Researchers have now discovered a potential mechanism that may contribute to the link between epilepsy and fragile X syndrome.
The protein that is missing in fragile X syndrome, FMRP, controls the production of a protein that regulates electrical signals in brain cells, scientists at Emory University School of Medicine have found. The results were published April 13 in the Journal of Neuroscience.
Individuals with fragile X syndrome tend to have a hyperexcitable nervous system, which can be displayed in several ways: hyperactivity, anxiety, increased sensory sensitivity, and epileptic seizures in 20 percent of all cases. The Emory team's findings suggest that a therapeutic strategy against fragile X syndrome now being tested in clinical trials could also address this aspect of the disease.
"The link between fragile X syndrome and epilepsy was not well understood," says senior author Gary Bassell, PhD, professor of cell biology and neurology at Emory University School of Medicine. "This finding might provide a molecular explanation that could also give some clues on therapeutic strategies."
The co-first authors of the paper are postdoctoral fellow Christina Gross and PhD candidate Xiaodi Yao. They and their colleagues found that in mice missing FMRP - a model for humans with fragile X syndrome - brain cells produce less of a protein called Kv4.2.
FMRP is known to regulate several genes, and it's possible that changes in others besides Kv4.2 contribute to the development of epilepsy. For many of the genes that FMRP controls, it normally acts as a brake, by interfering with the step in which RNA is made into protein. In FMRP's absence, this leads to runaway protein production at synapses the junctions between brain cells where chemical communication occurs. Kv4.2 appears to be an exception, because in FMRP's absence, less Kv4.2 protein is produced.
The protein Kv4.2 is an ion channel, which allows electrical charge to flow out of neurons when they are stimulated. Kv4.2 is the major ion channel regulating the excitability of neurons in the hippocampus, a region of the brain important for learning and memory. A mutation of the gene encoding Kv4.2 leads to temporal lobe epilepsy in humans.
In laboratory tests, drugs that tamp down glutamate signaling could partially restore levels of the Kv4.2 protein in mice missing the fragile X protein. This suggests that drugs that act against glutamate signaling, which are now in clinical trials, could reduce hyperexcitability in humans with fragile X syndrome.
Another strategy could be to identify drugs that target the Kv4.2 protein's function directly, Bassell says.
Not all individuals with fragile X syndrome develop epilepsy. The loss of FMRP doesn't shut Kv4.2 production off completely, and other genetic variations and environmental factors probably contribute to the development of epilepsy in individuals with fragile X syndrome, Bassell says.
The research was supported by the National Institutes of Health and the National Fragile X Foundation.
Reference:
C. Gross*, X. Yao*, D.L. Pong, A. Jeromin and G.J. Bassell. Fragile X Mental Retardation Protein Regulates Protein Expression and mRNA Translation of the Potassium Channel Kv4.2. J. Neurosci,31, pa.
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Three review articles in the May 2011 issue of Pediatrics (published online April 4) examine the scientific evidence behind medical, behavioral and developmental interventions for autism spectrum disorders (ASD). The studies, funded by the Agency for Healthcare Research and Quality, examined research published between 2000 and May 2010 on ASD interventions for children ages 12 and younger. Researchers found strong evidence for a few treatments, but also a critical need for additional studies to pinpoint specific approaches that are most effective for individual children.
In "A Systematic Review of Medical Treatments for Children with Autism Spectrum Disorders ," researchers found strikingly little evidence of benefit for most medications used to treat ASDs. Medications that address challenging behavior had the strongest evidence to support their use. The antipsychotic medications risperidone and aripiprazole each have at least two randomized controlled trials that found improvements in challenging behavior, hyperactivity and repetitive behavior. However, both medications also cause significant side effects, including weight gain and sedation, which limit their use to patients with severe impairment. Insufficient evidence is available to judge the potential benefits and adverse effects of all other medications used to treat autism, including serotonin-reuptake inhibitors and stimulant medications.
