Search

Progressive Myoclonus Epilepsy (PME) is a rare epilepsy syndrome characterized by the development of progressively worsening myoclonus, ataxia, and seizures. A molecular diagnosis can now be established in approximately 80% of individuals with PME. Almost fifty genetic causes of PME have now been established, although some remain extremely rare. Herein, we provide a review of clinical phenotypes and genotypes of the more commonly encountered PMEs. Using an illustrative case example, we describe appropriate clinical investigation and therapeutic strategies to guide the management of this often relentlessly progressive and devastating epilepsy syndrome. This manuscript in the Genetic Literacy series maps to Learning Objective 1.2 of the ILAE Curriculum for Epileptology (Epileptic Disord. 2019;21:129).

The self‐limited (familial) epilepsies with onset in neonates or infants, formerly called benign familial neonatal and/or infantile epilepsies, are autosomal dominant disorders characterized by neonatal‐ or infantile‐onset focal motor seizures and the absence of neurodevelopmental complications. Seizures tend to remit during infancy or early childhood and are therefore called “self‐limited”. A positive family history for epilepsy usually suggests the genetic etiology, but incomplete penetrance and de novo inheritance occur. Here, we review the phenotypic spectrum and the genetic architecture of self‐limited (familial) epilepsies with onset in neonates or infants. Using an illustrative case study, we describe important clues in recognition of these syndromes, diagnostic steps including genetic testing, management, and genetic counseling.

A 24‐year‐old man with non‐lesional bitemporal lobe epilepsy since age 16 years was found dead in bed around midday. He was last seen the previous night when he was witnessed to have a tonic–clonic seizure. Before his death, he was experiencing weekly focal impaired awareness seizures and up to two focal‐to‐bilateral tonic–clonic seizures each year. He had trialed several antiseizure medications and was on levetiracetam 1500 mg/day, lamotrigine 400 mg/day, and clobazam 10 mg/day at the time of death. Other than epilepsy, his medical history was unremarkable. Of note, he had an older brother with a history of febrile seizures and a paternal first cousin with epilepsy. No cause of death was identified following a comprehensive postmortem investigation. The coroner classified the death as “sudden unexpected death in epilepsy” (SUDEP), and it would qualify as “definite SUDEP” using the current definitions.1This left the family with many questions unanswered; in particular, they wish to know what caused the death and whether it could happen to other family members. Could postmortem genetic testing identify a cause of death, provide closure to the family, and facilitate cascade genetic testing of first‐degree family members who may be at risk of sudden death? While grieving family members struggle with uncertainty about the cause of death, we as clinicians also face similar uncertainties about genetic contributions to SUDEP, especially when the literature is sparse, and the utility of genetic testing is still being worked out. We aim to shed some light on this topic, highlighting areas where data is emerging but also areas where uncertainty remains, keeping our case in mind as we examine this clinically important area.

IMPORTANCE: Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown. OBJECTIVE: To test the association between pathogenic somatic variants in the hippocampus and MTLE. DESIGN, SETTING, AND PARTICIPANTS: This case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy–associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022. EXPOSURES: Drug-resistant MTLE. MAIN OUTCOMES AND MEASURES: Presence and abundance of pathogenic somatic variants in the hippocampus vs the unaffected temporal neocortex. RESULTS: Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years; of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippocampus relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9]; P = .01) were detected in patients with MTLE but not in controls. Ten of these variants were in PTPN11, SOS1, KRAS, BRAF, and NF1, all predicted to constitutively activate Ras/Raf/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism. CONCLUSIONS AND RELEVANCE: Hippocampal somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery.

•Inaccurate TLP-reporting in 1997 CBCTs from LA-NSCLC patients.•TLPs support RTT-led IGRT but may fail in interdisciplinary communication.•Contributing factors include the absence of IGRT classification in OBI software and lack of bidirectional communication flow.

KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20.

