Molecular Dynamics of Steroidal Rotors Probed by Theoretical, Spectroscopic and Dielectric Methods.

Our study focuses on molecular rotors with fast-moving rotators and their potential applications in the development of new amphidynamic crystals. Steroidal molecular rotors with a dipolar fluorine-substituted phenyl group as the rotator were synthesized and characterized. Three different rotors were investigated with varying numbers of fluorine atoms. A comprehensive analysis was performed using vibrational spectroscopy (Raman, FT-IR), electronic circular dichroism (ECD), and dielectric response to understand the behavior of the investigated model rotors. The results were supported by theoretical calculations using Density Functional Theory (DFT) methods. The angle-dependent polarized Raman spectra confirmed the crystallinity of the samples. Nearly frequency and temperature-independent permittivity suggest low-frequency librational motion of stators. An in-depth analysis of ECD spectra revealed high conformational flexibility in solution, resulting in low ECD effects, while in the solid-state with restricted rotation, significant ECD effects were observed. These findings shed light on the conformational behavior and potential applications of the studied steroidal molecular rotors.

Association between acute complications in PMM2-CDG patients and haemostasis anomalies: Data from a multicentric study and suggestions for acute management.

OBJECTIVES: Patients with PMM2-CDG develop acute events (stroke-like episodes (SLEs), thromboses, haemorrhages, seizures, migraines) associated with both clotting factors (factor XI) and coagulation inhibitors (antithrombin, protein C and protein S) deficiencies. The aim of the study was to correlate acute events to haemostasis and propose practical guidelines. METHODS: In this multicentric retrospective study, we evaluated clinical, radiological, haemostasis and electroencephalography data for PMM2-CDG patients hospitalized for acute events. Cerebral events were classified as thrombosis, haemorrhage, SLE, or "stroke mimic" (SM: normal brain imaging or evoking a migraine). RESULTS: Thirteen patients had a total of 31 acute episodes: 27 cerebral events with 7 SLEs, 4 venous thromboses, 4 haemorrhages (3 associated with thrombosis), 15 SMs at a mean age of 7.7 years; 4 non-cerebral thromboses, one of which included bleeding. A trigger was frequently involved (infection, head trauma). Although sometimes normal at baseline state, factor XI, antithrombin and protein C levels decreased during these episodes. No correlation between haemostasis anomalies and type of acute event was found. DISCUSSION: Acute events in PMM2-CDG are not negligible and are associated with haemostasis anomalies. An emergency protocol is proposed for their prevention and treatment (https://www.filiere-g2m.fr/urgences). For cerebral events, brain Magnetic Resonance Imaging with perfusion weight imaging and diffusion sequences, electroencephalogram and haemostasis protein levels guide the treatment: anticoagulation, antithrombin or fresh frozen plasma supplementation, antiepileptic therapy. Preventing bleeding and thrombosis is required in cases of surgery, prolonged immobilization, hormone replacement therapy. CONCLUSION: Acute events in PMM2-CDG are associated with abnormal haemostasis, requiring practical guidance.

Clinical and radiological description of 120 pediatric stroke-like episodes.

BACKGROUND AND PURPOSE: Stroke-like episodes (SLEs) are defined as acute onset of neurological symptoms mimicking a stroke and radiological lesions non-congruent to vascular territory. We aimed to analyze the acute clinical and radiological features of SLEs to determine their pathophysiology. METHODS: We performed a monocenter retrospective analysis of 120 SLEs in 60 children over a 20-year period. Inclusion criteria were compatible clinical symptoms and stroke-like lesions on brain magnetic resonance imaging (MRI; performed for all 120 events) with focal hyperintensity on diffusion-weighted imaging in a non-vascular territory. RESULTS: Three groups were identified: children with mitochondrial diseases (n = 22) involving mitochondrial DNA mutations (55%) or nuclear DNA mutations (45%); those with other metabolic diseases or epilepsy disorders (n = 22); and those in whom no etiology was found despite extensive investigations (n = 16). Age at first SLE was younger in the group with metabolic or epilepsy disorders (18 months vs. 128 months; p < 0.0001) and an infectious trigger was more frequent (69% vs. 20%; p = 0.0001). Seizures occurred in 75% of episodes, revealing 50% episodes of SLEs and mainly leading to status epilepticus (90%). Of the 120 MRI scans confirming the diagnosis, 28 were performed within a short and strict 48-h period and were further analyzed to better understand the underlying mechanisms. The scans showed primary cortical hyperintensity (n = 28/28) with decreased apparent diffusion coefficient in 52% of cases. Systematic hyperperfusion was found on spin labeling sequences when available (n = 18/18). CONCLUSION: Clinical and radiological results support the existence of a vicious circle based on two main mechanisms: energy deficit and neuronal hyperexcitability at the origin of SLE.

