Hereditary sensory and autonomic neuropathies: types II, III, and IV

The hereditary sensory and autonomic neuropathies (HSAN) encompass a number of inherited disorders that are associated with sensory dysfunction (depressed reflexes, altered pain and temperature perception) and varying degrees of autonomic dysfunction (gastroesophageal reflux, postural hypotention, excessive sweating). Subsequent to the numerical classification of four distinct forms of HSAN that was proposed by Dyck and Ohta, additional entities continue to be described, so that identification and classification are ongoing. As a group, the HSAN are rare diseases that affect both sexes. HSAN III is almost exclusive to individuals of Eastern European Jewish extraction, with incidence of 1 per 3600 live births. Several hundred cases with HSAN IV have been reported. The worldwide prevalence of HSAN type II is very low. This review focuses on the description of three of the disorders, HSAN II through IV, that are characterized by autosomal recessive inheritance and onset at birth. These three forms of HSAN have been the most intensively studied, especially familial dysautonomia (Riley-Day syndrome or HSAN III), which is often used as a prototype for comparison to the other HSAN. Each HSAN disorder is likely caused by different genetic errors that affect specific aspects of small fiber neurodevelopment, which result in variable phenotypic expression. As genetic tests are routinely used for diagnostic confirmation of HSAN III only, other means of differentiating between the disorders is necessary. Diagnosis is based on the clinical features, the degree of both sensory and autonomic dysfunction, and biochemical evaluations, with pathologic examinations serving to further confirm differences. Treatments for all these disorders are supportive

Defects in tRNA Modification Associated with Neurological and Developmental Dysfunctions in Caenorhabditis elegans Elongator Mutants

Elongator is a six subunit protein complex, conserved from yeast to humans. Mutations in the human Elongator homologue, hELP1, are associated with the neurological disease familial dysautonomia. However, how Elongator functions in metazoans, and how the human mutations affect neural functions is incompletely understood. Here we show that in Caenorhabditis elegans, ELPC-1 and ELPC-3, components of the Elongator complex, are required for the formation of the 5-carbamoylmethyl and 5-methylcarboxymethyl side chains of wobble uridines in tRNA. The lack of these modifications leads to defects in translation in C. elegans. ELPC-1::GFP and ELPC-3::GFP reporters are strongly expressed in a subset of chemosensory neurons required for salt chemotaxis learning. elpc-1 or elpc-3 gene inactivation causes a defect in this process, associated with a posttranscriptional reduction of neuropeptide and a decreased accumulation of acetylcholine in the synaptic cleft. elpc-1 and elpc-3 mutations are synthetic lethal together with those in tuc-1, which is required for thiolation of tRNAs having the 5′methylcarboxymethyl side chain. elpc-1; tuc-1 and elpc-3; tuc-1 double mutants display developmental defects. Our results suggest that, by its effect on tRNA modification, Elongator promotes both neural function and development

Olfactory Stem Cells, a New Cellular Model for Studying Molecular Mechanisms Underlying Familial Dysautonomia

International audienceBackground: Familial dysautonomia (FD) is a hereditary neuropathy caused by mutations in the IKBKAP gene, the most common of which results in variable tissue-specific mRNA splicing with skipping of exon 20. Defective splicing is especially severe in nervous tissue, leading to incomplete development and progressive degeneration of sensory and autonomic neurons. The specificity of neuron loss in FD is poorly understood due to the lack of an appropriate model system. To better understand and modelize the molecular mechanisms of IKBKAP mRNA splicing, we collected human olfactory ecto-mesenchymal stem cells (hOE-MSC) from FD patients. hOE-MSCs have a pluripotent ability to differentiate into various cell lineages, including neurons and glial cells.Methodology/Principal Findings: We confirmed IKBKAP mRNA alternative splicing in FD hOE-MSCs and identified 2 novel spliced isoforms also present in control cells. We observed a significant lower expression of both IKBKAP transcript and IKAP/hELP1 protein in FD cells resulting from the degradation of the transcript isoform skipping exon 20. We localized IKAP/hELP1 in different cell compartments, including the nucleus, which supports multiple roles for that protein. We also investigated cellular pathways altered in FD, at the genome-wide level, and confirmed that cell migration and cytoskeleton reorganization were among the processes altered in FD. Indeed, FD hOE-MSCs exhibit impaired migration compared to control cells. Moreover, we showed that kinetin improved exon 20 inclusion and restores a normal level of IKAP/hELP1 in FD hOE-MSCs. Furthermore, we were able to modify the IKBKAP splicing ratio in FD hOE-MSCs, increasing or reducing the WT (exon 20 inclusion):MU (exon 20 skipping) ratio respectively, either by producing free-floating spheres, or by inducing cells into neural differentiation.Conclusions/Significance: hOE-MSCs isolated from FD patients represent a new approach for modeling FD to better understand genetic expression and possible therapeutic approaches. This model could also be applied to other neurological genetic diseases

Outcomes following small bowel obstruction due to malignancy in the national audit of small bowel obstruction

