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      New Findings in a Global Approach to Dissect the Whole Phenotype of PLA2G6 Gene Mutations


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          Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients’ muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.

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          Functional Neuroanatomy of the Noradrenergic Locus Coeruleus: Its Roles in the Regulation of Arousal and Autonomic Function Part II: Physiological and Pharmacological Manipulations and Pathological Alterations of Locus Coeruleus Activity in Humans

          The locus coeruleus (LC), the major noradrenergic nucleus of the brain, gives rise to fibres innervating most structures of the neuraxis. Recent advances in neuroscience have helped to unravel the neuronal circuitry controlling a number of physiological functions in which the LC plays a central role. Two such functions are the regulation of arousal and autonomic activity, which are inseparably linked largely via the involvement of the LC. Alterations in LC activity due to physiological or pharmacological manipulations or pathological processes can lead to distinct patterns of change in arousal and autonomic function. Physiological manipulations considered here include the presentation of noxious or anxiety-provoking stimuli and extremes in ambient temperature. The modification of LC-controlled functions by drug administration is discussed in detail, including drugs which directly modify the activity of LC neurones (e.g., via autoreceptors, storage, reuptake) or have an indirect effect through modulating excitatory or inhibitory inputs. The early vulnerability of the LC to the ageing process and to neurodegenerative disease (Parkinson’s and Alzheimer’s diseases) is of considerable clinical significance. In general, physiological manipulations and the administration of stimulant drugs, α2-adrenoceptor antagonists and noradrenaline uptake inhibitors increase LC activity and thus cause heightened arousal and activation of the sympathetic nervous system. In contrast, the administration of sedative drugs, including α2-adrenoceptor agonists, and pathological changes in LC function in neurodegenerative disorders and ageing reduce LC activity and result in sedation and activation of the parasympathetic nervous system.
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            PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron.

            Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis.
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              Clinical and genetic delineation of neurodegeneration with brain iron accumulation.

              Neurodegeneration with brain iron accumulation (NBIA) describes a group of progressive neurodegenerative disorders characterised by high brain iron and the presence of axonal spheroids, usually limited to the central nervous system. Mutations in the PANK2 gene account for the majority of NBIA cases and cause an autosomal recessive inborn error of coenzyme A metabolism called pantothenate kinase associated neurodegeneration (PKAN). More recently, it was found that mutations in the PLA2G6 gene cause both infantile neuroaxonal dystrophy (INAD) and, more rarely, an atypical neuroaxonal dystrophy that overlaps clinically with other forms of NBIA. High brain iron is also present in a portion of these cases. Clinical assessment, neuroimaging, and molecular genetic testing all play a role in guiding the diagnostic evaluation and treatment of NBIA.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                9 October 2013
                : 8
                : 10
                : e76831
                [1 ]Division of Pediatric Neurology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
                [2 ]Institut du Cerveau et de la Moelle épinière (ICM), Genotyping and Sequencing Facility, Groupe Hospitalier Pitié-Salpêtrière (GHPS), Paris, France
                [3 ]Division of Paediatrics Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
                [4 ]Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
                [5 ]Department of Radiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
                [6 ]Department of Medical Genetics, King Faisal specialist Hospital & Research Centre, Riyadh, Saudi Arabia
                [7 ]Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
                [8 ]Institut für Neuropathologie, Universitätsklinikum der RWTH, Aachen, Germany
                [9 ]Department of Neurosciences, Armed Forces Hospital, Riyadh, Saudi Arabia
                [10 ]Department of Medical Genetics, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
                [11 ]Radboud University Medical Center, Nijmegen Center for Mitochondrial Disorders, Department of Pediatrics, Department of Laboratory Medicine, 774 Laboratory for Genetic, Endocrine and Metabolic disorders (LGEM), Nijmegen, The Netherlands
                [12 ]Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
                [13 ]Neurology Division, Cooper University Hospital, Camden, New Jersey, USA
                [14 ]Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)/ Institut National de la Santé et de la Recherche Médicale, (INSERM)/Université de Strasbourg, et Collège de, France, Illkirch, France
                [15 ]École Pratique des Hautes Etudes (EPHE), Paris, France
                [16 ]INSERM-U975, Paris, France
                [17 ]CNRS-UMR ( Unité mixte de Recherche, ) 7225, Paris, France
                [18 ]Université Pierre et Marie Curie, – Paris 6, (UMR-S)_975, Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, (cricm), Groupe Hospitalier Pitié-Salpêtrière, (GHPS), Paris, France
                [19 ]Assistance Publique des Hôpitaux de Paris, (APHP), département de Génétique et Cytogénétique, , GHPS, Paris, France
                Instituto de Ciencia de Materiales de Madrid - Instituto de Biomedicina de Valencia, Spain
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MAMS GS H. Azzedine. Performed the experiments: MAMS EM AOK AAD SAE HHH MAO HMSA IK MMK AYK H. Alzaidan RJR TMB JW. Analyzed the data: MAMS EM AOK AAD SAE HHH MAO HMSA IK MMK RC AYK H. Alzaidan RJR TMB JW MK GS H. Azzedine. Wrote the manuscript: MAMS H. Azzedine. Revision of the manuscript and approved the final version to be published: MAMS EM AOK AAD SAE HHH MAO HMSA IK MMK RC AYK H. Alzaidan RJR TMB JW MK GS H. Azzedine. Conception, design and coordination of the study: MAMS H. Azzedine.

                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                : 11 May 2013
                : 29 August 2013
                MAM and co-authors are thankful to the Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia, for supporting the work through the research group project number RGP-VPP. RC was supported by the Gebert Rüf Foundation (grant number GRS-046/09). GS was supported by the French National Agency for Research(ANR), Association Contre les Syndromes Cérébelleux, France, The Verum Foundation, the European Union (Omics call, "Neuromics"), The Fondation Roger de Spoelberch and the program "Investissements d'avenir" ANR-10-IAIHU-06 (to the Brain and Spine Institute). HA was supported by Association Française contre les Myopathies (AFM), France. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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