Recurrent de novo mutations in CLDN5 induce an anion-selective blood-brain barrier and alternating hemiplegia.

Claudin-5 is the most enriched tight junction protein at the blood-brain barrier. Perturbations in its levels of expression have been observed across numerous neurological and neuropsychiatric conditions; however, pathogenic variants in the coding sequence of the gene have never been reported previously. Here, we report the identification of a novel de novo mutation (c.178G>A) in the CLDN5 gene in two unrelated cases of alternating hemiplegia with microcephaly. This mutation (G60R) lies within the first extracellular loop of claudin-5 and based on protein modelling and sequence alignment, we predicted it would modify claudin-5 to become an anion-selective junctional component as opposed to a purely barrier-forming protein. Generation of stably transfected cell lines expressing wild-type or G60R claudin-5 showed that the tight junctions could still form in the presence of the G60R mutation but that the barrier against small molecules was clearly attenuated and displayed higher Cl- ion permeability and lower Na+ permeability. While this study strongly suggests that CLDN5 associated alternating hemiplegia is a channelopathy, it is also the first study to identify the conversion of the blood-brain barrier to an anion-selective channel mediated by a dominant acting variant in CLDN5.

Influence of sustainable packaging material and packaging conditions on physicochemical, microbiological, and sensorial properties of cheeses.

The aim of this study was to evaluate the influence of different packaging materials [standard foil: BOPP (biaxially oriented polypropylene)/PET (polyester)/PE (polyethylene) for upper layer, and APET (polyethylene terephthalate)/PE for bottom layer; foil 1: PP (polypropylene)/PET/PE/EVOH (ethylene-vinyl alcohol copolymer)/PE upper layer, and PP/PE/EVOH/PE bottom layer; foil 2: PP/PET/PE/EVOH/PE upper layer, and PA (polyamide)/EVOH/PE bottom layer; foil 3: PP/PET/PE upper layer, and PA/EVOH/PE bottom layer; foil 4: PP/PET/PE upper layer, and PA/PE bottom layer; foil 5: PP upper layer, and PP/PP bottom layer] on the quality of 3 different ripening rennet cheeses packed under different modified atmosphere (MAP) conditions as reflected in particular physicochemical, microbiological, and sensorial changes. The changes were monitored during a period of 90 d of storage at 2°C or 8°C. For Gouda cheese, CO2 content of the headspace of the packages was in the range 35% to 45%, whereas for Maasdamer and Sielski Klasyczny cheeses it was 55% to 65%. Three-way ANOVA showed that the foil type influenced the moisture content of Gouda cheese stored for 90 d at 2°C and for Sielski Klasyczny cheese at 8°C, whereas the moisture content was not dependent on MAP conditions during storage. Moreover, the foil type had a significant effect on free fatty acid changes for Gouda and Sielski Klasyczny cheeses stored at 2°C for 90 d. Sensory attributes changed significantly over storage time at 2°C for all studied cheeses as affected by foil type, whereas there was no effect of MAP conditions. In general, the cheeses packed in standard foil and foil 4 were characterized by the highest values of mean sensory attributes. Time was the most significant factor influencing most changes in physicochemical and sensory attributes of cheeses stored at 2°C and 8°C. The storage temperature did not affect the moisture of the samples during storage. In general, we found an increase in the pH value during storage regardless of storage temperature. It was possible to decrease the thickness of the packaging material from initial 103 and 250 µm (standard foil; lid and bottom, respectively) to 98 and 100 µm (foil 4) without affecting sensory attributes of the product.