Radiation-induced attenuation (RIA) of silica-based optical fibers is a well-known and documented phenomenon. Radiation-hardened fibers, mainly having pure silica core (PSC), combat this effect successfully. Even better results have been reported for fibers with Fluorine-doped cores, especially for the transmission of visible wavelengths. Here, we show the results of an experiment at telecom wavelengths (1310 and 1550 nm) in a nuclear reactor core, demonstrating that for dose levels up to tens of MGy (SiO2) the F-doped fiber indeed shows less RIA than PSC fibers. However, at higher levels, the F-doped fiber loses its advantage, and the PSC fiber shows lower RIA than the F-doped for these doses and wavelengths.

Hypothalamic hamartomas (HH) are rare, basilar developmental lesions with widespread comorbidities often associated with refractory epilepsy and encephalopathy. Imaging advances allow for early, even prenatal, detection. Genetic studies suggest mutations in GLI3and other patterning genes are involved in HH pathogenesis. About 50%–80% of children with HH have severe rage and aggression and a majority of patients exhibit externalizing disorders. Behavioral disruption and intellectual disability may predate epilepsy. Neuropsychological, sleep, and endocrine disorders are typical. The purpose of this article is to provide a summary of the current understanding of HH and to highlight opportunities for future research.

Epilepsy genetics is a rapidly developing field, in which novel disease‐associated genes, novel mechanisms associated with epilepsy, and precision medicine approaches are continuously being identified. In the past decade, advances in genomic knowledge and analysis platforms have begun to make clinical genetic testing accessible for, in principle, people of all ages with epilepsy. For this reason, the Genetics Commission of the International League Against Epilepsy (ILAE) presents this update on clinical genetic testing practice, including current techniques, indications, yield of genetic testing, recommendations for pre‐ and post‐test counseling, and follow‐up after genetic testing is completed. We acknowledge that the resources vary across different settings but highlight that genetic diagnostic testing for epilepsy should be prioritized when the likelihood of an informative finding is high. Results of genetic testing, in particular the identification of causative genetic variants, are likely to improve individual care. We emphasize the importance of genetic testing for individuals with epilepsy as we enter the era of precision therapy.

There are a number of familial focal epilepsy syndromes, each with distinct clinical characteristics. Here, we review the epilepsy phenotypes and the genetic architecture of these syndromes. Using an illustrative clinical case, we describe the important steps in making a diagnosis and ordering appropriate genetic tests. Our discussion on the genetics of the familial focal epilepsies will provide a framework for interpreting the results of genetic testing, and allow us to apply this information to patient management.

Pallister-Hall syndrome, typically caused by germline or de novovariants within the GLI3gene, has key features of hypothalamic hamartoma and polydactyly. Recently, a few similar cases have been described with bi-allelic SMOvariants. We describe two siblings born to non-consanguineous unaffected parents presenting with hypothalamic hamartoma, post-axial polydactyly, microcephaly amongst other developmental anomalies. Previous clinical diagnostic exome analysis had excluded a pathogenic variant in GLI3. We performed exome sequencing re-analysis and identified bi-allelic SMOvariants including a missense and synonymous variant in both affected siblings. We functionally characterised this synonymous variant showing it induces exon 8 skipping within the SMOtranscript. Our results confirm bi-allelic SMOvariants as an uncommon cause of Pallister-Hall syndrome and describe a novel exon-skipping mechanism, expanding the molecular architecture of this new clinico-molecular disorder.

Medpor porous polyethylene implants are commonly used for facial skeletal reconstruction due to reported biocompatibility, fibrovascularization, and durability. While uncommon, late implant infections are an important consideration. We report delayed infections in 2 patients after unilateral total oncologic maxillectomy and reconstruction using Medpor implants for an ossifying fibroma and squamous cell carcinoma, respectively. In the first patient, annual interval computed tomography (CT) scans showed no recurrence of tumor or inflammatory changes. The second was lost to follow-up after adjuvant chemoradiation 1 year after resection. Patients both presented with swelling, drainage, and erythema around the implant at a mean of 4.5 years following maxillectomy. Both failed several attempts at conservative treatment. Cultures of implants removed at a mean of 2.5 months after infection grew α-hemolytic Streptococcusin the first and multiple organisms in the second, showing that the potential for delayed infection should be considered years after reconstruction.

