HCV and HIV co-infection in pregnant women attending St. Camille Medical Centre in Ouagadougou (Burkina Faso)

Five hundred and forty-seven pregnant women with less than 32 weeks of amenorrhoea, attending an antenatal clinic of St. Camille Medical Centre (SCMC) of Ouagadougou were enrolled for a hepatitis C virus (HCV) and HIV co-infection study. Fifty-eight (10.6%) were HIV positive and 18 (3.3%) were anti-HCV positive. Only seven pregnant women (i.e., 1.3%) had a documented HIV and HCV co-infection. HCV-RNA was found in 5 out of 18 (27.8%) patients, who had anti-HCV antibodies. The genotype analysis of these five patients showed that two were of 1b whereas three were of 2a genotype. Mother-to-infant transmission of the same HCV genotype (2a) was documented in only one case. High 1b prevalence has been reported in other parts of Africa, while 2a is the prevalent genotype (60%) in Burkina Faso. This genotype has a higher response rate to treatment. Serum transaminases were normal, also in presence of HCV-RNA. The higher than expected rate of co-infection in Burkina Faso seems to demonstrate a correlation between these two infections, which could influence the evolution of HIV and HCV diseases

Developmental anomalies of the medial septal area. possible implication for limbic epileptogenesis

The maldevelopment of the midline structures is connected with neurologic disorders. The cavum septum pellucidum (CSP) exists in the fetal period, then it is re-absorbed. The presence of unfused leaflets/fornices may be considered important in the genesis of neurodevelopmental abnormalities inclunding epilepsy. The limbic system includes a group of interconnected gray and white matter structures; in this circuit, the fornix is an important white matter connection with the septum pellucidum. Five children, 3-10 years of age, with epilepsy and an unfused septum pellucidum and fornices on MRI, were evaluated by diffusion tensor imaging-fiber tracking (DTI-FT) in order to explore the integrity of the axonal microenviroment of these structures. The patients had generalized tonic-clonic seizures (GTCS). The electroencephalogram (EEG) showed focal-temporal abnormalities with secondary generalization. Magnetic resonance imaging (MRI) and DTI-FT demonstrated the CSP, and the presence of the fornix's body split into two bundles with the fornices separated. The fornix appears more involved than CSP alone, as suggested by fornix atrophy observed in MTLE. Even if epilepsy is suggested to be a grey matter disorder, changes in the underlying brain connectivity have an important contribution in seizure generation and diffusion. In addition, the interconnections of medial septal area with hyppocampus, amygdala and entorhinal cortex, have led to the hypothesis of functional limbic epilepsy. In our patients, the role of DTI was not conclusive since the definition of the number of unmyelinated fibers responsible for epilepsy could not be demonstrated probably for a limited number of seizures and for a short period of drug administration

An interstitial 17q11.2 de novo deletion involving the CDK5R1 gene in a high-functioning autistic patient

We describe a 32-year-old male patient diagnosed with high-functioning autism spectrum disorder carrying a de novo 196-kb interstitial deletion at chromosome 17q11.2. The deletion was detected by array CGH (180K Agilent) and confirmed by quantitative PCR on genomic DNA. The deleted region spans the entire PSMD11 and CDK5R1 genes and partially the MYO1D gene. The CDK5R1 gene encodes for a regulatory subunit of the cyclin-dependent kinase 5 responsible for its brain-specific activation. This gene has been previously associated with intellectual disability in humans. A reduction in CDK5R1 transcript was detected, consistent with the genomic deletion. Based on the functional role of CDK5R1 , this gene appears as the best candidate to explain the clinical phenotype of our patient, whose neuropsychological profile has more resemblance with some of the higher brain function anomalies recently described in the CreERp35 conditional knockout mouse model than previously described patients with intellectual disability

The genetics of monogenic idiopathic epilepsies and epileptic encephalopathies

The group of idiopathic epilepsies encompasses numerous syndromes without known organic substrate. Genetic anomalies are thought to be responsible for pathogenesis, with a monogenic or polygenic model of inheritance. Over the last two decades, a number of genetic anomalies and encoded proteins have been related to particular idiopathic epilepsies and epileptic encephalopathies. Most of these mutations involve subunits of neuronal ion channels (e.g. potassium, sodium, and chloride channels), and may result in abnormal neuronal hyperexcitability manifesting with seizures. However non-ion channel proteins may also be affected. Correlations between genotype and phenotype are not easy to establish, since genetic and non-genetic factors are likely to play a role in determining the severity of clinical features. The growing number of discoveries on this topic are improving classification, prognosis and counseling of patients and families with these forms of epilepsy, and may lead to targeted therapeutic approaches in the near future. In this article the authors have reviewed the main genetic discoveries in the field of the monogenic idiopathic epilepsies and epileptic encephalopathies, in order to provide epileptologists with a concise and comprehensive summary of clinical and genetic features of these seizure disorders. (C) 2011 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved

RNA sequencing of blood from sex- and age-matched discordant siblings supports immune and transcriptional dysregulation in autism spectrum disorder