De novo mutations of SCN1A are responsible for arthrogryposis broadening the SCN1A-related phenotypes.

BACKGROUND: Arthrogryposis multiplex congenita (AMC) is the direct consequence of reduced fetal movements. AMC includes a large spectrum of diseases which result from variants in genes encoding components required for the formation or the function of the neuromuscular system. AMC may also result from central nervous involvement. SCN1A encodes Nav1.1, a critical component of voltage-dependent sodium channels which underlie action potential generation and propagation. Variants of SCN1A are known to be responsible for Dravet syndrome, a severe early-onset epileptic encephalopathy. We report pathogenic heterozygous missense de novo variants in SCN1A in three unrelated individuals with AMC. METHODS: Whole-exome sequencing was performed from DNA of the index case of AMC families. Heterozygous missense variants in SCN1A (p.Leu893Phe, p.Ala989Thr, p.Ile236Thr) were identified in three patients. Sanger sequencing confirmed the variants and showed that they occurred de novo. RESULTS: AMC was diagnosed from the second trimester of pregnancy in the three patients. One of them developed drug-resistant epileptic seizures from birth. We showed that SCN1A is expressed in both brain and spinal cord but not in skeletal muscle during human development. The lack of motor denervation as established by electromyographic studies or pathological examination of the spinal cord or skeletal muscle in the affected individuals suggests that AMC is caused by brain involvement. CONCLUSION: We show for the first time that SCN1A variants are responsible for early-onset motor defect leading to AMC indicating a critical role of SCN1A in prenatal motor development and broadening the phenotypic spectrum of variants in SCN1A.

Value of short exercise and short exercise with cooling tests in diagnosis of recessive form of myotonia congenita (Becker disease) - are sex differences important?

INTRODUCTION: In myotonia congenita (MC), activation with exercise or cooling can induce transient changes in compound motor action potential (CMAP) parameters, thus providing a guide to genetic analysis. MATERIAL AND METHODS: We performed the short exercise test (SET) and the short exercise test with cooling (SETC) in 30 patients with genetically confirmed Becker disease (BMC) to estimate their utility in the diagnosis of BMC. RESULTS: Although we observed a significant decrease in CMAP amplitude immediately after maximal voluntary effort in both tests in the whole BMC group, in men this decline was significantly smaller than in women, especially in SET. Clinical implications/future directions: In men with a clinical suspicion of BMC, a small decrease in CMAP amplitude in SET together with a typical decline in SETC does not exclude the diagnosis of BMC. Our results show a sex-specific difference in chloride channel function in BMC, which needs further investigation.

Novel approach to antiangiogenic factors in age-related macular degeneration therapy.

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss among the population above 85 worldwide. There are two main types of AMD: neovascular and dry AMD. Neovascular AMD leads to macular changes resulting from abnormal choroidal neovascularization. Untreated neovascular AMD leads to scar formation and irreversible sight deterioration. Dry AMD in consequence leads to atrophic changes of the macula. The last decades brought a breakthrough in the therapy of neovascular age-related macular degeneration by introduction of, firstly, photodynamic therapy and, later, anti-VEGF agents administered intravitreally in order to stop neoangiogenesis. However, the treatment of dry AMD is still challenging. Among the directions in dry AMD treatment, the most promising are complement cascade inhibitors and complement cascade targeted gene therapy. In the article we outline the main directions in up-to-date experimental and practical approaches to wet and dry AMD therapy with the emphasis on antiangiogenic factors and gene therapy focused on the inhibition of pathological angiogenesis.

Deep phenotyping unstructured data mining in an extensive pediatric database to unravel a common KCNA2 variant in neurodevelopmental syndromes.

PURPOSE: Electronic health records are gaining popularity to detect and propose interdisciplinary treatments for patients with similar medical histories, diagnoses, and outcomes. These files are compiled by different nonexperts and expert clinicians. Data mining in these unstructured data is a transposable and sustainable methodology to search for patients presenting a high similitude of clinical features. METHODS: Exome and targeted next-generation sequencing bioinformatics analyses were performed at the Imagine Institute. Similarity Index (SI), an algorithm based on a vector space model (VSM) that exploits concepts extracted from clinical narrative reports was used to identify patients with highly similar clinical features. RESULTS: Here we describe a case of "automated diagnosis" indicated by Dr. Warehouse, a biomedical data warehouse oriented toward clinical narrative reports, developed at Necker Children's Hospital using around 500,000 patients' records. Through the use of this warehouse, we were able to match and identify two patients sharing very specific clinical neonatal and childhood features harboring the same de novo variant in KCNA2. CONCLUSION: This innovative application of database clustering clinical features could advance identification of patients with rare and common genetic conditions and detect with high accuracy the natural history of patients harboring similar genetic pathogenic variants.