Introduction Patients with cancer who develop small bowel obstruction are at high risk of malnutrition and morbidity following compromise of gastrointestinal tract continuity. This study aimed to characterise current management and outcomes following malignant small bowel obstruction. Methods A prospective, multicentre cohort study of patients with small bowel obstruction who presented to UK hospitals between 16th January and 13th March 2017. Patients who presented with small bowel obstruction due to primary tumours of the intestine (excluding left-sided colonic tumours) or disseminated intra-abdominal malignancy were included. Outcomes included 30-day mortality and in-hospital complications. Cox-proportional hazards models were used to generate adjusted effects estimates, which are presented as hazard ratios (HR) alongside the corresponding 95% confidence interval (95% CI). The threshold for statistical significance was set at the level of P ≤ 0.05 a-priori. Results 205 patients with malignant small bowel obstruction presented to emergency surgery services during the study period. Of these patients, 50 had obstruction due to right sided colon cancer, 143 due to disseminated intraabdominal malignancy, 10 had primary tumours of the small bowel and 2 patients had gastrointestinal stromal tumours. In total 100 out of 205 patients underwent a surgical intervention for obstruction. 30-day in-hospital mortality rate was 11.3% for those with primary tumours and 19.6% for those with disseminated malignancy. Severe risk of malnutrition was an independent predictor for poor mortality in this cohort (adjusted HR 16.18, 95% CI 1.86 to 140.84, p = 0.012). Patients with right-sided colon cancer had high rates of morbidity. Conclusions Mortality rates were high in patients with disseminated malignancy and in those with right sided colon cancer. Further research should identify optimal management strategy to reduce morbidity for these patient groups

Pedagogia: concepções e práticas em transformação Pedagogy: conceptions and practices in transformation

Este artigo apresenta uma análise das concepções educacionais do curso de Pedagogia voltadas para a formação social do Educador ao longo da história. Neste curso, ainda não existe uma clareza em relação a sua identidade. Os documentos oficiais e algumas entidades representativas priorizam a docência como base de formação, outras priorizam o Pedagogo como cientista da educação. Nas últimas décadas no Brasil, surgiu a Educação Popular, precursora da Pedagogia Social, que aborda o trabalho com os grupos sociais historicamente excluídos e valoriza a diversidade cultural nos processos de Educação Não Formal. Este artigo faz parte de uma pesquisa que analisa os documentos e produções bibliográficas a respeito das Diretrizes Curriculares Nacionais para o Curso de Pedagogia, instituída pela Resolução CNE/CP n. 1 de 15/05/2006. Percebe-se nas produções acadêmicas analisadas, que existem avanços no sentido de uma abordagem mais social no aspecto de formação nos cursos de Pedagogia. Mas, ao mesmo tempo, existem incoerências na base de formação dos profissionais, pois a ênfase na docência restringe sua atuação. Esses estudos revelaram que a Pedagogia tem tornado-se, ainda que superficialmente, mais social e a Educação Popular tem tido a necessidade de organizar o seu trabalho de forma mais pedagógica. Ou seja, a Pedagogia Social tem surgido como instrumento da Educação para atender às novas demandas da sociedade e formar o Educador Social como o seu agente transformador.<br>This article presents an analysis of the educational conceptions of the Pedagogy course dimensioned for Educators social formation through history. In this course their identity isn't clear yet. The official documents and some representative entities consider teaching as priority base for formation, others prioritise the Pedagogy professional an education scientist. In the last decades in Brazil, the Popular Education appeared, precedent of the Social Pedagogy, which approaches the work with social groups historically excluded and values the cultural diversity in the Not-Formal Education process. This article makes part of a research that analyses the documents and bibliography productions about the National Curricular Rule for the Pedagogy Course, instituted by the Resolution CNE/CP n. 1 of 05/15th/2006. It is realized on the academic productions analyzed, that exist advances on the meaning of a more social approach in the aspect of the formation in the Pedagogy's courses. But, at the same time, there are incoherences in the base of the vocational training, because the emphasis on the teaching profession restricts its actuation. Those studies revealed that the Education has become itself, even thought superficially, more social and the Popular Education has had the necessity to organize its work in a more educational way. In other words, the Social Pedagogy has appeared as an instrument of the Education to answer the new demands of the society and to form the Social Educator as its transformer agent

Modulation of aberrant NF1 pre-mRNA splicing by kinetin treatment

Neurofibromatosis type 1 is one of the most common neurocutaneous autosomal dominant disorders. It is caused by mutations in the neurofibromatosis type 1 (NF1) gene and approximately 30–40% of them affect the correct splicing of NF1 pre-mRNA. In this report, we evaluate the effect of five different drugs, previously found to modify splicing in several genetic disorders, on the splicing of mutated NF1 alleles. For this purpose, cell lines derived from patients bearing 19 different NF1-splicing defects were used. Our results showed that kinetin partially corrects the splicing defect in four of the studied mutations (c.910C>T, c.3113G>A, c.6724C>T and c.6791dupA). Our study is a valuable contribution to the field because it identifies new exon-skipping events that can be reversed by kinetin treatment and provides new information about kinetin splicing modulation. However, owing to the nature of mutations in our patients, kinetin treatment could not be used as a therapeutic agent in these cases