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      Dystonia in neurodegeneration with brain iron accumulation: outcome of bilateral pallidal stimulation


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          Neurodegeneration with brain iron accumulation encompasses a heterogeneous group of rare neurodegenerative disorders that are characterized by iron accumulation in the brain. Severe generalized dystonia is frequently a prominent symptom and can be very disabling, causing gait impairment, difficulty with speech and swallowing, pain and respiratory distress. Several case reports and one case series have been published concerning therapeutic outcome of pallidal deep brain stimulation in dystonia caused by neurodegeneration with brain iron degeneration, reporting mostly favourable outcomes. However, with case studies, there may be a reporting bias towards favourable outcome. Thus, we undertook this multi-centre retrospective study to gather worldwide experiences with bilateral pallidal deep brain stimulation in patients with neurodegeneration with brain iron accumulation. A total of 16 centres contributed 23 patients with confirmed neurodegeneration with brain iron accumulation and bilateral pallidal deep brain stimulation. Patient details including gender, age at onset, age at operation, genetic status, magnetic resonance imaging status, history and clinical findings were requested. Data on severity of dystonia (Burke Fahn Marsden Dystonia Rating Scale—Motor Scale, Barry Albright Dystonia Scale), disability (Burke Fahn Marsden Dystonia Rating Scale—Disability Scale), quality of life (subjective global rating from 1 to 10 obtained retrospectively from patient and caregiver) as well as data on supportive therapy, concurrent pharmacotherapy, stimulation settings, adverse events and side effects were collected. Data were collected once preoperatively and at 2–6 and 9–15 months postoperatively. The primary outcome measure was change in severity of dystonia. The mean improvement in severity of dystonia was 28.5% at 2–6 months and 25.7% at 9–15 months. At 9–15 months postoperatively, 66.7% of patients showed an improvement of 20% or more in severity of dystonia, and 31.3% showed an improvement of 20% or more in disability. Global quality of life ratings showed a median improvement of 83.3% at 9–15 months. Severity of dystonia preoperatively and disease duration predicted improvement in severity of dystonia at 2–6 months; this failed to reach significance at 9–15 months. The study confirms that dystonia in neurodegeneration with brain iron accumulation improves with bilateral pallidal deep brain stimulation, although this improvement is not as great as the benefit reported in patients with primary generalized dystonias or some other secondary dystonias. The patients with more severe dystonia seem to benefit more. A well-controlled, multi-centre prospective study is necessary to enable evidence-based therapeutic decisions and better predict therapeutic outcomes.

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          Most cited references31

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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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            Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease.

            We describe here a previously unknown, dominantly inherited, late-onset basal ganglia disease, variably presenting with extrapyramidal features similar to those of Huntington's disease (HD) or parkinsonism. We mapped the disorder, by linkage analysis, to 19q13.3, which contains the gene for ferritin light polypeptide (FTL). We found an adenine insertion at position 460-461 that is predicted to alter carboxy-terminal residues of the gene product. Brain histochemistry disclosed abnormal aggregates of ferritin and iron. Low serum ferritin levels also characterized patients. Ferritin, the main iron storage protein, is composed of 24 subunits of two types (heavy, H and light, L) which form a soluble, hollow sphere. Brain iron deposition increases normally with age, especially in the basal ganglia, and is a suspected causative factor in several neurodegenerative diseases in which it correlates with visible pathology, possibly by its involvement in toxic free-radical reactions. We found the same mutation in five apparently unrelated subjects with similar extrapyramidal symptoms. An abnormality in ferritin strongly indicates a primary function for iron in the pathogenesis of this new disease, for which we propose the name 'neuroferritinopathy'.
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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

                Oxford University Press
                March 2010
                5 March 2010
                5 March 2010
                : 133
                : 3
                : 701-712
                1 Department of Neurology, Uniklinik Köln, University of Cologne, Cologne, Germany
                2 Department of Neurology, Charles University in Prague, First Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic
                3 Department of Paediatric Neurology, University Children's Hospital, Muenster, Germany
                4 Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
                5 Institute of Neurosciences, Frenchay Hospital, Bristol, UK
                6 Hôpital des Enfants, Geneve, Switzerland
                7 Oregon Health and Science University, Portland, OR, USA
                8 Department of Neurology, University Medical Centre Groningen, Groningen, Netherlands
                9 Unit of Functional Neurosurgery, Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, UK
                10 Department of Neurology, Division of Child Neurology, University of North Carolina at Chapel Hill, NC, USA
                11 Division of Neurology, Toronto Western Hospital, University of Toronto, Toronto, Canada
                12 Department of Neurology, University of California San Francisco, San Francisco, CA, USA
                13 Department of Neurology, Movement Disorders Centre, University of Cincinnati, Cincinnati, OH, USA
                14 Department of Neurology, Ghent University Hospital, Ghent, Belgium
                15 Institute of Clinical Neuroscience and Medical Psychology, Department of Neurology, Heinrich Heine University, Düsseldorf, Germany
                16 Hospital Clinic, Institut de Neurociencies Universitat de Barcelona, Barcelona, Spain
                17 Functional Neurosurgery, Department of Neurosurgery, Heinrich Heine University, Düsseldorf, Germany
                18 Department of Neurology, Christian-Albrechts-University, Kiel, Germany
                19 Department of Neurology, St. Josef Hospital, Ruhr University, Bochum, Germany
                20 Department of Neurosurgery, Hospital for Neurological Sciences, Acibadem University School of Medicine, Istanbul, Turkey
                Author notes
                Correspondence to: Prof. Dr Lars Timmermann, Klinik und Poliklinik für Neurologie, Uniklinik Köln, Kerpener Str. 62, 50924 Köln, Germany E-mail: lars.timmermann@ 123456uk-koeln.de Correspondence may also be addressed to: Dr Amande Pauls. E-mail: amande.pauls@ 123456uk-koeln.de

                *These authors contributed equally to this work.

                © The Author(s) 2010. Published by Oxford University Press on behalf of Brain.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 14 October 2009
                : 18 December 2009
                : 18 January 2010
                Original Articles

                globus pallidus,deep brain stimulation,neurodegeneration with brain iron accumulation,dystonia


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