@article{c625bbe69c1b42c887cf772834db7449,
title = "Beta-propeller protein-associated neurodegeneration: A new X-linked dominant disorder with brain iron accumulation",
abstract = "Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a 'halo' of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.",
keywords = "NBIA, Rett syndrome, autophagy, basal ganglia, iron",
author = "Hayflick, {Susan J.} and Kruer, {Michael C.} and Allison Gregory and Haack, {Tobias B.} and Kurian, {Manju A.} and Houlden, {Henry H.} and James Anderson and Nathalie Boddaert and Lynn Sanford and Harik, {Sami I.} and Dandu, {Vasuki H.} and Nardo Nardocci and Giovanna Zorzi and Todd Dunaway and Mark Tarnopolsky and Steven Skinner and Holden, {Kenton R.} and Steven Frucht and Era Hanspal and Connie Schrander-Stumpel and Cyril Mignot and Delphine H{\'e}ron and Saunders, {Dawn E.} and Margaret Kaminska and Lin, {Jean Pierre} and Karine Lascelles and Cuno, {Stephan M.} and Esther Meyer and Barbara Garavaglia and Kailash Bhatia and {De Silva}, Rajith and Sarah Crisp and Peter Lunt and Martyn Carey and John Hardy and Thomas Meitinger and Holger Prokisch and Penelope Hogarth",
note = "Funding Information: This work was supported by our advocacy partners: the NBIA Disorders Association; Hoffnungsbaum e.V.; and Associazione Italiana Sindromi Neurodegenerative da Accumulo di Ferro. This work was made possible with support from the Oregon Clinical and Translational Research Institute (UL1 RR024140 NCRR), a component of the NIH and NIH Roadmap for Medical Research. P.H., N.N., T.M., H.P. and S.J.H. participate in the TIRCON consortium (European Commission Seventh Framework Programme-FP7/2007-2013, HEALTH-F2-2011, Grant Agreement #277984). M.C.K. receives support from American Academy of Neurology, Dystonia Medical Research Foundation, Child Neurology Foundation and American Philosophical Society. M.A.K.{\textquoteright}s research is supported by Great Ormond Street Children{\textquoteright}s Charities, Action Medical Research and the Wellcome Trust. T.M. and H.P. were supported by German Federal Ministry of Education and Research (BMBF)-funded Systems Biology of Metabotypes grant (SysMBo 0315494A) and German Network for Mitochondrial Disorders (mitoNET 01GM0867). T.M. was supported by European Commission 7th Framework Program (N. 261123), Genetic European Variation in Disease Consortium, and German Ministry for Education and Research (01GR0804-4). Funding Information: We gratefully acknowledge the support and participation world-wide of families with NBIA, who inspire us every day through their dedication and partnership via the NBIA Disorders Association, Hoffnungsbaum e.V., and Associazione Italiana Sindromi Neurodegenerative da Accumulo di Ferro. We thank Evelyn Botz and Carola Fischer for technical support, the Cell line and DNA bank of paediatric movement disorders of the Telethon Genetic Biobank Network (GTB07001), the UK Parkinson{\textquoteright}s Disease Consortium, UCL/Institute of Neurology, University of Sheffield and University of Dundee, the Medical Research Council, the Parkinson{\textquoteright}s Disease Foundation, the Dystonia Medical Research Foundation and the Brain Research Trust.",
year = "2013",
month = jun,
doi = "10.1093/brain/awt095",
language = "English (US)",
volume = "136",
pages = "1708--1717",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "6",
}