Migration Disorders Research Articles

The association between long-distance migration and PTSD prevalence in Syrian refugees

BackgroundRefugees are forced migrants but there is a large variation in the distance that refugees cover and there is a paucity in the evidence of how this may affect refugees’ health and health care needs. Objective: We investigated the association between long-distance migration and post-traumatic stress disorder (PTSD), a serious psychiatric disorder associated with deteriorating mental and somatic health.MethodsIncluded from 2016–2019 were adult Syrian refugees in Lebanon and Denmark that arrived up to 12 months prior to inclusion. PTSD was assessed using the Harvard Trauma Questionnaire and the estimate of association was obtained by multiply imputing missing data and adjusting for confounding by propensity score-weighting with covariates age, sex, socioeconomic status, trauma experience and general mental well-being, reporting the bootstrap 95-percentile confidence interval (95% CI). Additionally, a number of sensitivity analyses were performed.ResultsIncluded were 599 participants in Lebanon (mean age 35 years old, 73% being female) and 133 participants in Denmark (mean age 30 years old, 47% being female). After multiply imputing missing data and propensity score-weighted adjustment for confounding, migration to Denmark instead of Lebanon was associated with an increase in PTSD prevalence of 9 percentage point (95% CI [-1; 19] percentage point).ConclusionsLong-distance migration may be associated with an increase in PTSD prevalence in refugees. The migration could be an important factor to consider when assessing refugees’ and asylum seekers’ health. Practitioners should consider “long-distance migration” in refugee health screenings and in particular when assessing the risk of post-traumatic stress disorder. Future research should be designed to ultimately lead to studies of relevant interventions to lower the risk of post-traumatic stress disorder in refugees.

Computational analysis of missense filamin-A variants, including the novel p.Arg484Gln variant of two brothers with periventricular nodular heterotopia.

Periventricular nodular heterotopia (PNH) is a cell migration disorder associated with mutations in Filamin-A (FLNA) gene on chromosome X. Majority of the individuals with PNH-associated FLNA mutations are female whereas liveborn males with FLNA mutations are very rare. Fetal viability of the males seems to depend on the severity of the variant. Splicing or severe truncations presumed loss of function of the protein product, lead to male lethality and only partial-loss-of-function variants are reported in surviving males. Those variants mostly manifest milder clinical phenotypes in females and thus avoid detection of the disease in females. We describe a novel p.Arg484Gln variant in the FLNA gene by performing whole exome analysis on the index case, his one affected brother and his healthy non-consanguineous parents. The transmission of PNH from a clinically asymptomatic mother to two sons is reported in a fully penetrant classical X-linked dominant mode. The variant was verified via Sanger sequencing. Additionally, we investigated the impact of missense mutations reported in affected males on the FLNa protein structure, dynamics and interactions by performing molecular dynamics (MD) simulations to examine the disease etiology and possible compensative mechanisms allowing survival of the males. We observed that p.Arg484Gln disrupts the FLNa by altering its structural and dynamical properties including the flexibility of certain regions, interactions within the protein, and conformational landscape of FLNa. However, these impacts existed for only a part the MD trajectories and highly similar patterns observed in the other 12 mutations reported in the liveborn males validated this mechanism. It is concluded that the variants seen in the liveborn males result in transient pathogenic effects, rather than persistent impairments. By this way, the protein could retain its function occasionally and results in the survival of the males besides causing the disease.

Neuropathology findings in KCNQ2 neonatal epileptic encephalopathy.

PurposeKCNQ2-epileptic encephalopathy (EE) is a neonatal epilepsy syndrome characterized by a typical clinical presentation and EEG recording, but without any brain or cortical abnormal development on MRI. Most of the patients have a severe developmental impairment. The epileptogenic mechanisms are thought to be the result of the changes of the M-current density causing a change of brain excitability. Although recent studies allow us to better understand the physiopathology of KCNQ2-EE, the neuropathology of this ion channel dysfunction has only been previously described in a single case report. MethodsWe report the neuropathology study of a case of KCNQ2-EE with a typical electro-phenotype due to a de novo heterozygous single nucleotide pathogenic variant in the exon 5 of the KCNQ2 gene (NM_172107.2:c.802C>T; p.Leu268Phe). ResultsAt the macroscopic level, the brain had a normal structure with a normal neocortical gyral pattern. At the histological level, the cortex had a usual six-layer lamination in all lobes but blurred gray-white matter boundaries due to excessive heterotopic neurons in deep white matter were observed. This diffuse mild malformation of cortical development is suggestive of a neuronal migration disorder. ConclusionIn recent years, our understanding of the role of ion channel dysfunctions in early brain development has expanded from the occurrence of EE to brain malformation. Through this rare neuropathological report, we emphasize the role of KCNQ2 channels in the process of cortical development. As for other genetic neonatal onset epilepsies, more reports are needed to further delineate the range of neuropathological abnormalities for KCNQ2-EE.