The phenotypic spectrum of X-linked, infantile onset ALG13-related developmental and epileptic encephalopathy.

OBJECTIVE: Asparagine-linked glycosylation 13 (ALG13) deficiencies have been repeatedly described in the literature with the clinical phenotype of a developmental and epileptic encephalopathy (DEE). Most cases were females carrying the recurrent ALG13 de novo variant, p.(Asn107Ser), with normal transferrin electrophoresis. METHODS: We delineate the phenotypic spectrum of 38 individuals, 37 girls and one boy, 16 of them novel and 22 published, with the most common pathogenic ALG13 variant p.(Asn107Ser) and additionally report the phenotype of three individuals carrying other likely pathogenic ALG13 variants. RESULTS: The phenotypic spectrum often comprised pharmacoresistant epilepsy with epileptic spasms, mostly with onset within the first 6 months of life and with spasm persistence in one-half of the cases. Tonic seizures were the most prevalent additional seizure type. Electroencephalography showed hypsarrhythmia and at a later stage of the disease in one-third of all cases paroxysms of fast activity with electrodecrement. ALG13-related DEE was usually associated with severe to profound developmental delay; ambulation was acquired by one-third of the cases, whereas purposeful hand use was sparse or completely absent. Hand stereotypies and dyskinetic movements including dystonia or choreoathetosis were relatively frequent. Verbal communication skills were absent or poor, and eye contact and pursuit were often impaired. SIGNIFICANCE: X-linked ALG13-related DEE usually manifests as West syndrome with severe to profound developmental delay. It is predominantly caused by the recurrent de novo missense variant p.(Asn107Ser). Comprehensive functional studies will be able to prove or disprove an association with congenital disorder of glycosylation.

De novo SCAMP5 mutation causes a neurodevelopmental disorder with autistic features and seizures.

BACKGROUND: Autistic spectrum disorders (ASDs) with developmental delay and seizures are a genetically heterogeneous group of diseases caused by at least 700 different genes. Still, a number of cases remain genetically undiagnosed. OBJECTIVE: The objective of this study was to identify and characterise pathogenic variants in two individuals from unrelated families, both of whom presented a similar clinical phenotype that included an ASD, intellectual disability (ID) and seizures. METHODS: Whole-exome sequencing was used to identify pathogenic variants in the two individuals. Functional studies performed in the Drosophila melanogaster model was used to assess the protein function in vivo. RESULTS: Probands shared a heterozygous de novo secretory carrier membrane protein (SCAMP5) variant (NM_001178111.1:c.538G>T) resulting in a p.Gly180Trp missense variant. SCAMP5 belongs to a family of tetraspanin membrane proteins found in secretory and endocytic compartments of neuronal synapses. In the fly SCAMP orthologue, the p.Gly302Trp genotype corresponds to human p.Gly180Trp. Western blot analysis of proteins overexpressed in the Drosophila fat body showed strongly reduced levels of the SCAMP p.Gly302Trp protein compared with the wild-type protein, indicating that the mutant either reduced expression or increased turnover of the protein. The expression of the fly homologue of the human SCAMP5 p.Gly180Trp mutation caused similar eye and neuronal phenotypes as the expression of SCAMP RNAi, suggesting a dominant-negative effect. CONCLUSION: Our study identifies SCAMP5 deficiency as a cause for ASD and ID and underscores the importance of synaptic vesicular trafficking in neurodevelopmental disorders.

New perspectives of immunomodulation and neuroprotection in glaucoma.

