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.     

The autism-epilepsy connection

Summary   The high prevalence of epilepsy in children with autism supports a neurobiologic etiology for autism. It remains unclear whether seizures and epileptiform activity on the EEG are causative or comorbid. It is also uncertain if focal epileptiform EEG abnormalities may be associated with stable cognitive impairment. Even less clear is whether these EEG abnormalities can result in the combination of language and social dysfunction seen in autistic spectrum disorders.     

The transient global amnesia-migraine connection

Twelve patients with transient global amnesia (TGA) were studied. Seven (58%) of the 12 had a headache during their attack; five (42%) of the 12 were migraineurs. Measurement of regional cerebral blood flow (rCBF) by the xenon Xe 133 inhalation method showed similar patterns of flow in five of the seven patients tested. The rCBF abnormalities were impaired vasomotor response in the watershed area between the middle cerebral artery and posterior cerebral artery territories, and/or focal ischemia in the inferior part of the temporal lobe. These rCBF abnormalities differed from those seen in patients with carotid transient ischemic attacks (TIAs) and vertebrobasilar TIAs. We speculate that the vasomotor phenomena in migraine may play a major role in the cause of TGA.     

The G protein-channel connection.

Recent interest in the regulation of ion currents by hormones and neurotransmitters has focused on the role of G proteins as modulators. Which G proteins are involved? How is this regulation achieved? Initial results suggest that the pathways and mechanisms of action are complex and that delineation of this area of regulation has just begun.     

The fragile X premutation presenting as essential tremor

CONTEXT: The fragile X premutation has recently been reported to be associated with a neurodegenerative syndrome, chiefly characterized by intention tremor, gait ataxia, and executive cognitive deficits in men older than 50 years. Essential tremor is a frequent cause of tremor in elderly patients and in some cases is associated with impaired tandem gait and cognitive deficits. OBJECTIVE: To describe 2 fragile X carriers whose clinical presentation mimicked essential tremor. DESIGN: The 2 patients described herein underwent neurologic examinations by experienced movement disorders neurologists, magnetic resonance imaging, and fragile X gene, messenger RNA, and protein analyses. One underwent detailed neuropsychological testing. SETTING: Patients were studied at 2 large university movement disorders clinics. PATIENTS: Both patients were white men older than 50 years who had been diagnosed as having essential tremor and then found to be fragile X carriers. RESULTS: Besides disabling intention tremor, the 2 patients had impaired tandem, generalized brain atrophy, and unusual bilateral T2 middle cerebellar hyperintensities on magnetic resonance imaging. The patient who underwent neuropsychological testing had frontal executive deficits. Both patients had elevated fragile X mental retardation gene 1 messenger RNA and reduced fragile X mental retardation 1 protein levels. CONCLUSION: The fragile X carrier state may underlie the clinical findings in some older men diagnosed as having essential tremor.     

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.     

The fragile X marker and autism in perspective

Recent reports link the fragile X chromosome abnormality to autism, with the association ranging from 0 to 53%, but the diagnostic criteria for autism were unclear in some of the studies. The need for fragile X chromosome studies in larger populations of autistic children and adults was recognized. In this study, chromosome analyses were performed on 85 carefully diagnosed autistic males, yielding a 2.4% incidence of the fragile X abnormality. It is concluded that the incidence of the fragile X chromosome abnormality in autistic individuals is likely the same as that in the mentally retarded male population and therefore does not increase the risk for autism above that of mental retardation itself.     

The cyclic AMP phenotype of fragile X and autism

Cyclic AMP (cAMP) is a second messenger involved in many processes including mnemonic processing and anxiety. Memory deficits and anxiety are noted in the phenotype of fragile X (FX), the most common heritable cause of mental retardation and autism. Here we review reported observations of altered cAMP cascade function in FX and autism. Cyclic AMP is a potentially useful biochemical marker to distinguish autism comorbid with FX from autism per se and the cAMP cascade may be a viable therapeutic target for both FX and autism.     

The fragile X continuum: new advances and perspectives

Fragile X syndrome is the world's most common hereditary cause of intellectual disability in men and to a lesser extent in women. The disorder is caused by the silencing of a single gene on the X chromosome, the Fragile X Mental Retardation Gene-1. A substantial body of research across the disciplines of molecular genetics, child psychiatry and developmental neuroscience bears testament to a decade of exciting and innovative science that has advanced our knowledge about the fragile X 'signature' or influence across cognitive and social development. The core aims of this review are to first discuss fragile X syndrome and premutation involvement in the context of current advances that demonstrate the dynamic nature of the genotype on phenotypic outcomes. Second, to discuss the implications of these recent advances for the development of clinical and educational interventions and resource tools that target specific phenotypic 'signatures' within the fragile X continuum.     

The heat shock/oxidative stress connection

Involvement of free-radical oxidations in the aging process has been a topic of interest since Harman's original contribution. Because of the close association between aging and Alzheimer disease (AD) and the qualitative similarity in the neuropathology of both conditions, it has been proposed by many investigators that oxidative stress may be important in AD. If such modality of injury was indeed involved, one should expect to find markers of oxidation and heat shock (since free radicals are key mediators of heat-shock induction) in brains of patients with AD. In fact, several studies documented abnormal expression of antioxidant enzymes and heat-shock proteins (HSP) along with other markers of oxidation in AD brains. We showed that abnormally expressed antioxidant enzymes are topographically associated with senile plaques and neurofibrillary tangles, and that the activity of these enzymes is (contrary to what one would expect) markedly reduced. These findings have recently been confirmed by other investigators. Despite a large amount of evidence that suggests an association between oxidative stress and the pathogenesis of AD, it is not yet known whether oxidative stress is a cause or consequence of the disorder. Future research efforts regarding the oxidative stress hypothesis of AD should include attempts, at generating AD pathology by oxidative means in laboratory animals, determining the role and integrity of the heat-shock response in AD, as well as that of various antioxidant systems, growth factors, and hormones with antioxidant and neuroprotective properties.     