•Encompass with Moldcare cushion validated as a safe alternative for Dual Shell Encompass system.•No significant difference in intrafractional motion.•No significant difference in patient-comfort.

The financial experience faced by working‐age people with arthritis includes living below the poverty line for many. Financial distress among people with arthritis is known to contribute to poorer health outcomes, including high psychological distress and more severe pain. Despite the demonstrated societal cost of arthritis care and management, the personal costs borne by the individual are not well understood. The aim of this study was to explore the perceived financial impacts of living with arthritis among younger adults (defined as those ages 18–50 years). A qualitative descriptive study design was used. Participants with inflammatory arthritis or osteoarthritis were recruited from the community, including urban and rural settings. An interview schedule was developed, informed by existing literature, which was piloted prior to data collection. Deductive and inductive coding techniques were used to identify financial‐related themes arising from the data. Semistructured interviews were conducted with 21 adults (90% female) with a mix of arthritis conditions, including rheumatoid arthritis, psoriatic arthritis, and osteoarthritis. Four themes were identified: direct arthritis‐attributable medical costs, indirect arthritis‐attributable costs, insurance and pension costs, and broader financial impacts on the family. Nonsubsidized costs were frequently referenced by participants as burdensome and existed even within the publicly funded Australian health care system. Adults with arthritis experience significant arthritis‐attributable financial burden and related distress. Financial concerns should be actively identified and considered within shared clinical decision‐making to provide more patient‐centered care for these individuals.

ObjectiveThe aim of this review was to systematically identify, appraise and synthesise evidence on work-related outcomes experienced by younger to middle-aged adults (aged 16–50 years) with arthritis.MethodsEligible studies were identified in Medline, PsycINFO, Embase and CINAHL in January 2020. Quantitative and qualitative studies containing self-reported data on work-related outcomes on younger/middle-aged adults with arthritis were included. Quality assessment was undertaken using validated quality appraisal tools from the Joanna Briggs Institute.ResultsThirty-four studies were identified for inclusion. Work outcomes were organised around five themes: (1) arthritis-related work productivity outcomes, (2) arthritis-related work participation outcomes, (3) other arthritis-related workplace outcomes, (4) barriers to work participation associated with arthritis and (5) enablers to work participation associated with arthritis. Arthritis was associated with work limitations on the Workplace Activity Limitations Scale (average scores ranging from 5.9 (indicating moderate workplace difficulty) to 9.8 (considerable workplace difficulty)), and higher work disability prevalence rates (range: 6%–80%) relative to healthy populations. Arthritis was not associated with decreased absenteeism on the Work Productivity and Activity Impairment Questionnaire (mean (SD) 7.9% (14.0%)), indicating low levels of absenteeism, similar to healthy populations. As work outcomes were commonly binary, person-centred (qualitative) perspectives on barriers and enablers augmented the quantitative findings.ConclusionArthritis is commonly associated with poorer work outcomes for younger/middle-aged adults relative to healthy populations. Additional research focusing solely on the workplace needs of younger/middle-aged population groups is required to inform tailored interventions and workplace support initiatives to maximise productive working years.

Familial adult myoclonic epilepsy 1 (FAME1), first recognised in Japanese families, was recently shown to be caused by a TTTCA repeat insertion in intron 4 of SAMD12on chromosome 8. We performed whole genome sequencing on two families with FAME, one of Sri Lankan origin and the other of Indian origin, and identified a TTTCA repeat insertion in SAMD12in both families. Haplotype analysis revealed that both families shared the same core ancestral haplotype reported in Japanese and Chinese families with FAME1. Mutation dating, based on the length of shared haplotypes, estimated the age of the ancestral haplotype to be ~670 generations, or 17,000 years old. Our data extend the geographic range of this repeat expansion to Southern Asia and potentially implicate an even broader regional distribution given the age of the variant. This finding suggests patients of Asian ancestry with suspected FAME should be screened for the SAMD12TTTCA expansion.

To explore perspectives of adult critical illness survivors and identify important aspects to care and recovery.