Glaucoma is the neurodegenerative disease of retinal ganglion cells. The main risk factor for glaucoma is increased intraocular pressure. The processes leading to cell death due to presence of the injury factor comprise multiple molecular mechanisms, as well as the immunological response. The knowledge of immunological mechanisms occurring in glaucomatous degeneration makes it possible to introduce glaucoma treatment modulating the cellular degradation. The glaucoma treatment of the future will make it possible not only to lower the intraocular pressure, but also to moderate the intracellular mechanisms in order to prevent retinal cell degeneration. Citicoline is a drug modulating glutamate excitotoxicity that is already in use. Rho kinase inhibitors were found to stimulate neurite growth and axon regeneration apart from lowering intraocular pressure. The complementary action of brimonidine is to increase neurotrophic factor (NTF) concentrations and inhibit glutamate toxicity. Immunomodulatory therapies with antibodies and gene therapies show promising effects in the current studies. The supplementation of NTFs prevents glaucomatous damage. Resveratrol and other antioxidants inhibit reactive oxygen species formation. Cell transplantation of stem cells, Schwann cells and nerve extracts was reported to be successful so far. Our review presents the most promising new strategies of neuroprotection and immunomodulation in glaucoma.

Neonatal factors related to survival and intellectual and developmental outcome of patients with early-onset urea cycle disorders.

PURPOSE: We aimed to identify prognostic factors for survival and long-term intellectual and developmental outcome in neonatal patients with early-onset urea cycle disorders (UCD) experiencing hyperammonaemic coma. METHODS: We retrospectively analysed ammonia (NH3) and glutamine levels, electroencephalogram and brain images obtained during neonatal coma of UCD patients born between 1995 and 2011 and managed at a single centre and correlated them to survival and intellectual and developmental outcome. RESULTS: We included 38 neonates suffering from deficiencies of argininosuccinate synthetase (ASSD, N = 12), ornithine transcarbamylase (OTCD, N = 10), carbamoylphosphate synthetase 1 (CPSD, N = 7), argininosuccinate lyase (ASLD, N = 7), N-acetylglutamate synthase (NAGS, N = 1) or arginase (ARGD, N = 1). Symptoms occurred earlier in mitochondrial than in cytosolic UCD. Sixty-eight percent of patients survived, with a mean (standard deviation-SD) follow-up of 10.4 (5.3) years. Mortality was mostly observed in OTCD (N = 7/10) and CPSD (N = 4/7) patients. Plasma NH3 level during the neonatal period, expressed as area under the curve, but not glutamine level was associated with mortality (p = .044 and p = .610). 62.1% of the patients had normal intellectual and developmental outcome. Intellectual and developmental outcome tended to correlate with UCD subtype (p = .052). No difference in plasma NH3 or glutamine level during the neonatal period among developmental outcomes was identified. EEG severity was linked to UCD subtypes (p = .004), ammonia levels (p = .037), duration of coma (p = .043), and mortality during the neonatal period (p = .020). Status epilepticus was recorded in 6 patients, 3 of whom died neonatally, 1 developed a severe intellectual disability while the 2 last patients had a normal development. CONCLUSION: UCD subtypes differed by survival rate, intellectual and developmental outcome and EEG features in the neonatal period. Hyperammonaemia expressed as area under the curve was associated with survival but not with intellectual and developmental outcome whereas glutamine was not associated with one of these outcomes. Prognostic value of video-EEG monitoring and the association between status epilepticus and mortality should be assessed in neonatal hyperammonaemic coma in further studies.

KCNT1 epilepsy with migrating focal seizures shows a temporal sequence with poor outcome, high mortality and SUDEP.