Pediatric Brain Maturation and Migration Disorders.

Neurodevelopmental disorders, including neuronal migration disorders, are best understood in the context of altered normal development. Neurons normally migrate from their site of origin to their (usually cortical) destination using a wide range of molecular and cellular signaling as a guide. In the case of abnormal migration neurons: (1) do not migrate and remain at their site of origin; (2) incompletely migrate and remain within the white matter; (3) migrate to the cortex but fail to organize correctly; or (4) over-migrate, beyond the cortex. In this review, we discuss normal brain development, along with the malformations that result from these different migration abnormalities.

Serine Proteases and Their Inhibitors Affect the Rate of GnRH Neuronal Migration in the Embryonic Chick Model: A Thesis Proposal

Development in an organism is a highly complex task that requires a specific sequence for proper function. One of these tasks is neuronal migration and the extracellular cues that help to guide neurons to their appropriate locations. If neurons do not migrate to their appropriate locations, then there are abnormal neural connections, which can result in neuronal migration disorders (NMD). It has been shown that the inhibition and stimulation of migration may be balanced due to effects of serine protease inhibitors and serine proteases. Serine proteases and their inhibitors can alter the various chemoattraction-signaling cues and thereby modulate neuronal migratory processes. Furthermore, there exists a delicate balance between serine proteases and their inhibitors to modulate migration of neurons within development. Thus, by understanding how the balance of serine protease and serine protease inhibitor activity works, one can further understand how these changes affect neuronal migration in development. Experiments to test in vivo neuronal migration of chick GnRH neurons during embryogenesis were investigated to elucidate the role these proteins play in migration. Protein coated beads were inserted and GnRH levels measured to control. Such experimentation is crucial, as these studies are the first to explore the role of proteases in neural migration in an in vivo model. These findings indicate that the ability to initiate migration lies inherently within the neuron itself such that changes of the extracellular matrix composition are irrelevant in the initial timing. Neurons entering the CNS earlier in trypsin-treated embryos indicates continuous movement may be a cell autonomous event with trypsin-induced proteolysis. In other words, the ability of GnRH neurons to migrate across glial boundaries and through the brain to its target site is independent of further maturation of the neuron or the brain. Taken together, this study can provide knowledge regarding these proteins and their relation to development. This knowledge can potentially lead to therapies that can provide ameliorative care for patients suffering with NMD.

Structural Consequence of Non-Synonymous Single-Nucleotide Variants in the N-Terminal Domain of LIS1.

Disruptive neuronal migration during early brain development causes severe brain malformation. Characterized by mislocalization of cortical neurons, this condition is a result of the loss of function of migration regulating genes. One known neuronal migration disorder is lissencephaly (LIS), which is caused by deletions or mutations of the LIS1 (PAFAH1B1) gene that has been implicated in regulating the microtubule motor protein cytoplasmic dynein. Although this class of diseases has recently received considerable attention, the roles of non-synonymous polymorphisms (nsSNPs) in LIS1 on lissencephaly progression remain elusive. Therefore, the present study employed combined bioinformatics and molecular modeling approach to identify potential damaging nsSNPs in the LIS1 gene and provide atomic insight into their roles in LIS1 loss of function. Using this approach, we identified three high-risk nsSNPs, including rs121434486 (F31S), rs587784254 (W55R), and rs757993270 (W55L) in the LIS1 gene, which are located on the N-terminal domain of LIS1. Molecular dynamics simulation highlighted that all variants decreased helical conformation, increased the intermonomeric distance, and thus disrupted intermonomeric contacts in the LIS1 dimer. Furthermore, the presence of variants also caused a loss of positive electrostatic potential and reduced dimer binding potential. Since self-dimerization is an essential aspect of LIS1 to recruit interacting partners, thus these variants are associated with the loss of LIS1 functions. As a corollary, these findings may further provide critical insights on the roles of LIS1 variants in brain malformation.