Abstract Autism spectrum disorder (ASD) is a neurodevelopmental condition with onset in early childhood, still diagnosed only through clinical observation due to the lack of laboratory biomarkers. Early detection strategies would be especially useful in screening high-risk newborn siblings of children already diagnosed with ASD. We performed RNA sequencing on peripheral blood, comparing 27 pairs of ASD children vs their sex- and age-matched unaffected siblings. Differential gene expression profiling, performed applying an unpaired model found two immune genes, EGR1 and IGKV3D-15, significantly upregulated in ASD patients (both p adj = 0.037). Weighted gene correlation network analysis identified 18 co-expressed modules. One of these modules was downregulated among autistic individuals (p = 0.035) and a ROC curve using its eigengene values yielded an AUC of 0.62. Genes in this module are primarily involved in transcriptional control and its hub gene, RACK1, encodes for a signaling protein critical for neurodevelopment and innate immunity, whose expression is influenced by various hormones and known "endocrine disruptors". These results indicate that transcriptomic biomarkers can contribute to the sensitivity of an intra-familial multimarker panel for ASD and provide further evidence that neurodevelopment, innate immunity and transcriptional regulation are key to ASD pathogenesis

Diagnostic yield and clinical impact of chromosomal microarray analysis in autism spectrum disorder

Abstract Background Autism spectrum disorder (ASD) is characterized by high heritability estimates and recurrence rates; its genetic underpinnings are very heterogeneous and include variable combinations of common and rare variants. Array‐comparative genomic hybridization (aCGH) offers significant sensitivity for the identification of copy number variants (CNVs), which can act as susceptibility or causal factors for ASD. Methods The aim of this study was to evaluate both diagnostic yield and clinical impact of aCGH in 329 ASD patients of Italian descent. Results Pathogenic/likely pathogenic CNVs were identified in 50/329 (15.2%) patients, whereas 89/329 (27.1%) carry variants of uncertain significance. The 10 most enriched gene sets identified by Gene Ontology Enrichment Analysis are primarily involved in neuronal function and synaptic connectivity. In 13/50 (26.0%) patients with pathogenic/likely pathogenic CNVs, the outcome of array‐CGH led to the request of 25 additional medical exams which would not have otherwise been prescribed, mainly including brain MRI, EEG, EKG, and/or cardiac ultrasound. A positive outcome was obtained in 12/25 (48.0%) of these additional tests. Conclusions This study confirms the satisfactory diagnostic yield of aCGH, underscoring its potential for better, more in‐depth care of children with autism when genetic results are analyzed also with a focus on patient management

Young Human Cholinergic Neurons Respond to Physiological Regulators and Improve Cognitive Symptoms in an Animal Model of Alzheimer’s Disease

The degeneration of cholinergic neurons of the nucleus basalis of Meynert (NBM) in the basal forebrain (BF) is associated to the cognitive decline of Alzheimer’s disease (AD) patients. To date no resolutive therapies exist. Cell-based replacement therapy is a strategy currently under consideration, although the mechanisms underlying the generation of stem cell-derived NBM cholinergic neurons able of functional integration remain to be clarified. Since fetal brain is an optimal source of neuronal cells committed towards a specific phenotype, this study is aimed at isolating cholinergic neurons from the human fetal NBM (hfNBMs) in order to study their phenotypic, maturational and functional properties. Extensive characterization confirmed the cholinergic identity of hfNBMs, including positivity for specific markers (such as choline acetyltransferase) and acetylcholine (Ach) release. Electrophysiological measurements provided the functional validation of hfNBM cells, which exhibited the activation of peculiar sodium (INa) and potassium (IK) currents, as well as the presence of functional cholinergic receptors. Accordingly, hfNBMs express both nicotinic and muscarinic receptors, which were activated by Ach. The hfNBMs cholinergic phenotype was regulated by the nerve growth factor (NGF), through the activation of the high-affinity NGF receptor TrkA, as well as by 17-β-estradiol through a peculiar recruitment of its own receptors. When intravenously administered in NBM-lesioned rats, hfNBMs determined a significant improvement in memory functions. Histological examination of brain sections showed that hfNBMs (labeled with PKH26 fluorescent dye prior to administration) reached the damaged brain areas. The study provides a useful model to study the ontogenetic mechanisms regulating the development and maintenance of the human brain cholinergic system and to assess new lines of research, including disease modeling, drug discovery and cell-based therapy for AD

FARP‐1 deletion is associated with lack of response to autism treatment by early start denver model in a multiplex family

Abstract Background Children with autism spectrum disorder (ASD) display impressive clinical heterogeneity, also involving treatment response. Genetic variants can contribute to explain this large interindividual phenotypic variability. Methods Array‐CGH (a‐CGH) and whole genome sequencing (WGS) were performed on a multiplex family with two small children diagnosed with ASD at 17 and 18 months of age. Both brothers received the same naturalistic intervention for one year according to the Early Start Denver Model (ESDM), applied by the same therapists, yielding dramatically different treatment outcomes. Results The older sibling came out of the autism spectrum, while the younger sibling displayed very little, in any, improvement. This boy was subsequently treated applying a structured Early Intensive Behavioral Intervention paired with Augmentative Alternative Communication, which yielded a partial response within another year. The ESDM nonresponsive child carries a novel maternally inherited 65 Kb deletion at chr. 13q32.2 spanning FARP1. Farp1 is a synaptic scaffolding protein, which plays a significant role in neural plasticity. Conclusion These results represent a paradigmatic example of the heuristic potential of genetic markers in predicting treatment response and possibly in supporting the targeted prescription of specific early intervention approaches