Epilepsy of infancy with migrating focal seizures was first described in 1995. Fifteen years later, KCNT1 gene mutations were identified as the major disease-causing gene of this disease. Currently, the data on epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations are heterogeneous and many questions remain unanswered including the prognosis and the long-term outcome especially regarding epilepsy, neurological and developmental status and the presence of microcephaly. The aim of this study was to assess data from patients with epilepsy in infancy with migrating focal seizures with KCNT1 mutations to refine the phenotype spectrum and the outcome. We used mind maps based on medical reports of children followed in the network of the French reference centre for rare epilepsies and we developed family surveys to assess the long-term outcome. Seventeen patients were included [age: median (25th-75th percentile): 4 (2-15) years, sex ratio: 1.4, length of follow-up: 4 (2-15) years]. Seventy-one per cent started at 6 (1-52) days with sporadic motor seizures (n = 12), increasing up to a stormy phase with long lasting migrating seizures at 57 (30-89) days. The others entered this stormy phase directly at 1 (1-23) day. Ten patients entered a consecutive phase at 1.3 (1-2.8) years where seizures persisted at least daily (n = 8), but presented different semiology: brief and hypertonic with a nocturnal (n = 6) and clustered (n = 6) aspects. Suppression interictal patterns were identified on the EEG in 71% of patients (n = 12) sometimes from the first EEG (n = 6). Three patients received quinidine without reported efficacy. Long-term outcome was poor with neurological sequelae and active epilepsy except for one patient who had an early and long-lasting seizure-free period. Extracerebral symptoms probably linked with KCNT1 mutation were present, including arteriovenous fistula, dilated cardiomyopathy and precocious puberty. Eight patients (47%) had died at 3 (1.5-15.4) years including three from suspected sudden unexpected death in epilepsy. Refining the electro-clinical characteristics and the temporal sequence of epilepsy in infancy with migrating focal seizures should help diagnosis of this epilepsy. A better knowledge of the outcome allows one to advise families and to define the appropriate follow-up and therapies. Extracerebral involvement should be investigated, in particular the cardiac system, as it may be involved in the high prevalence of sudden unexpected death in epilepsy in these cases.

Children and adolescents with epilepsy in rehabilitation centers: A French prospective transversal study.

INTRODUCTION: The reason why some children and adolescent with epilepsy (CAWE) still challenge the "inclusive" educative policy needs to be explored. METHODS/PATIENTS: We conducted a transversal study in French medical, social, and educative rehab centers (MSERCs) dedicated to CAWE to describe the profile of 263 centers-involved (CI)-CAWE. Centers-involved CAWE were prospectively followed from September 2012 to August 2013. Medical, social, and educative rehab centers were dichotomized according to their care-provider agreement (i.e., CAWE of "moderate" (M) vs. "severe" (S) conditions). Clinical factors known to impact clinical outcome and quality of life (QoL) in epilepsy and four disabling conditions at risk to impact school life (i.e., cognitive and psychiatric/behavioral disorders, risk of physical hazards (i.e., refractory seizures with unpredictable loss of tone and/or awareness), and one or more seizure/week) were evaluated. The electronic chart of the French collaborative database (namely GRENAT) was used for data collection allowing comparison with the profile of 731 "normally integrated and schooled" (NIS)-CAWE extracted from GRENAT and matching for generation (i.e., born between 1988 and 2006). RESULTS: Centers-involved CAWE's profile was found, after adjustment, to be associated with clinical factors and disabling conditions reflecting the poorest clinical outcome and health-related quality of life (HR-QoL) (all p < 0.001). A cutoff of two disabilities/child highly discriminated NIS-CAWE vs. CI-CAWE. Centers-involved CAWE of S-MSERCs were the most severe (all p < 0.001), and the type of cognitive disability (i.e., intellectual disability (ID) vs. specific learning disorders (SLD)) highly paralleled the types of MSERCs (S vs. M). Using a parent-informant questionnaire, the number of disabilities/child was found to correlate with both the evaluation of the impact of epilepsy (r = 0.47, p < 0.001) and the HR-QoL (r = 0.37, p < 0.001). A satisfactory social life was reported (83.8%) even after S vs. M dichotomization (77.2% vs. 94.7%; p < 0.001). CONCLUSION: Multiple disabilities rather than epilepsy per se challenge the inclusive educative policy. Evaluation of disabilities could be the missing bridge to optimize this policy and understand its limits.

Social and emotional intelligence as a basis for communicative resource formation in family caregivers of patients with endogenous mental disorders.

