TY  - JOUR
AU  - Rattay, Tim W
AU  - Lindig, Tobias
AU  - Baets, Jonathan
AU  - Smets, Katrien
AU  - Deconinck, Tine
AU  - Söhn, Anne S
AU  - Hörtnagel, Konstanze
AU  - Eckstein, Kathrin N
AU  - Wiethoff, Sarah
AU  - Reichbauer, Jennifer
AU  - Döbler-Neumann, Marion
AU  - Krägeloh-Mann, Ingeborg
AU  - Auer-Grumbach, Michaela
AU  - Plecko, Barbara
AU  - Münchau, Alexander
AU  - Wilken, Bernd
AU  - Janauschek, Marc
AU  - Giese, Anne-Katrin
AU  - De Bleecker, Jan L
AU  - Ortibus, Els
AU  - Debyser, Martine
AU  - Lopez de Munain, Adolfo
AU  - Pujol, Aurora
AU  - Bassi, Maria Teresa
AU  - D'Angelo, Maria Grazia
AU  - De Jonghe, Peter
AU  - Züchner, Stephan
AU  - Bauer, Peter
AU  - Schöls, Ludger
AU  - Schüle, Rebecca
TI  - FAHN/SPG35: a narrow phenotypic spectrum across disease classifications.
JO  - Brain
VL  - 142
IS  - 6
SN  - 0006-8950
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2020-07221
SP  - 1561-1572
PY  - 2019
AB  - The 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
KW  - Child
KW  - Cohort Studies
KW  - Demyelinating Diseases: genetics
KW  - Female
KW  - Heredodegenerative Disorders, Nervous System: genetics
KW  - Humans
KW  - Male
KW  - Mixed Function Oxygenases: genetics
KW  - Mutation: genetics
KW  - Pedigree
KW  - Phenotype
KW  - Retrospective Studies
KW  - Spastic Paraplegia, Hereditary: classification
KW  - Spastic Paraplegia, Hereditary: genetics
LB  - PUB:(DE-HGF)16
C6  - pmid:31135052
C2  - pmc:PMC6536916
DO  - DOI:10.1093/brain/awz102
UR  - https://pub.dzne.de/record/140899
ER  -