The French connection: folie à quatre

A socially isolated family in which the three children shared their mother's delusional beliefs is reported. After separation, the children rapidly adjusted to normal school and foster family life. Difficulties in establishing the family's true identity and problems raised in reuniting the family, while the mother was felt to be concealing her remaining delusions, are discussed.     

Stress and obesity: The ghrelin connection

Ghrelin is a hormone associated with feeding and energy balance. Not surprisingly, this hormone is secreted in response to acute stressors and it is chronically elevated after exposure to chronic stress in tandem with a number of metabolic changes aimed at attaining homeostatic balance. In the present review, we propose that ghrelin plays a key role in these stress‐induced homeostatic processes. Ghrelin targets the hypothalamus and brain stem nuclei that are part of the sympathetic nervous system to increase appetite and energy expenditure and promote the use of carbohydrates as a source of fuel at the same time as sparing fat. Ghrelin also targets mesolimbic brain regions such as the ventral segmental area and the hippocampus to modulate reward processes, to protect against damage associated with chronic stress, as well as to potentially increase resilience to stress. In all, these data support the notion that ghrelin, similar to corticosterone, is a critical metabolic hormone that is essential for the stress response.     

The neuroimmune connection in human tonsils.

The present light microscopic immunohistochemical study evaluates the distribution of peptidergic nerve fibers in human tonsil and describes their spatial relationship with specific cells of the immune system. Further, using a panneural marker protein gene product (PGP) 9.5, a qualitative evaluation of the density of specific peptidergic innervation of the human tonsil was performed. Nerve fibers staining for tachykinins, calcitonin gene-related peptide, neuropeptide Y, or vasoactive intestinal polypeptide/peptide histidine isoleucine showed characteristic distribution patterns, but constituted only a minor subfraction of the PGP 9.5-stained fiber population. Both peptide- and PGP 9.5-immunopositive fibers predominantly supplied the vasculature; nonvascular areas were less densely innervated. Double staining for surface antigens thought to be associated with subsets of lymphoid cells, i.e., T-cells, B-cells, granulocytes, and macrophages, and for peptides or PGP 9.5 revealed close proximity of characteristic subpopulations of neurochemically defined nerve fibers and the various immune cells. The presence of peptidergic nerve fibers among T-cells was more prevalent than peptidergic nerve fibers adjacent to macrophages. Few positively stained nerve fibers resided in B-cell compartments. Neuro-B-cell interrelations were extremely infrequent. Neuroimmune connections were restricted to paravascular, subepithelial, and interfollicular regions, while germinal centers were devoid of nerve supply. The results are compatible with the view that peptides, being present in small-diameter nerve fibers, could exert an indirect immunoregulatory role by influencing vascular tone and/or permeability. In quantitative terms, a direct neuroimmunomodulatory action of endogenous neurally derived peptides appears to be of minor importance, because nonvascular neuroimmune circuits were found infrequently and were regionally restricted. However, we cannot be sure that all fibers were stained. The functional state of the peptidergic and nonpeptidergic innervation of the human palatine tonsil may be of physiological and pathophysiological significance within the psycho-neuro-immuno-endocrine network. The peptide-coded neuroimmune link may play a role in tonsillar pain.     

Adult fragile X syndrome

Summary Fragile X syndrome [fra (X)] is currently accepted as the second most frequent chromosomal disorder associated with developmental disability. Although next to Down syndrome in frequency, no postmortem studies of confirmed adult cases had been reported.The autopsy examination of a 62-year-old, moderately retarded man with the fra (X) syndrome confirmed the preferential involvement of cerebral and testicular structures in this disorder.Dendritic spine abnormalities of the type observed in trisomic chromosomal disorders were associated with synaptic immaturity. Severe testicular hypogonadism accompanied bilateralmacro-orchidism, normal penis, and unilateral hydrocele. Valvular, articular, and testicular interstitial compartments showed normal histochemical staining characteristics for glycoproteins and lipids.     

The heat shock/oxidative stress connection

Involvement of free-radical oxidations in the aging process has been a topic of interest since Harman's original contribution. Because of the close association between aging and Alzheimer disease (AD) and the qualitative similarity in the neuropathology of both conditions, it has been proposed by many investigators that oxidative stress may be important in AD. If such modality of injury was indeed involved, one should expect to find markers of oxidation and heat shock (since free radicals are key mediators of heat-shock induction) in brains of patients with AD. In fact, several studies documented abnormal expression of antioxidant enzymes and heat-shock proteins (HSP) along with other markers of oxidation in AD brains. We showed that abnormally expressed antioxidant enzymes are topographically associated with senile plaques and neurofibrillary tangles, and that the activity of these enzymes is (contrary to what one would expect) markedly reduced. These findings have recently been confirmed by other investigators. Despite a large amount of evidence that suggests an association between oxidative stress and the pathogenesis of AD, it is not yet known whether oxidative stress is a cause or consequence of the disorder. Future research efforts regarding the oxidative stress hypothesis of AD should include attempts, at generating AD pathology by oxidative means in laboratory animals, determining the role and integrity of the heat-shock response in AD, as well as that of various antioxidant systems, growth factors, and hormones with antioxidant and neuroprotective properties.