A commercial chromatic confocal displacement sensor, designed for probing a target at normal incidence, is adapted to probe reflective targets at an oblique incidence angle. The sensor is modified by positioning two low-cost optical elements—a collimating lens and a retro-reflector—in the reflection plane.

•One-third of the cases would have a different decision for ART when utilizing Type-C instead of Type-B.•Type-C is more sensitive to altered anatomy during treatment compared to Type-B.•No substantial increase in the total number of plan-adaptations for LA-NSCLC.•Recalculating Type-B plans with the Type-C algorithm revealed an increase from 13 to 21 cases triggering ART.

There is increasing use of extracorporeal membrane oxygenation (ECMO) in intensive care, where nurses provide the majority of the required ongoing care of cannulas, circuit, and console. Limited evidence currently exists that details nursing perspectives, experiences, and challenges with workload in the provision of ECMO care.

The article discusses that two doctors, John Gill and the John Herron from the notorious Chelmsford Private Hospital, claimed to be defamed in a book, "Fair Game: The Incredible Untold Story of Scientology in Australia."

A new implementation of heterodyning to measure spectral shifts of fiber Bragg gratings is described. A pair of closely matched phase-shifted gratings is used, and the separation of their transmission peaks is measured as a heterodyne beat frequency when illuminated with spectrally filtered incoherent light. This method can potentially offer high (<1  pm) resolution, fast (μs) measurement, and strain-temperature discrimination.

ObjectivePsychosis of epilepsy (POE) occurs more frequently in temporal lobe epilepsy, raising the question as to whether abnormalities of the hippocampus are aetiologically important. Despite decades of investigation, it is unclear whether hippocampal volume is reduced in POE, perhaps due to small sample sizes and methodological limitations of past research.MethodsIn this study, we examined the volume of the total hippocampus, and the hippocampal head, body and tail, in a large cohort of patients with POE and patients with epilepsy without psychosis (EC). One hundred adults participated: 50 with POE and 50 EC. Total and subregional hippocampal volumes were manually traced and compared between (1) POE and EC; (2) POE with temporal lobe epilepsy, extratemporal lobe epilepsy and generalised epilepsy; and (3) patients with POE with postictal psychosis (PIP) and interictal psychosis (IP).ResultsCompared with EC the POE group had smaller total left hippocampus volume (13.5% decrease, p<0.001), and smaller left hippocampal body (13.3% decrease, p=0.002), and left (41.5% decrease, p<0.001) and right (36.4% decrease, p<0.001) hippocampal tail volumes. Hippocampal head volumes did not differ between groups.ConclusionPosterior hippocampal volumes are bilaterally reduced in POE. Volume loss was observed on a posteroanterior gradient, with severe decreases in the tail and moderate volume decreases in the body, with no difference in the hippocampal head. Posterior hippocampal atrophy is evident to a similar degree in PIP and IP. Our findings converge with those reported for the paradigmatic psychotic disorder, schizophrenia, and suggest that posterior hippocampal atrophy may serve as a biomarker of the risk for psychosis, including in patients with epilepsy.

We present results for the mechanical characterization of a bisphenol-A acrylate-based polymer optical fiber (POF) manufactured using a novel light polymerization spinning (LPS) process. The particular manufacturing process allows the development of POFs having unique mechanical characteristics, which result from an exceptionally low Young’s modulus. The lower Young’s modulus enables optical sensors for measuring stress or pressure with improved sensitivity and potentially a higher tunable mechanical range than conventional POFs. Moreover, properties such as the storage modulus variations with respect to the temperature and humidity were studied. Fiber Bragg gratings (FBGs), were inscribed in the POF using the plane-by-plane femtosecond laser, direct-write method for selective FBG mode excitation, and were characterized for changes to temperature, pressure, and relative humidity. The response of FBGs in this LPS-POF for all the three aforementioned measurands was several times higher than that measured for conventional POFs.

