Dataset Information

FAHN/SPG35: a narrow phenotypic spectrum across disease classifications.

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.

SUBMITTER: Rattay TW

PROVIDER: S-EPMC6536916 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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FAHN/SPG35: a narrow phenotypic spectrum across disease classifications.

Rattay Tim W TW Lindig Tobias T Baets Jonathan J Smets Katrien K Deconinck Tine T Söhn Anne S AS Hörtnagel Konstanze K Eckstein Kathrin N KN Wiethoff Sarah S Reichbauer Jennifer J Döbler-Neumann Marion M Krägeloh-Mann Ingeborg I Auer-Grumbach Michaela M Plecko Barbara B Münchau Alexander A Wilken Bernd B Janauschek Marc M Giese Anne-Katrin AK De Bleecker Jan L JL Ortibus Els E Debyser Martine M Lopez de Munain Adolfo A Pujol Aurora A Bassi Maria Teresa MT D'Angelo Maria Grazia MG De Jonghe Peter P Züchner Stephan S Bauer Peter P Schöls Ludger L Schüle Rebecca R

Brain : a journal of neurology 20190601 6

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 spasticit ...[more]

PMID: 31135052

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FAHN/SPG35: a narrow phenotypic spectrum across disease classifications.

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FAHN/SPG35: a narrow phenotypic spectrum across disease classifications.

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