title: β-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.
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA. hayflick@ohsu.edu
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Hayflick
authors.forename: Michael C
authors.initials: MC
authors.lastname: Kruer
authors.forename: Allison
authors.initials: A
authors.lastname: Gregory
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.forename: Manju A
authors.initials: MA
authors.lastname: Kurian
authors.forename: Henry H
authors.initials: HH
authors.lastname: Houlden
authors.forename: James
authors.initials: J
authors.lastname: Anderson
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.forename: Lynn
authors.initials: L
authors.lastname: Sanford
authors.forename: Sami I
authors.initials: SI
authors.lastname: Harik
authors.forename: Vasuki H
authors.initials: VH
authors.lastname: Dandu
authors.forename: Nardo
authors.initials: N
authors.lastname: Nardocci
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zorzi
authors.forename: Todd
authors.initials: T
authors.lastname: Dunaway
authors.forename: Mark
authors.initials: M
authors.lastname: Tarnopolsky
authors.forename: Steven
authors.initials: S
authors.lastname: Skinner
authors.forename: Kenton R
authors.initials: KR
authors.lastname: Holden
authors.forename: Steven
authors.initials: S
authors.lastname: Frucht
authors.forename: Era
authors.initials: E
authors.lastname: Hanspal
authors.forename: Connie
authors.initials: C
authors.lastname: Schrander-Stumpel
authors.forename: Cyril
authors.initials: C
authors.lastname: Mignot
authors.forename: Delphine
authors.initials: D
authors.lastname: Héron
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Saunders
authors.forename: Margaret
authors.initials: M
authors.lastname: Kaminska
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Lin
authors.forename: Karine
authors.initials: K
authors.lastname: Lascelles
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Cuno
authors.forename: Esther
authors.initials: E
authors.lastname: Meyer
authors.forename: Barbara
authors.initials: B
authors.lastname: Garavaglia
authors.forename: Kailash
authors.initials: K
authors.lastname: Bhatia
authors.forename: Rajith
authors.initials: R
authors.lastname: de Silva
authors.forename: Sarah
authors.initials: S
authors.lastname: Crisp
authors.forename: Peter
authors.initials: P
authors.lastname: Lunt
authors.forename: Martyn
authors.initials: M
authors.lastname: Carey
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.forename: Penelope
authors.initials: P
authors.lastname: Hogarth
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; C578284:WDR45 protein, human; D007501:Iron
keywords: NBIA; Rett syndrome; autophagy; basal ganglia; iron