Role of Ultrasonography in the Evaluation of Normal Developmental Pattern of Fetal Cerebral Sulci Between 18 and 32 Weeks of Gestational Age.

BackgroundBrain development is a crucial process of intrauterine life and can be readily visualized on ultrasonography. This study aims to visualize developmental patterns of various fetal cerebral sulci using ultrasonography between 18 and 32 weeks of gestation. Sulci are best visualized on images that are taken perpendicular to their expected course of development. Initially, they appear as small dot/dimple on the brain surface and later develop into a V-shaped indentation and finally deepen to form notch and echogenic line into the brain forming a Y-shaped configuration.Material and methodsThis was a cross-sectional observational study conducted on 241 antenatal mothers with a singleton pregnancy between 18 and 32 weeks of gestational age. Demographic and clinical data were obtained. Ultrasonography was performed using PHILIPS EPIQ 5, a curvilinear probe of frequency 2-5MHz. Sulci/fissures that are reported to appear early on anatomical studies were evaluated, specifically the parieto-occipital fissure, calcarine fissure, cingulate sulci, insula/Sylvian fissure, and convexity sulci. Comparison of the categorical outcomes was performed between study groups using the chi-square test. A p-value of <0.05 was considered statistically significant.ResultsThe study included 241 participants. The mean age of antenatal mothers was 24.09 ± 4.13 years, and the mean fetal gestational age was 24.99 ± 4.13 weeks. Parieto-occipital fissure was the first fissure to develop and was present as a V-shaped indentation at 18 weeks and as a Y-shaped configuration by 21-22 weeks. Calcarine fissure was the next fissure to appear; it appeared as a dot by 18 weeks and developed into a V-shaped indentation by 20 weeks and as a Y-shaped configuration by 23 weeks. All fissures except cingulate sulci had appeared by 20 weeks, and calcarine sulci appeared later in the gestation by 21 weeks. Sylvian fissure initially appeared as a smooth surface and later underwent operculization to form obtuse and acute angulations with the adjacent temporal lobe by 20 and 24 weeks, respectively. Convexity sulci appeared later in gestation, beyond 25-26 weeks.ConclusionsUltrasonography, which is the commonest modality used in antenatal assessment of the fetus, can also be used to identify, familiarize, and provide a standard reference to assess normality of fetal sulcations. Neuronal migration disorders result in a wide spectrum of malformations of cortical development whose clinical manifestations include severe psychomotor retardation, developmental delays, motor deficits, seizures, and failure to thrive. Knowledge of normal development patterns of fetal cerebral sulci helps in early suspicion and detection of these cortical malformations, when present.

Genotype-phenotype correlations for the type 1 lissencephaly of eight Tunisian children

Background: Lissencephaly represents a rare subgroup of genetically distinct neurological disorders of neuronal migration characterized by a paucity or absence of cerebral gyration. The most common form of lissencephaly has been isolated and referred to as classic or type 1 lissencephaly. It is frequently related to abnormalities within LIS1 or DCX genes, with abnormalities ranging from single base pair substitutions to contiguous gene deletions. Methods: In this study, we report, for the first time, a clinical and genetic characterization of eight unrelated Tunisian children presenting type 1 lissencephaly. We screened LIS1 and DCX abnormalities thanks to a combination of molecular cytogenetic methods and next generation sequencing. Results: One deletion of DCX and three deletions of LIS1 were observed. One of these deletions was inherited from a maternal reciprocal translocation and estimated to approximately 2,9 Mb length. In addition, a 26 Kb LIS1 deletion was detected and refined between exon 3 up to exon 11 by target capture and sequencing. The last LIS1 rearrangement was a mutation (c.779T&gt;A, p.V260E). Finally, two novel DCX mutations were found out (c.910G&gt;C, p.G304R/c.436T&gt;C, p.F146L). Conclusions: Our data confirm the individuality and originality of type 1 lissencephaly on both the phenotypic and the genetic levels. Furthermore, our data confirm again that LIS1 and DCX are the most genes associated with type 1 lissencephaly and spotlight the usefulness of developing approaches and methods for detecting a large number of known causative gene mutations.