Genetic epilepsy with febrile seizures plus(GEFS+) is a familial epilepsy syndrome in which affected individuals within a family typically have a variety of epilepsy phenotypes, varying from simple febrile seizures and febrile seizures pluswith a good outcome to severe epileptic encephalopathies. Here, we review the spectrum of epilepsy phenotypes, the genetic architecture of GEFS+, and the implicated genes. Using an illustrative clinical case study, we describe important steps in managing patients with GEFS+: making the diagnosis of GEFS+, appropriate genetic testing, and counselling.

Epilepsy is a common and serious neurologic disease with a strong genetic component. Genetic studies have identified an increasing collection of disease-causing genes. The impact of these genetic discoveries is wide reaching—from precise diagnosis and classification of syndromes to the discovery and validation of new drug targets and the development of disease-targeted therapeutic strategies. About 25% of genes identified in epilepsy encode ion channels. Much of our understanding of disease mechanisms comes from work focused on this class of protein. In this study, we review the genetic, molecular, and physiologic evidence supporting the pathogenic role of a number of different voltage- and ligand-activated ion channels in genetic epilepsy. We also review proposed disease mechanisms for each ion channel and highlight targeted therapeutic strategies.

Aims. Somatic mutation of the lissencephaly‐1 gene is a cause of subcortical band heterotopia (“double cortex”). The severity of the phenotype depends on the level of mutation in brain tissue. Detecting and quantifying low‐level somatic mosaic mutations is challenging. Here, we utilized droplet digital PCR, a sensitive method to detect low‐level mutation. Methods. Droplet digital PCR was used in concert with classic genotyping techniques (SNaPshot assays and pyrosequencing) to detect and characterize the tissue mosaicism of a somatic mutation (LIS1c.190A>T; p.K64X) in a patient with posterior bilateral SBH and refractory epilepsy. Results. The high sensitivity of droplet digital PCR and the ability to target individual DNA molecules allowed us to detect the mutation at low level in the brain, despite the low quality of the DNA sample derived from formalin‐fixed paraffin‐embedded tissue. This low mutation frequency in the brain was consistent with the relatively subtle malformation resolved by magnetic resonance imaging. The presence of the mutation in other tissues from the patient permitted us to predict the timing of mutagenesis. Conclusion. This sensitive methodology will have utility for a variety of other brain malformation syndromes associated with epilepsy for which historical pathological specimens are available and specific somatic mosaic mutations are predicted.

Purpose:Sudden death in the young is a devastating complication of inherited heart disorders. Finding the precise cause of death is important, but it is often unresolved after postmortem investigation. The addition of postmortem genetic testing, i.e., the molecular autopsy, can identify additional causes of death. We evaluated DNA extracted from formalin-fixed paraffin-embedded postmortem tissue for exome sequencing–based molecular autopsy after sudden death in the young.Methods:We collected clinical and postmortem information from patients with sudden death. Exome sequencing was performed on DNA extracted from fixed postmortem tissue. Variants relevant to the cause of death were sought.Results:Five patients with genetically unresolved sudden death were recruited. DNA extracted from fixed postmortem tissue was degraded. Exome sequencing achieved 20-fold coverage of at least 82% of coding regions. A threefold excess of singleton variants was found in the exome sequencing data of one patient. We found a de novo SCN1A frameshift variant in a patient with sudden unexpected death in epilepsy and a LMNA nonsense variant in a patient with dilated cardiomyopathy.Conclusion:DNA extracted from fixed postmortem tissue is applicable to exome sequencing–based molecular autopsy. Fixed postmortem tissues are an untapped resource for exome-based studies of rare causes of sudden death.Genet Med advance online publication 23 March 2017