In a companion article, "A Systematic Review of Secretin for Children With Autism Spectrum Disorders," researchers examined evidence for treating children with autism with secretin, a gastrointestinal polypeptide used to treat peptic ulcers. Study authors found strong evidence that secretin is not effective for children with ASDs, and that further studies are not warranted.
The study, "A Systematic Review of Early Intensive Intervention for Autism Spectrum Disorders," examined 34 studies of early intensive behavioral and developmental interventions for young children with ASDs. Gains were seen in studies of intensive interventions emphasizing both specific behavioral (e.g., UCLA/Lovaas approach) and developmental principles (e.g., the Early Start Denver Model). Such interventions resulted in improved cognitive performance, language skills and adaptive behavior skills in some young children with ASDs. However, few research studies were rated of good quality and the existing evidence did not provide strong evidence in favor of any single early intervention approach. Study authors conclude these early intensive intervention approaches have significant potential but need further research to determine which interventions are most likely to benefit specific children.
Source:
American Academy of Pediatrics
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Researchers at the Mario Negri Institute for Pharmacological Research in Milan, Italy led by Mattia Maroso and colleagues have found that giving mice repeated doses of a specific enzyme inhibitor significantly reduced both chronic epileptic activity and acute seizures.
Their findings, published online in the Springer journal Neurotherapeutics, open up the possibility of a new target system for anticonvulsant drug intervention, to control epileptic activity that does not respond to certain anticonvulsant treatments.
An enzyme known as ICE/Caspase-1 is involved in epileptic seizures; it induces inflammatory processes by producing IL-1beta, a pro-inflammatory molecule, in brain regions where epileptic activity originates and spreads. Mattia Maroso and colleagues looked at the elective inhibitor for this enzyme, in a mouse model of acute seizures and in mice with chronic epilepsy showing spontaneous recurrent epileptic activity.
The researchers artificially induced chronic epileptic seizures in 21 adult male mice and acute seizures in 46 mice. They then injected them with the enzyme inhibitor (VX-765) and recorded the resulting epileptic activity in brains of the mice.
They found that the enzyme inhibitor had powerful anticonvulsant effects. Repeated systemic administration reduced chronic epileptic activity in mice in a dose-dependent manner, and the effect was reversible after four days of treatment when the drug regime was discontinued. The same dose regimen also reduced acute seizures in the mice.
The authors concluded that their results support a new target system for anticonvulsant drug intervention opening new perspectives for the clinical use of this anti-inflammatory strategy for treating established drug-resistant epileptic conditions.
Citation
Maroso M, Balosso S, Ravizza T, Iori V, Wright CI, French J, et al. Interleukin-1β Biosynthesis Inhibition Reduces Acute Seizures and Drug Resistant Chronic Epileptic Activity in Mice. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2011 Mar ( 
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A newly published report reveals that children with epilepsy are more likely to have psychiatric symptoms, with gender a determining factor in their development. Findings showed that girls had more emotional problems, while boys had more hyperactivity/inattention problems and issues regarding peer relationships. Details of this study in Norwegian children are now available online in Epilepsia, a journal published by Wiley-Blackwell on behalf of the International League Against Epilepsy.
Previous studies have shown that children with epilepsy are at increased risk of developing behavioral problems and psychiatric disorders including anxiety, depression, and attention-deficit/hyperactivity disorder (ADHD). In a 2003 population-based study, psychiatric disorders were reported in 37% of children with epilepsy, while children with diabetes and those in the healthy control group were much lower at 11% and 9%, respectively (Davies et al., 2003). Medical evidence, however, has not clearly established when children or teens with epilepsy may be vulnerable to developing psychiatric issues, or how gender influences psychopathology in epilepsy.
