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| Brain : a journal of neurology. pii: 5480427. doi: 10.1093/brain/awz102 |
| FAHN/SPG35: a narrow phenotypic spectrum across disease classifications. |
| Rattay TW1, Lindig T2, Baets J3, Smets K4, Deconinck T5, Söhn AS6, Hörtnagel K7, Eckstein KN8, Wiethoff S9, Reichbauer J10, Döbler-Neumann M11, Krägeloh-Mann I12, Auer-Grumbach M13, Plecko B14, Münchau A15, Wilken B16, Janauschek M17, Giese AK18, De Bleecker JL19, Ortibus E20, Debyser M21, Lopez de Munain A22, Pujol A23, Bassi MT24, D'Angelo MG25, De Jonghe P26, Züchner S27, Bauer P28, Schöls L29, Schüle R30 |
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Abstract 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% 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. |
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© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com. |
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KEYWORDS: FA2H , FAHN, SPG35, hereditary spastic paraplegia, imaging biomarker |
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Publikations ID: 31135052 Quelle: öffnen |
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