Gene panel and exome sequencing have revealed a high rate of molecular diagnoses among diseases where the genetic architecture has proven suitable for sequencing approaches, with a large number of distinct and highly penetrant causal variants identified among a growing list of disease genes. The challenge is, given the DNA sequence of a new patient, to distinguish disease-causing from benign variants. Large samples of human standing variation data highlight regional variation in the tolerance to missense variation within the protein-coding sequence of genes. This information is not well captured by existing bioinformatic tools, but is effective in improving variant interpretation. To address this limitation in existing tools, we introduce the missense tolerance ratio (MTR), which summarizes available human standing variation data within genes to encapsulate population level genetic variation. We find that patient-ascertained pathogenic variants preferentially cluster in low MTR regions (P< 0.005) of well-informed genes. By evaluating 20 publicly available predictive tools across genes linked to epilepsy, we also highlight the importance of understanding the empirical null distribution of existing prediction tools, as these vary across genes. Subsequently integrating the MTR with the empirically selected bioinformatic tools in a gene-specific approach demonstrates a clear improvement in the ability to predict pathogenic missense variants from background missense variation in disease genes. Among an independent test sample of case and control missense variants, case variants (0.83 median score) consistently achieve higher pathogenicity prediction probabilities than control variants (0.02 median score; Mann-Whitney Utest, P< 1 × 10−16). We focus on the application to epilepsy genes; however, the framework is applicable to disease genes beyond epilepsy.

Whole-brain constrained spherical deconvolution–based tractography and track-density imaging maps reveal the presence of abnormal fiber tracks projecting from heterotopic nodules in patients with periventricular nodular heterotopia that are not detected with conventional neuroimaging techniques routinely used to investigate malformations of cortical development in vivo.

Hexadecylphosphocholine (HePC) is the first representative of the alkylphosphocholines (APC), a new group of biologically active compounds. HePC has pronounced antiproliferative effects on neoplastic cells in vitro and in vivo. The molecular mechanism by which HePC exerts its biological effects is still under investigation. Recently there has been growing evidence that HePC probably interferes with cellular signalling via phospholipases. It has been shown to inhibit both forms of phospholipase C (PLC), the phosphatidylinositol- and the phosphatidylcholine-specific PLC, and phospholipase A₂. Here we present data showing that HePC inhibits the activity of phospholipase D in vitro, whereas the action of this enzyme in leukemic cell lines is not affected. Furthermore HePC does not seem to disturbe the activity of sphingomyelinase, another enzyme of phospholipid metabolism which has been shown to play an important role in cellular signalling as well.

The objective of this study was to compare differences in glucoregulation, frequency of hypoglycemic episodes, glucose variability and lipid profiles of inpatients with poorly regulated type 1 diabetes mellitus (T1DM) after evening versus morning glargine application. Eighteen patients with poorly regulated T1DM, glycated hemoglobin (Hba1c) levels ≥7% and frequent nocturnal and/or morning hypoglycemic episodes were included in this study. There was a 12-week screening phase where patients continued their usual insulin regimen and were encouraged to achieve optimal glycemic control; however, all patients maintained HbA1c values ≥7% and continued to have frequent nocturnal and/or morning hypoglycemic events and were therefore transitioned to morning application of insulin glargine for 12 weeks. The primary outcome was to investigate changes in HbA1c values 12 weeks after the transition. The secondary outcome was to evaluate the effect of transition on glucose variability, incidence of hypoglycemic episodes, insulin doses, lipid profile and weight. Data were analyzed using paired Student’s t test and Pearson correlation. After the transition, there was no significant change in total daily dose of basal insulin (p0.114) and the average body weight remained unchanged, while significant reduction of HbA1c was present (8.02 ± 0.5 vs. 7.4 ± 0.3%) (p< 0.01) resulting in a decrease in nocturnal and daytime hypoglycemic episodes per month per person (p< 0.01). Parameters of glucose variability (glycemic standard deviations and J-index) were also improved after transition period (p< 0.01). As for the lipid profile, increase of high-density lipoprotein cholesterol and decrease of triglycerides (p< 0.01) were noticed, while other lipid parameters remained unaffected. Furthermore, insignificant association of basal insulin dose with HbA1c values regardless of the time of administration was observed. In patients with poorly regulated T1DM, transition to morning application of glargine improved glucoregulation (including a decrease in HbA1c, glucose variability and number of nocturnal hypoglycemic episodes), followed by favorable changes in lipid profile without affecting body weight. These effects were associated with the time of application, but not with the insulin dose.

The human GABAA2(R43Q) mutation is associated with genetic epilepsy. Because of the role of -aminobutyric acid (GABA) in brain development, we asked whether this epilepsy mutation might affect excitability by changing cortical cytoarchitecture.