroencephalography (EEG). Eight boys with cytogenetically confirmed fragile X syndrome (mean age 8.8 +/- 4.4 years, range 5-18 years), were included. All patients had mental retardation, with a mean IQ of 58.9 +/- 8.8 (range 40-68), and additional neurobehavioral symptoms. SPECT revealed cerebral perfusion abnormalities in six patients (75%), most commonly in the frontoparietotemporal area and prominent in the right hemisphere. The SPECT and EEG findings were concordant: hypoperfused areas in SPECT corresponded to regions of persistent slow-wave paroxysms on EEG. On the other hand, cranial MRI was abnormal qualitatively only in two patients (25%) showing cerebellar and vermal hypoplasia and cerebral hemispheric asymmetry. Our results indicate that cerebral perfusion abnormalities, which are correlated with electrophysiologic findings but not necessarily with anatomic abnormalities, can underlie the pathogenesis of the clinical findings observed in fragile X syndrome.     

A study of ring 20 chromosome karyotype with epilepsy

Abstract We reported a 24-year-old woman with moderate mental retardation and partial epilepsy. She developed complex partial seizures at 3 years of age and generalized tonic convulsions at 9 years. Chromosome analysis revealed that she had mosaicism (87%) of 46, XX, and r(20) (p13, q13.3). Her electroencephalogram showed bilateral 2–3 Hz sharp and wave complex over the bilateral frontopolar, and centro-parieto-occipital areas. Computed tomographic and magnetic resonance image examinations were normal. Twenty-five cases of ring 20 chromosome karyotypes (including this case) have been reported in the literature; 19 showed epilepsy, and 18 showed moderate mental retardation. Many of the patients showed growth retardation and minor malformations. The ring 20 syndrome is associated with a high incidence of epilepsy, particularly partial epilepsy. Our findings indicate that the main features of the ring 20 syndrome are partial epilepsy and mental retardation.     

Molecular genetic analysis of mentally retarded males with features of the fragile-X syndrome

The fragile-X [fra(X)] or Martin-Bell syndrome is the most common familial cause of mental retardation and is characterized by the presence of an Xq27.3 chromosome fragile site. Unstable DNA sequences representing large increases in the number of CGG trinucleotide DNA base repeats of the FMR-1 gene are located at the fragile site and responsible for the fra(X) syndrome. In order to identify whether cytogenetically normal yet mentally retarded males without 3 known cause of their retardation had expansion of the CGG repeat segment of the FMR-1 gene, molecular genetic studies using Southern hybridization were Performed with two DNA probes (fxa24l and Ox1.9) following digestion of genomic DNA from each patient with restriction enzymes PstI and EcoRI/EagI, respectively. DNA studies were performed on 20 (12.3%) out of 162 (122 white and 40 black people) cytogenetically normal mentally retarded males without a known cause of their retardation, but with high anthropometric discriminant values and/or clinical checklist scores identified previously and consistent with the fra(X) syndrome. None of the 20 males showed expansion of the CGG repeat of the FMR-1 gene detectable with the two probes used in this study. While heterogeneous single base pair substitutions, or small deletions or insertions in the FMR-1 gene could exist in our patients, aberrations in other X-tinked mental retardation genes, not identified to date but whose gene product can produce a phenotype similar to fra(X), either independently or in conjunction with the recently identified FMR-1 protein, should be considered and are under investigation. Our study supports the idea that major FMR-1 gene expansion detectable with Southern hybridization is rare in cytogenetically normal mentally retarded males, including those with physical and behavioural features seen in the fra(X) syndrome.     

孤独症患者染色体脆性位点的研究

为了解孤独症与脆性位点的相关性，尤其是与Ｘ染色体长臂末端的脆性位点的相关性，应用细胞遗传学方法对５０例孤独症、４０例精神发育迟滞、１７名正常人进行了脆性位点的对照研究。结果：孤独症组脆性位点检出率为３８％，精神发育迟滞组为２０％，正常对照组为１２％，孤独症组明显高于正常组（Ｐ＜０．０５）。孤独症组共检出９种脆性位点，其中１０ｑ２５只见于孤独症组。另外，通过分析样本中的５例高功能孤独症，其中３例仅表现为普通性脆性位点，２例无脆性位点。提示孤独症出现罕见的脆性位点可能与智力低下有关。认为孤独症有较高的脆性位点检出率（３８％），但未能证实孤独症与脆性Ｘ综合征间的关系。     