LIS1, an RNA-binding protein, regulates the physical properties of embryonic stem cells

LIS1 (Lissencephaly-1) was identified as the first gene involved in a neuronal migration disorder. The dosage of the LIS1 protein is important for proper brain development, whereas the absence of the protein results in early embryonic lethality. LIS1 interacts with the molecular motor cytoplasmic dynein, and this interaction impacts multiple activities. In this study, we set out to investigate the functions of LIS1 in embryonic stem cells. We found that LIS1 interacts with numerous RNA-binding proteins, including the Argonaute complex, and that LIS1 binds directly to RNA.

Identification of the most damaging nsSNPs in the human CFL1 gene and their functional and structural impacts on cofilin-1 protein

The cofilin-1 protein, encoded by CFL1, is an actin-binding protein that regulates F-actin depolymerization and nucleation activity through phosphorylation and dephosphorylation. CFL1 has been implicated in the development of neurodegenerative diseases (Alzheimer’s disease and Huntington’s disease), neuronal migration disorders (lissencephaly, epilepsy, and schizophrenia), and neural tube closure defects. Mutations in CFL1 have been associated with impaired neural crest cell migration and neural tube closure defects. In our study, various computational approaches were utilized to explore single-nucleotide polymorphisms (SNPs) in CFL1. The Variation Viewer and gnomAD databases were used to retrieve CFL1 SNPs, including 46 nonsynonymous SNPs (nsSNPs). The functional and structural annotation of SNPs was performed using 12 sequence-based web applications, which identified 20 nsSNPs as being the most likely to be deleterious or disease-causing. The conservation of cofilin-1 protein structures was illustrated using the ConSurf and PROSITE web servers, which projected the 12 most deleterious nsSNPs onto conserved domains, with the potential to disrupt the protein's functionality. These 12 nsSNPs were selected for protein structure construction, and the DynaMut/DUET servers predicted that the protein variants V7G, L84P, and L99A were the most likely to be damaging to the cofilin-1 protein structure or function. The evaluation of molecular docking studies demonstrated that the L99A and L84P cofilin-1 variants reduce the binding affinity for actin compared with the native cofilin-1 structure, and molecular dynamic simulation studies confirmed that these variants might destabilize the protein structure. The consequences of putative mutations on protein–protein interactions and post-translational modification sites in the cofilin-1 protein structure were analyzed. This study represents the first complete approach to understanding the effects of nsSNPs within the actin-depolymerizing factor/cofilin family, which suggested that SNPs resulting in L84P (rs199716082) and L99A (rs267603119) variants represent significant CFL1 mutations associated with disease development.

Expression Profile of miRs in Mesial Temporal Lobe Epilepsy: Systematic Review.

Temporal lobe epilepsy (TLE) is one of the most common forms of focal epilepsy in children and adults. TLE is characterized by variable onset and seizures. Moreover, this form of epilepsy is often resistant to pharmacotherapy. The search for new mechanisms for the development of TLE may provide us with a key to the development of new diagnostic methods and a personalized approach to the treatment. In recent years, the role of non-coding ribonucleic acids (RNA) has been actively studied, among which microRNA (miR) is of the greatest interest. (1) Background: The purpose of the systematic review is to analyze the studies carried out on the role of miRs in the development of mesial TLE (mTLE) and update the existing knowledge about the biomarkers of this disease. (2) Methods: The search for publications was carried out in the databases PubMed, Springer, Web of Science, Clinicalkeys, Scopus, OxfordPress, Cochrane. The search was carried out using keywords and combinations. We analyzed publications for 2016–2021, including original studies in an animal model of TLE and with the participation of patients with TLE, thematic and systemic reviews, and Cochrane reviews. (3) Results: this thematic review showed that miR‒155, miR‒153, miR‒361‒5p, miR‒4668‒5p, miR‒8071, miR‒197‒5p, miR‒145, miR‒181, miR‒199a, miR‒1183, miR‒129‒2‒3p, miR‒143‒3p (upregulation), miR–134, miR‒0067835, and miR‒153 (downregulation) can be considered as biomarkers of mTLE. However, the roles of miR‒146a, miR‒142, miR‒106b, and miR‒223 are questionable and need further study. (4) Conclusion: In the future, it will be possible to consider previously studied miRs, which have high specificity and sensitivity in mTLE, as prognostic biomarkers (predictors) of the risk of developing this disease in patients with potentially epileptogenic structural damage to the mesial regions of the temporal lobe of the brain (congenital disorders of the neuronal migration and neurogenesis, brain injury, neuro-inflammation, tumor, impaired blood supply, neurodegeneration, etc.).