The current study used data collected by the Norwegian Health Services Research Centre in a 2002 health profile questionnaire. For children in the 8-13 years of age group, there were 14,699 (response rate of 78%) parents who completed the questionnaire which included questions on topics such as sociodemographic conditions, physical and mental health, and psychosocial conditions. To assess psychiatric symptoms, researchers used the parent report of the Strengths and Difficulties Questionnaire (SDQ) which included questions covering four problem domains - emotional symptoms, conduct problems, hyperactivity-inattention, and peer problems - and prosocial behavior. The SDQ scores were classified as normal, borderline, or abnormal.
Based upon parent's response to the health questionnaire, 111 children were identified with epilepsy (a frequency of 0.8%), of whom 110 completed the questions included in the SDQ (64 boys and 46 girls). Researchers found that children with epilepsy had a significantly higher frequency of psychiatric symptoms (38%) compared with healthy controls (17%). Boys had a higher risk of psychiatric symptoms than girls in both the epilepsy population and in controls.
Additional risk factors were low socioeconomic status (living in a single family home, family income below poverty limit), having another chronic disease (asthma/diabetes) and epilepsy. However, these independent risk factors contributed with different prominence (odds ratio) to psychiatric problems in boys and girls in the epilepsy population. Having or having had epilepsy was a much stronger risk factor of developing psychiatric problems in girls, whereas boys with epilepsy seemed almost as affected by low socioeconomic status as having epilepsy. The authors say the reason for this remains unclear, however a previous study found a more negative attitude towards having epilepsy in girls than in boys.
Further results showed that 33% of children with epilepsy who were 8-9 years had a borderline/abnormal SDQ score compared with 18% of healthy children of the same age; 41% compared to 16% in the 10-13 year age group. "We chose to divide the groups at the age of ten years as this is the start of preadolescence. The wish 'to be like the others' and to participate in different activities as an equal may be issues of particular importance for children with epilepsy," said Dr. Kristin Alfstad of the National Centre for Epilepsy at Oslo University Hospital in Norway, and lead study author. Analysis also showed an increased risk of psychiatric problems for girls with epilepsy in the 10-13 year age group.
The current study findings confirm the psychiatric co-morbidity of epilepsy reported in prior studies. The authors noted that a lack of a standard age groups and methodology differences makes comparison of these studies difficult. "Multiple risk factors contribute to the high prevalence of psychiatric symptoms, differently in boys and girls, it seems," concluded Dr. Alfstad. "Identifying high risk groups may help clinicians who can implement interventions that prevent more serious psychiatric problems."
Source:
Dawn Peters
Wiley-Blackwell
Citation
Alfstad KÅ, Clench-Aas J, Van Roy B, Mowinckel P, Gjerstad L, Lossius MI. Psychiatric symptoms in Norwegian children with epilepsy aged 8-13 years: Effects of age and gender? Epilepsia. 2011 Mar ( Free Full Text )
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Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. Researchers have now identified a gene, called HLA-A*3101, in Caucasian patients that increases the risk of developing a reaction to the drug from 5% to 26%.
The research undertaken, in collaboration with the Wellcome Trust Sanger Institute, screened more than a million variants in DNA across the human genome to understand why some patients are more prone to the drug's side-effects than others. Research in Taiwan has already shown that carbamazepine-induced Steven Johnson Syndrome–Toxic Epidermal Necropysis is strongly associated with the HLA-B*1502 allele gene in the south east asian population , but Liverpool scientists discovered that this gene could not be used to predict the reaction in Caucasian people.
Dr Ana Alfirevic, from the University's Wolfson Centre for Personalised Medicine, said: "This is a significant finding that highlights the importance and advancement of new genetic technologies. We aim to support the development of medicines based on a patient's unique genetic make-up to allow clinicians to prescribe the most effective and safe treatments."
Citation
McCormack M, Alfirevic A, Bourgeois S, Farrell JJ, Kasperavičiūtė D, Carrington M, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. The New England journal of medicine. 2011 Mar ;364(12):1134-43. [pubmed]
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