Mutations in the creatine (Cr) transporter (CrT; Slc6a8) gene lead to absence of brain Cr and intellectual disabilities, loss of speech, and behavioral abnormalities. To date, no mouse model of CrT ...deficiency exists in which to understand and develop treatments for this condition. The purpose of this study was to generate a mouse model of human CrT deficiency. We created mice with exons 2-4 of Slc6a8 flanked by loxP sites and crossed these to Cre:CMV mice to create a line of ubiquitous CrT knockout expressing mice. Mice were tested for learning and memory deficits and assayed for Cr and neurotransmitter levels. Male CrT(⁻/y) (affected) mice lack Cr in the brain and muscle with significant reductions of Cr in other tissues including heart and testes. CrT(⁻/y) mice showed increased path length during acquisition and reversal learning in the Morris water maze. During probe trials, CrT(⁻/y) mice showed increased average distance from the platform site. CrT(⁻/y) mice showed reduced novel object recognition and conditioned fear memory compared to CrT(+/y). CrT(⁻/y) mice had increased serotonin and 5-hydroxyindole acetic acid in the hippocampus and prefrontal cortex. Ubiquitous CrT knockout mice have learning and memory deficits resembling human CrT deficiency and this model should be useful in understanding this disorder.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A novel X-linked mental retardation (XLMR) syndrome was recently identified, resulting from creatine deficiency in the brain caused by mutations in the creatine transporter gene,
SLC6A8. We have ...studied the prevalence of
SLC6A8 mutations in a panel of 290 patients with nonsyndromic XLMR archived by the European XLMR Consortium. The full-length open reading frame and splice sites of the
SLC6A8 gene were investigated by DNA sequence analysis. Six pathogenic mutations, of which five were novel, were identified in a total of 288 patients with XLMR, showing a prevalence of at least 2.1% (6/288). The novel pathogenic mutations are a nonsense mutation (p.Y317X) and four missense mutations. Three missense mutations (p.G87R, p.P390L, and p.P554L) were concluded to be pathogenic on the basis of conservation, segregation, chemical properties of the residues involved, as well as the absence of these and any other missense mutation in 276 controls. For the p.C337W mutation, additional material was available to biochemically prove (i.e., by increased urinary creatine:creatinine ratio) pathogenicity. In addition, we found nine novel polymorphisms (IVS1+26G→A, IVS7+37G→A, IVS7+87A→G, IVS7-35G→A, IVS12-3C→T, IVS2+88G→C, IVS9-36G→A, IVS12-82G→C, and p.Y498) that were present in the XLMR panel and/or in the control panel. Two missense variants (p.V629I and p.M560V) that were not highly conserved and were not associated with increased creatine:creatinine ratio, one translational silent variant (p.L472), and 10 intervening sequence variants or untranslated region variants (IVS6+9C→T, IVS7-151_152delGA, IVS7-99C→A, IVS8-35G→A, IVS8+28C→T, IVS10-18C→T, IVS11+21G→A, IVS12+15C→T, *207G→C, IVS12+32C→A) were found only in the XLMR panel but should be considered as unclassified variants or as a polymorphism (p.M560V). Our data indicate that the frequency of
SLC6A8 mutations in the XLMR population is close to that of CGG expansions in
FMR1, the gene responsible for fragile-X syndrome.
The second-largest cause of X-linked mental retardation is a deficiency in creatine transporter (CRT; encoded by SLC6A8), which leads to speech and language disorders with severe cognitive ...impairment. This syndrome, caused by the absence of creatine in the brain, is currently untreatable because CRT is required for creatine entry into brain cells. Here, we developed a brain-specific Slc6a8 knockout mouse (Slc6a8-/y) as an animal model of human CRT deficiency in order to explore potential therapies for this syndrome. The phenotype of the Slc6a8-/y mouse was comparable to that of human patients. We successfully treated the Slc6a8-/y mice with the creatine analog cyclocreatine. Brain cyclocreatine and cyclocreatine phosphate were detected after 9 weeks of cyclocreatine treatment in Slc6a8-/y mice, in contrast to the same mice treated with creatine or placebo. Cyclocreatine-treated Slc6a8-/y mice also exhibited a profound improvement in cognitive abilities, as seen with novel object recognition as well as spatial learning and memory tests. Thus, cyclocreatine appears promising as a potential therapy for CRT deficiency.
We report the first X-linked creatine-deficiency syndrome caused by a defective creatine transporter. The male index patient presented with developmental delay and hypotonia. Proton ...magnetic-resonance spectroscopy of his brain revealed absence of the creatine signal. However, creatine in urine and plasma was increased, and guanidinoacetate levels were normal. In three female relatives of the index patient, mild biochemical abnormalities and learning disabilities were present, to various extents. Fibroblasts from the index patient contained a hemizygous nonsense mutation in the gene
SLC6A8 and were defective in creatine uptake. The three female relatives were heterozygous for this mutation in
SLC6A8, which has been mapped to Xq28.
Abstract Individuals with epilepsy have difficulties with social function that are not adequately accounted for by seizure severity or frequency. This study examined the relationship between language ...ability and social functioning in 193 children with epilepsy over a period of 36 months following their first recognized seizure. The findings show that children with persistent seizures have poorer language function, even at the onset of their seizures, than do their healthy siblings, children with no recurrent seizures, and children with recurrent but not persistent seizures. They continue to demonstrate poorer language function 36 months later. This poor language function is associated with declining social competence. Intervention aimed at improving social competence should include consideration of potential language deficits that accompany epilepsy and social difficulty.