Pachygyria in a Saudi preteen female: A case report and review of literature

Pachygyria is a component of a spectrum of malformation of cerebral neuronal migration. MRI is a fundamental neuroimaging tool for adequate description of cerebral structural pathology. As a component of lissencephaly-pachygyria spectrum, there are severe intertwined clinical and pathological manifestations, with/without other brain and systemic malformations. Clinical features include protracted seizures, delay or absence of developmental milestones, and varying degrees of mental retardation. This is a case of a preteen with previous infantile seizures and delay in developmental milestones. Her MRI showed uncommon but classic “leopord” and “tigroid” appearances of deep white matter changes, as well as the typical shallow and few cerebral cortical sulci, as well as cortical thickening of pachygyria. Despite several established genetic mutations documented in various disorders of cerebral neural migration, there was however no genetic assay yet for the patient at the time of this publication. Keywords: pachygyria; lissencephaly; neuronal-migration; heterotopia.

Mutations in the COL18A1 gen associated with knobloch syndrome and structural brain anomalies: a novel case report and literature review of neuroimaging findings

ABSTRACT . COL18A1 gene mutations have been associated with Knobloch syndrome, which is characterized by ocular and brain abnormalities. Here we report a 4.5 years-old male child with autism and two novel COL18A1 mutations (NM_030582.4: c.1883_1891dup and c.1787C>T). Hypermetropic astigmatism, but not brain migration disorders, was observed. However, an asymmetric pattern of cerebellar perfusion and a smaller arcuate fascicle were found. Low levels of collagen XVIII were also observed in the patient´s serum. Thus, biallelic loss-of-function mutations in COL18A1 may be a new cause of autism without the brain malformations typically reported in patients with Knobloch syndrome.

Magnetic resonance imaging findings in children with intractable epilepsy compared to children with medical responsive epilepsy

ObjectiveEpilepsy is a common brain disorder characterized by a persistent tendency to develop seizures in neurological, cognitive, and psychological contents. Magnetic Resonance Imaging (MRI ) is a neuroimaging test facilitating the detection of structural epileptogenic lesions. This study aimed to compare the MRI findings between patients with intractable and drug-responsive epilepsy.Material & MethodsThis case-control study was conducted from 2007 to 2019. The research population encompassed all 1-16-year-old patients with intractable epilepsy referred to the Shafa Neuroscience Center (n=72) (a case group) and drug-responsive patients referred to the pediatric neurology clinic of Baqiyatallah Hospital (a control group).ResultsThere were 72 (23.5%) patients in the intractable epilepsy group and 200 (76.5%) patients in the drug-responsive group. The participants’ mean age was 6.70± 4.13 years, and there were 126 males and 106 females in this study. Normal brain MRI was noticed in 21 (29.16%) patients in the case group and 184 (92.46%) patients in the control group.Neuronal migration disorder (NMD) was also exhibited in 7 (9.72%) patients in the case group and no patient in the control group. There were hippocampal abnormalities and focal lesions (mass, dysplasia, etc.) in 10 (13.88%) patients in the case group and only 1 (0.05%) patient in the control group.Gliosis and porencephalic cysts were presented in 3 (4.16%) patients in the case group and no patient in the control group. Cerebral and cerebellar atrophy was revealed in 8 (11.11%) patients in the case group and 4 (2.01%) patients in the control group. Corpus callosum agenesis, hydrocephalus, brain malacia, and developmental cyst were more frequent in the case group; however, the difference between the groups was not significant.ConclusionThe MRI findings such as hippocampal abnormalities, focal lesions (mass, dysplasia), NMD, porencephalic cysts, gliosis, and atrophy are significantly more frequent in children with intractable epilepsy than in those with drug-responsive epilepsy.