The fragile X syndrome

Males who possess the fragile X chromosome, a marker on the end of the X chromosome at position Xq27.3, have a distinct form of mental retardation, which has come to be known as the fragile X [fra(X)] syndrome. This X-linked syndrome is the most common Mendelian form of mental retardation. Males who inherit the fra(X) chromosome are usually moderately to severely retarded. There are also normal carrier men who are nonpenetrant for the mutation. They transmit the mutation to their daughters, who can have affected sons. The development of methods for detecting fra(X) in blood and amniotic fluid cells has allowed for population screening and prenatal diagnosis of the syndrome. New methods using DNA probes and restriction fragment length polymorphisms (RFLPs) are being applied to study the inheritance of fra(X). They have revealed apparent genetic linkage heterogeneity. Molecular studies to analyze the underlying mutation are underway to define the structural basis.     

Klinefelter syndrome and associated Fragile-X syndrome

ABSTRACT. During screening of male individuals for Fragile-X syndrome in a residential facility for persons with mental retardation, the authors found a 21-year-old profoundly retarded man who displayed facial features and behaviour suggestive of Fragile-X syndrome. The chromosome analysis revealed 47, fra(X)(q27)fra(X)(q27)Y. His physically and intellectually normal sister had 14% of X chromosomes with a fragile site. Her two sons, who were subsequently examined, were found to have Fragile-X syndrome.
Thus, the identification of Fragile-X syndrome in the proband during the screening process of a large institution led to the investigation of the proband's family and the subsequent diagnosis of Fragile-X syndrome in the proband's two nephews. The ascertainment of the two affected boys permitted prompt introduction of early intervention and special education services. Genetic counselling of other at-risk family members was carried out.     

Fragile X syndrome in Japanese patients with infantile autism

Forty-seven patients (39 boys and 8 girls) with infantile autism whose clinical symptoms had matched the diagnostic criteria of DSM III were studied cytogenetically for the occurrence of fragile X [fra(X)] syndrome. The existence of fra(X) chromosome in these patients was screened first by culturing peripheral blood lymphocytes in a medium in which folic acid was absent; the fra(X) chromosome then was confirmed by reculturing in another medium to which 5-fluoro-2'-deoxyuridine was added for the last 24 hours of culture. Fra(X) chromosome was found in 2 of 39 male patients, but in none of the female patients; the 2 patients are siblings. Thus, fra(X) syndrome occurs in 2.6% (1/38) in this study population of male autistic children. The frequencies of fra(X) expression in the older brother with mild mental retardation, in the more severely retarded younger brother, and in their mother were 3-5%, 17-20%, and 9-3%, respectively. Of the two methods used in the present study, the method employing 5-fluoro-2'-deoxyuridine tended to be more sensitive to fra(X) chromosome detection, especially for a suspected carrier.     

Associated features in females with an FMR1 premutation

Changes in the fragile X mental retardation 1 gene (FMR1) have been associated with specific phenotypes, most specifically those of fragile X syndrome (FXS), fragile X tremor/ataxia syndrome (FXTAS), and fragile X primary ovarian insufficiency (FXPOI). Evidence of increased risk for additional medical, psychiatric, and cognitive features and conditions is now known to exist for individuals with a premutation, although some features have been more thoroughly studied than others. This review highlights the literature on medical, reproductive, cognitive, and psychiatric features, primarily in females, that have been suggested to be associated with changes in the FMR1 gene. Based on this review, each feature is evaluated with regard to the strength of evidence of association with the premutation. Areas of need for additional focused research and possible intervention strategies are suggested.     

Ring 14 chromosome presenting as early-onset isolated partial epilepsy

We report four infants (two males, two females) with ring 14 chromosome presenting with early-onset partial epilepsy. The first seizure occurred between 3 and 6 months (3, 3, 4, and 6mo respectively). In all four cases, diagnosis was based on early focal seizures, rather than on psychomotor retardation or morphological features, which were not prominent at seizure onset. Moreover, despite the young age of the patients and the high frequency of seizures, neither epileptic spasms nor progression to 'epileptic encephalopathy', such as hypsarrhythmia, were observed. Epilepsy remained partial in these patients. At the most recent follow-up, all four children had slight or mild psychomotor delay, and two of them had moderate non-specific dysmorphic traits. Data from the literature about epilepsy in ring 14 chromosome syndrome were also reviewed. Ring 14 chromosome syndrome may be revealed by isolated, early-onset focal epilepsy suggestive of focal lesions with only mild mental retardation and morphological features at the time of diagnosis. The characteristics of these observations differ from classic ring 14 syndrome, and may enlarge this clinical spectrum. Many unanswered questions remain concerning phenotype–genotype correlation and identification of the potential genes and molecular mechanisms responsible for epilepsy in patients with ring 14 syndrome.     

