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

June 01, 2019

Rattay TW1,2, Lindig T3, Baets J4,5,6, Smets K4,5,6, Deconinck T4,5, Söhn AS7, Hörtnagel K8, Eckstein KN1,2,9, Wiethoff S1,2, Reichbauer J1, Döbler-Neumann M10, Krägeloh-Mann I10, Auer-Grumbach M11, Plecko B12, Münchau A13, Wilken B14, Janauschek M15, Giese AK16, De Bleecker JL17, Ortibus E18, Debyser M19, Lopez de Munain A20,21, Pujol A22,23,24, Bassi MT25, D’Angelo MG26, De Jonghe P4,5,6, Züchner S27,28, Bauer P7,29, Schöls L1,2, Schüle R1,2.


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.

Keywords: FA2H ; FAHN; SPG35; hereditary spastic paraplegia; imaging biomarker