Uncommon variants of speech disorder in children: congenital bilateral perisylvian syndrome

This paper describes two cases of congenital bilateral perisylvian syndrome (CBPS), a rare disorder of late neuronal migration, which is characterized by language delay, intellectual disorders, epilepsy and bilateral perisylvian polymicrogyria. Pseudobulbar paralysis and orofacial muscles dyspraxia causing drooling and feeding difficulties are common for patients with CBPS. Communicational problems lead to low self-esteem and social maladaptation. Literature data regarding correlation between polymicrogyria topography and speech disorders and articulation impairment severity are presented. The results demonstrate the association of diffuse spreading of bilateral polymicrogyria and more severe speech disorders comparing to mild speech disorders in patients with more local polymicrogyria. Known etiology factors of this syndrome are bilateral cerebral hypoperfusion, brain damage while neuronal migration period, postmigrational vascular insults and gene mutations. Syndrome can be inherited in autosome dominant and X-linked manner. Speech apraxia with normal impressive speech, refractory epileptic seizures and status dysraphicus must be red flags for a physician regarding this syndrome. Overnight video-EEG monitoring and brain MRI confirm a thesis that this syndrome is underdiagnosed in everyday clinical practice.

The Genetic Landscape of Polymicrogyria.

Polymicrogyria (PMG) is a relatively common complex malformation with cortical development, characterized by an exorbitant number of abnormally tiny gyri separated by shallow sulci. It is a neuronal migration disorder. Familial cases of PMG and the manifestation of PMG in patients with chromosomal aberrations and mutations indicate their important role of genetics in this disorder. The highly stereotyped and well-conserved nature of the cortical folding pattern in humans is suggestive of the genetic regulation of the process. The chromosomal abnormalities observed in PMG include deletions, duplications, chromosomal rearrangements, and aneuploidies. Two of the most common deletions in PMG are 22q11.2 deletion and 1p36 deletion. Further, mutations in several genes such as GPR56, TUBB2B, SRPX2, PAX6, EOMES, WDR62, TUBA8, KIAA1279, and COL18A1 are known to be associated with PMG. Intriguingly, these genes are responsible only for a small number of cases of PMG. The protein products of these genes are implicated in diverse molecular and cellular functions. Taken together, PMG could be the result of the disruption of several biological pathways. Different modes of Mendelian inheritance and non-Mendelian inheritance are seen in PMG. We have suggested a gene panel that can be used for the detection of malformations of cortical development.

Fetal central nervous system anomalies according to RT-PCR and trimester of maternal infection with Zika virus: A prospective cohort study.

In October 2015, an epidemic of Zika began in Colombia's geographic areas with a high population of mosquitoes of the genusAedes. We aimed to describe the fetal brain ultrasound findings in pregnant women with active symptoms or a history of symptoms suggestive of Zika virus (ZIKV) infection. Eligible pregnant women were tested with reverse transcriptase-polymerase chain reaction (RT-PCR) for ZIKV and followed prospectively using detailed anatomic ultrasound and transvaginal neurosonography to detect structural anomalies of the fetal central nervous system (CNS). A total of 115 symptomatic women with a positive ZIKV RT-PCR and 55 with a negative ZIKV RT-PCR were enrolled in the study; CNS compromise of the fetus occurred in 22% and 17%, respectively (p=0.255). Callosal dysgenesis (14.5%) was the most frequent anomaly of the CNS, followed by microcephaly (13.6%) and neuronal migration disorders (8.3%). When symptomatic ZIKV RT-PCR-positive women were categorized by trimester of infection, CNS anomalies were present in 40% of first-trimester infections, compared with 21% and 7% in second- and third-trimester infections (p=0.002). CNS anomalies were also more severe in first-trimester-infected fetuses than in second- and third-trimester-infected fetuses. The high prevalence of CNS anomalies in fetuses of symptomatic ZIKV RT-PCR negative women suggests a high rate of false-negative cases and an even higher prevalence of CNS anomalies than observed in this study. The prevalence of fetal CNS anomalies was higher than previously reported in the literature for both symptomatic RT-PCR-positive and -negative pregnant women. Corpus callosum anomalies, microcephaly, neuronal migration disorders, and brain parenchymal hyperechogenicities were the most frequent CNS anomalies detected. In addition, CNS anomalies were more frequent and severe in infected fetuses during the first trimester of pregnancy than during the second or third trimester.

