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000140899 041__ $$aEnglish
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000140899 1001_ $$0P:(DE-2719)2811827$$aRattay, Tim W$$b0$$eFirst author$$udzne
000140899 245__ $$aFAHN/SPG35: a narrow phenotypic spectrum across disease classifications.
000140899 260__ $$aOxford$$bOxford Univ. Press$$c2019
000140899 264_1 $$2Crossref$$3online$$bOxford University Press (OUP)$$c2019-04-26
000140899 264_1 $$2Crossref$$3print$$bOxford University Press (OUP)$$c2019-06-01
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000140899 520__ $$aThe endoplasmic reticulum enzyme fatty acid 2-hydroxylase (FA2H) plays a major role in the formation of 2-hydroxy glycosphingolipids, main components of myelin. FA2H deficiency in mice leads to severe central demyelination and axon loss. In humans it has been associated with phenotypes from the neurodegeneration with brain iron accumulation (fatty acid hydroxylase-associated neurodegeneration, FAHN), hereditary spastic paraplegia (HSP type SPG35) and leukodystrophy (leukodystrophy with spasticity and dystonia) spectrum. We performed an in-depth clinical and retrospective neurophysiological and imaging study in a cohort of 19 cases with biallelic FA2H mutations. FAHN/SPG35 manifests with early childhood onset predominantly lower limb spastic tetraparesis and truncal instability, dysarthria, dysphagia, cerebellar ataxia, and cognitive deficits, often accompanied by exotropia and movement disorders. The disease is rapidly progressive with loss of ambulation after a median of 7 years after disease onset and demonstrates little interindividual variability. The hair of FAHN/SPG35 patients shows a bristle-like appearance; scanning electron microscopy of patient hair shafts reveals deformities (longitudinal grooves) as well as plaque-like adhesions to the hair, likely caused by an abnormal sebum composition also described in a mouse model of FA2H deficiency. Characteristic imaging features of FAHN/SPG35 can be summarized by the 'WHAT' acronym: white matter changes, hypointensity of the globus pallidus, ponto-cerebellar atrophy, and thin corpus callosum. At least three of four imaging features are present in 85% of FA2H mutation carriers. Here, we report the first systematic, large cohort study in FAHN/SPG35 and determine the phenotypic spectrum, define the disease course and identify clinical and imaging biomarkers.
000140899 536__ $$0G:(DE-HGF)POF3-345$$a345 - Population Studies and Genetics (POF3-345)$$cPOF3-345$$fPOF III$$x0
000140899 536__ $$0G:(DE-HGF)POF3-344$$a344 - Clinical and Health Care Research (POF3-344)$$cPOF3-344$$fPOF III$$x1
000140899 542__ $$2Crossref$$i2019-04-27$$uhttps://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model
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000140899 650_2 $$2MeSH$$aChild
000140899 650_2 $$2MeSH$$aCohort Studies
000140899 650_2 $$2MeSH$$aDemyelinating Diseases: genetics
000140899 650_2 $$2MeSH$$aFemale
000140899 650_2 $$2MeSH$$aHeredodegenerative Disorders, Nervous System: genetics
000140899 650_2 $$2MeSH$$aHumans
000140899 650_2 $$2MeSH$$aMale
000140899 650_2 $$2MeSH$$aMixed Function Oxygenases: genetics
000140899 650_2 $$2MeSH$$aMutation: genetics
000140899 650_2 $$2MeSH$$aPedigree
000140899 650_2 $$2MeSH$$aPhenotype
000140899 650_2 $$2MeSH$$aRetrospective Studies
000140899 650_2 $$2MeSH$$aSpastic Paraplegia, Hereditary: classification
000140899 650_2 $$2MeSH$$aSpastic Paraplegia, Hereditary: genetics
000140899 7001_ $$0P:(DE-HGF)0$$aLindig, Tobias$$b1
000140899 7001_ $$aBaets, Jonathan$$b2
000140899 7001_ $$aSmets, Katrien$$b3
000140899 7001_ $$aDeconinck, Tine$$b4
000140899 7001_ $$aSöhn, Anne S$$b5
000140899 7001_ $$aHörtnagel, Konstanze$$b6
000140899 7001_ $$0P:(DE-2719)9000953$$aEckstein, Kathrin N$$b7$$udzne
000140899 7001_ $$0P:(DE-2719)2814026$$aWiethoff, Sarah$$b8$$udzne
000140899 7001_ $$0P:(DE-HGF)0$$aReichbauer, Jennifer$$b9
000140899 7001_ $$0P:(DE-HGF)0$$aDöbler-Neumann, Marion$$b10
000140899 7001_ $$0P:(DE-HGF)0$$aKrägeloh-Mann, Ingeborg$$b11
000140899 7001_ $$aAuer-Grumbach, Michaela$$b12
000140899 7001_ $$aPlecko, Barbara$$b13
000140899 7001_ $$aMünchau, Alexander$$b14
000140899 7001_ $$aWilken, Bernd$$b15
000140899 7001_ $$aJanauschek, Marc$$b16
000140899 7001_ $$aGiese, Anne-Katrin$$b17
000140899 7001_ $$aDe Bleecker, Jan L$$b18
000140899 7001_ $$aOrtibus, Els$$b19
000140899 7001_ $$aDebyser, Martine$$b20
000140899 7001_ $$aLopez de Munain, Adolfo$$b21
000140899 7001_ $$aPujol, Aurora$$b22
000140899 7001_ $$aBassi, Maria Teresa$$b23
000140899 7001_ $$aD'Angelo, Maria Grazia$$b24
000140899 7001_ $$aDe Jonghe, Peter$$b25
000140899 7001_ $$aZüchner, Stephan$$b26
000140899 7001_ $$aBauer, Peter$$b27
000140899 7001_ $$0P:(DE-2719)2810795$$aSchöls, Ludger$$b28$$udzne
000140899 7001_ $$0P:(DE-2719)2812018$$aSchüle, Rebecca$$b29$$eLast author$$udzne
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000140899 773__ $$0PERI:(DE-600)1474117-9$$a10.1093/brain/awz102$$gVol. 142, no. 6, p. 1561 - 1572$$n6$$p1561-1572$$q142:6<1561 - 1572$$tBrain$$v142$$x0006-8950$$y2019
000140899 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536916
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