OBJECTIVE: The aim of our study was to determine features of social and emotional intelligence in family caregivers of patients with endogenous mental disorders as a basis for communicative resource formation in family where a patient lives. PATIENTS AND METHODS: Materials and methods: A total of 273 family caregivers of patients with paranoid schizophrenia and bipolar disorder were involved into this survey under informed consent conditions. Control group included 55 mentally healthy respondents, in whose families there is no mentally sick family member. Emotional intelligence of family caregivers was measured using the psychodiagnostic test "EQ" by N. Hall. To assess level of social intelligence the J. Gilford and M. Sullivan test (in adaptation done by Mikhailova E.S.) was used. Values of p <0.05 were considered significant. RESULTS: Results: The study revealed that family caregivers of patients with schizophrenia and affective disorders demonstrate a decrease in emotional and social intelligence indicators, which creates significant obstacles for effective interpersonal family communication and for the harmonious functioning of a family, in which a mentally sick patient lives, in general. Difficulties of emotional regulation, emotional management, recognition of emotional states of other participants of communication related to the level of emotional and social intelligence of FC are factors, that complicate interpersonal relations in families of patients and reduce possibilities for psychosocial adaptation of all family members. CONCLUSION: Conclusions: Revealed features should be taken into consideration when creating appropriate psycho-educational and psycho-corrective programs for family caregivers of patients with endogenous mental disorders.

Correction: IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients.

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IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients.

PURPOSE: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences. METHODS: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms. RESULTS: IQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments. CONCLUSION: This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.

Quantitative analysis and EEG markers of KCNT1 epilepsy of infancy with migrating focal seizures.

OBJECTIVE: We aimed to characterize epilepsy of infancy with migrating focal seizures (EIMFS), a rare, severe early onset developmental epilepsy related to KCNT1 mutation, and to define specific electroencephalography (EEG) markers using EEG quantitative analysis. The ultimate goal would be to improve early diagnosis and to better understand seizure onset and propagation of EIMFS as compared to other early onset developmental epilepsy. METHODS: EEG of 7 EIMFS patients with KCNT1 mutations (115 seizures) and 17 patients with other early onset epilepsies (30 seizures) was included in this study. After detection of seizure onset and termination, spatiotemporal characteristics were quantified. Seizure propagation dynamics were analyzed using chronograms and phase coherence. RESULTS: In patients with EIMFS, seizures started and were localized predominantly in temporal and occipital areas, and evolved with a stable frequency (4-10 Hz). Inter- and intrahemispheric migrations were present in 60% of EIMFS seizures with high intraindividual reproducibility of temporospatial dynamics. Interhemispheric migrating seizures spread in 71% from temporal or occipital channels to the homologous contralateral ones, whereas intrahemispheric seizures involved mainly frontotemporal, temporal, and occipital channels. Causality links were present between ictal activities detected under different channels during migrating seizures. Finally, time delay index (based on delays between the different ictal onsets) and phase correlation index (based on coherence of ictal activities) allowed discrimination of EIMFS and non-EIMFS seizures with a specificity of 91.2% and a sensitivity of 84.4%. SIGNIFICANCE: We showed that the migrating pattern in EIMFS is not a random process, as suggested previously, and that it is a particular propagation pattern that follows the classical propagation pathways. It is notable that this study reveals specific EEG markers (time delay and phase correlation) accessible to visual evaluation, which will improve EIMFS diagnosis.

Screening for late-onset Pompe disease in Poland.

OBJECTIVES: We aimed to screen for late-onset Pompe disease using the dried blood spot (DBS) test in a cohort of patients with limb-girdle muscle weakness or persistent hyperCKemia. MATERIALS AND METHODS: Patients with limb-girdle muscle weakness, persistently elevated CK, rigid spine syndrome, dyspnoea, myalgia or sibling of the patient diagnosed with LOPD were included in the study. Acid α-glucosidase (GAA) activity was measured on DBS by tandem mass spectrometry and followed by genetic testing when required. Study was conducted between June 2014 and May 2017. RESULTS: A total of 337 patients aged 32.2 years (range 2-80) were included in the study. Late-onset Pompe disease was diagnosed in 10 patients (3.0% of tested cohort). All were compound heterozygotes with common c.32-13T>G mutation on one allele and missense or frameshift mutation on the other. Two of the mutations (c.1951delG and c.397T>G) were not reported previously. Seven of the patients started enzyme replacement therapy. CONCLUSIONS: DBS test is a reliable method for screening for late-onset Pompe disease.