The neuropathological findings of developmental and epileptic encephalopathy-43 (DEE43) and delineation of a the molecular spectrum of novel case

Developmental and epileptic encephalopathies (DEE) constitute an expanding group of severely disabling and, most frequently, drug-resistant disorders starting in the first year of life. Among them, there is DEE43, caused by dominant mutations in the GABRB3 gene. We present first neuropathological findings in a novel, molecularly confirmed case with the fatal course. The neuropathological analysis revealed co-existing developmental anomalies and retardation of myelination resulting from disturbed early brain growth as well as lesions caused by epileptic hypoxic-ischemic episodes. Developmental anomalies included misplaced neurons in the cerebellar white matter, heterotopic neurons in the cortical molecular layer and in the molecular layer of the hippocampal dentate gyrus, dysmorphic cerebellar dentate nuclei and inferior olivary nuclei in the medulla oblongata. The migrational and maturational disorders leading to the neuronal network dysfunction could be the cause of both the lack of development and the ineffectiveness of antiepileptic treatment in children affected by DEE. Giving the presented neuropathological description and based on the literature, we discuss the pathomechanism of the disease, to improve current understanding of both the lack of development and the ineffectiveness of treatment of affected children.

The prevalence of post-traumatic stress disorder increased in refugees after long-distance migration

Abstract Background Refugees are forced migrants but there is a large variation in the distance that refugees cover. This may importantly affect their health needs. Previous studies suggest an inverse association between long-distance migration and self-rated health in the general population, possibly related to difficulty in acculturation but there is a knowledge gap in the health effects of migration in refugee populations. Here, we estimate the association between long-distance migration and post-traumatic stress disorder (PTSD), a severe mental health disorder associated with deteriorating psychiatric and somatic health and highly prevalent in refugees. Methods Included were 712 adult Syrian refugees and asylum seekers in Lebanon and Denmark arriving no more than 12 months prior to inclusion. The Harvard Trauma Questionnaire was used to assess PTSD and the estimate of association was obtained by multiply imputing missing data and adjusting for confounding by propensity score-weighting with covariates age, sex, socioeconomic status, trauma experience, and WHO-5-score, reporting the bootstrap 95-percentile confidence interval (CI). Additionally, a number of sensitivity analysis were carried out. Results The prevalence of PTSD was high in both Lebanon (55%) and Denmark (60%). After adjusting for biases the prevalence difference increased from 5 percentage point (95-percentile CI [-5; 15] percentage point) to 9 percentage point (95-percentile CI [-1; 19] percentage point). All sensitivity analysis produced estimates of the same direction and magnitude, except when grossly violating the assumption of multiple imputation which halved the magnitude of the association. Conclusions We found that long-distance migration was associated with an increase in the prevalence of PTSD among newly arrived Syrian refugees and asylum-seekers. This is a first step in examining the effects of migration in refugee health. Key messages Long-distance migration was positively associated with prevalence of post-traumatic stress disorder in Syrian refugees. This is a first step to investigate the impact of migration in refugee health.

Electromyography in Congenital Zika Syndrome.

Congenital Zika virus syndrome is a distinct pattern of birth defects in fetuses infected by the Zika virus. It presents a broad clinical spectrum that includes occurrences of microcephaly, hypertonia, dysphagia, hyperexcitability, seizures, and arthrogryposis. Imaging findings show neuronal migration disorders. Case reports have suggested that arthrogryposis has a neurogenic cause. We analyzed needle electromyography and nerve conduction examinations on 77 patients aged 2-24 months presenting highly probable congenital Zika virus syndrome, with or without arthrogryposis. All those with arthrogryposis presented with chronic muscle denervation in the electromyography examination. Similarly, children with single or reversible joint abnormalities at birth showed the same findings. Denervation in the paravertebral musculature was found in all of the children with diaphragmatic paralysis or thoracic deformities. We propose that congenital contractures associated with congenital Zika virus syndrome are caused by the malformation of upper and lower motor neurons during embryogenesis.