Psychiatric and autistic comorbidity in fragile X syndrome across ages

Fragile X syndrome is caused by CGG trinucleotide repeat expansion within the fragile X mental retardation 1 gene, when repeat number exceeds 200. The typical psychiatric profile of fragile X syndrome patients includes cognitive and behavioral deficits, psychiatric comorbidity, and autistic characteristics. Specific psychiatric features have not yet been clarified, specifically in relationship to age and genetic characteristics. The objective of this study was to characterize psychiatric comorbidities in subjects with fragile X syndrome at different ages. Subjects with fragile X syndrome and their unaffected siblings were recruited and their parents filled out functional-behavioral and psychiatric comorbidities questionnaires. Adolescents with fragile X syndrome showed decreased prevalence of functional-behavioral deficits. Incidence and severity of most psychiatric comorbidities were lower in older subjects. Incidence of generalized anxiety disorder increased with age in the fragile X syndrome group. The typical profile of patients with fragile X syndrome changes with age. Unaffected siblings exhibit anxiety and motor tics.     

Epilepsy in fragile X syndrome

Epilepsy is reported to occur in 10 to 20% of individuals with fragile X syndrome (FXS). A frequent seizure/EEG pattern in FXS appears to resemble that of benign focal epilepsy of childhood (BFEC, benign rolandic epilepsy). To evaluate seizure frequency and type in a Chicago FXS cohort, data regarding potential seizure history were reviewed for 136 individuals with FXS (age range 2 to 51 years: 113 males and 23 females). Seizures occurred in 15 males (13.3%) and one female (4.8%): of these, 12 had partial seizures. EEG findings were available for 35 individuals (13 of 16 with seizures and 22 of 120 without seizures) and showed an epileptiform abnormality in 10 (77%) individuals with seizures and five (23%) individuals without seizures--the most common epileptiform pattern being centrotemporal spikes. Seizures were easily controlled in 14 of the 16 individuals with seizures. Many individuals, including all with centrotemporal spikes, had remission of seizures in childhood. The most common seizure syndrome resembled BFEC and this pattern had the best prognosis for epilepsy remission. Deficiency of FMRP (fragile X mental retardation protein) appears to lead to increased neuronal excitability and susceptibility to epilepsy, but particularly seems to facilitate mechanisms leading to the BFEC pattern.     

The mGluR theory of fragile X mental retardation

Many of the diverse functional consequences of activating group 1 metabotropic glutamate receptors require translation of pre-existing mRNA near synapses. One of these consequences is long-term depression (LTD) of transmission at hippocampal synapses. Loss of fragile X mental retardation protein (FMRP), the defect responsible for fragile X syndrome in humans, increases LTD in mouse hippocampus. This finding is consistent with the growing evidence that FMRP normally functions as a repressor of translation of specific mRNAs. Here we present a theory that can account for diverse neurological and psychiatric aspects of fragile X syndrome, based on the assumption that many of the protein-synthesis-dependent functions of metabotropic receptors are exaggerated in fragile X syndrome. The theory suggests new directions for basic research as well as novel therapeutic approaches for the treatment of humans with fragile X, the most frequent inherited cause of mental retardation and an identified cause of autism.     

Epilepsy and fragile X gene mutations

We used two strategies to investigate a possible link between predisposition for epilepsy and mutations in the fragile X mental retardation-1 gene. The first entailed performing electroencephalography on 14 patients with an amplification in the fragile X mental retardation-1 gene, and the second involved molecular genetic analysis of the fragile X mental retardation-1 gene in 16 children with benign childhood epilepsy with centrotemporal spikes (BECT, Rolandic epilepsy). Fourteen young male patients with fragile X syndrome, verified by a full mutation in exon 1 of the fragile X mental retardation-1 gene, were studied by electroencephalography. In eight boys aged between 4–8 years we observed focal sharp waves, activated by sleep. In six of these patients, partial seizures occurred during sleep. We detected no epileptiform electroencephalographic abnormalities under the age of 4 and over the age of 8. In 16 children with Rolandic epilepsy who were studied for fragile X gene mutations, one boy proved to carry a fragile X premutation. In the waking state electroencephalography of a 5-year-old girl with a premutation in one of her fragile X mental retardation-1 genes, we found groups of generalized spike wave complexes. Our observations suggest a possible impact of the fragile X mental retardation-1 gene mutations on brain maturation and epileptogenesis.