Summary Purpose Magnetoencephalography (MEG) has been shown a useful diagnostic tool for presurgical evaluation of pediatric medically intractable partial epilepsy as MEG source localization has been ...shown to improve the likelihood of seizure onset zone (SOZ) sampling during subsequent evaluation with intracranial EEG (ICEEG). We investigated whether ictal MEG onset source localization further improves results of interictal MEG in defining the SOZ. Methods We identified 20 pediatric patients with one habitual seizure during MEG recordings between October 2007 and April 2011. MEG was recorded with sampling rates of 600 Hz and 4000 Hz for 10 and 2 min respectively. Continuous head localization (CHL) was applied. Source localization analyses were applied using multiple algorithms, both at the beginning of ictal onset and for interictal MEG discharges. Ictal MEG onsets were identified by visual inspection and power spectrum using short-time Fourier transform (STFT). Source localizations were compared with ICEEG, surgical procedure and outcome. Key findings Eight patients met all inclusion criteria. Five of the 8 patients (63%) had concordant ictal MEG onset source localization and interictal MEG discharge source localizations in the same lobe, but the source of ictal MEG onset was closer to the SOZ defined by ICEEG. Significance Although the capture of seizures during MEG recording is challenging, the source localization for ictal MEG onset proved to be a useful tool for presurgical evaluation in our pediatric population with medically intractable epilepsy.
•The study identified more than 2 million new TBI patients over a seven-year period.•Early seizures, more severe TBI and age were associated with a higher risk of PTE.•AED’s did not prevent PTE with ...the exception of acetazolamide.•Cumulative incidences of PTE continued to increase throughout the duration of follow up for all age groups.
About 2.8 million TBI-related emergency department visits, hospitalizations and deaths occurred in 2013 in the United States. Post-traumatic epilepsy (PTE) can be a disabling, life-long outcome of TBI.
The purpose of this study is to address the probability of developing PTE within 9 years after TBI, the risk factors associated with PTE, the prevalence of anti-epileptic drug (AEDs) use, and the effectiveness of using AEDs prophylactically after TBI to prevent the development of PTE.
Using MarketScan® databases covering commercial, Medicare Supplemental, and multi-state Medicaid enrollees from 2004 to 2014, we examined the incidence of early seizures (within seven days after TBI) and cumulative incidence of PTE, the hazard ratios (HR) of PTE by age, gender, TBI severity, early seizure and AED use (carbamazepine, clonazepam, divalproex sodium, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, pregabalin, topiramate, acetazolamide). We used backward selection to build the final Cox proportional hazard model and conducted multivariable survival analysis to obtain estimates of crude and adjusted HR (cHRs, aHRs) of PTE and 95% confidence intervals (CI).
The incidence of early seizure among TBI patients in our study was 0.5%. The cumulative incidence of PTE increased from 1.0% in one year to 4.0% in nine years. Most patients with TBI (93%) were not prescribed any AED. Gender was not associated with PTE. The risk of PTE was higher for individuals with older age, early seizures, and more severe TBI. Only individuals using prophylactic acetazolamide had significantly lower risk of PTE (aHR = 0.6, CI 0.4-0.9) compared to those not using any AED.
The probability of developing PTE increased within the study period. The risk of developing PTE significantly increased with age, early seizure and TBI severity. Most of the individuals did not receive AED after TBI. There was no evidence suggesting AEDs helped to prevent PTE with the possible exception of acetazolamide. However, further studies may be needed to test the efficacy of acetazolamide in preventing PTE.
We report the design and implementation of the first phase 3 trial of CoenzymeQ
10
(CoQ
10
) in children with genetic mitochondrial diseases. A novel, rigorous set of eligibility criteria was ...established. The trial, which remains open to recruitment, continues to address multiple challenges to the recruitment of patients, including widely condoned empiric use of CoQ
10
by individuals with proven or suspected mitochondrial disease and skepticism among professional and lay mitochondrial disease communities about participating in placebo-controlled trials. These attitudes represent significant barriers to the ethical and scientific evaluation–and ultimate approval–of nutritional and pharmacological therapies for patients with life-threatening inborn errors of energy metabolism.
Summary
Purpose: To test over time the relationships of neuropsychological functioning to mental health in children following a first recognized seizure and, of primary importance, to determine if ...the strength of these relationships differs based on risk and protective factors.
Methods: In a larger prospective study, 135 children with a first seizure (ages 8–14 years) and 73 healthy sibling controls completed neuropsychological testing at baseline and 36 months. Structured telephone interviews were used to obtain data from children on mental health and family environment; major caregiving parents provided data on demographic and family variables. Data analyses included correlation coefficients and linear regression models.
Results: Children with seizures showed an overall trend for improvement in mental health. More children with seizures than siblings had declines in processing speed. Declines in neuropsychological functioning were correlated with worse mental health. With regard to risk and protective factors, higher parent education protected against decline in self‐esteem related to decline in processing speed. Better family functioning and greater parental support protected against decline in self‐esteem related to decrease in verbal memory and learning. Older child age protected against increase in depressive symptoms related to decline in processing speed.
Discussion: Seizure onset had a negative impact on mental health in children with declines in cognitive functioning except for older children and those with more family resources. Children should be assessed for declines in processing speed and, if found, those subgroups of children with less educated or more anxious parents and those in less supportive families should be targeted for interventions.