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.
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Keywords: FA2H ; FAHN; SPG35; hereditary spastic paraplegia; imaging biomarker
- Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, and Center for Neurology, University of Tübingen, Tübingen, Germany.
- German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany.
- Department of Diagnostic and Interventional Neuroradiology, University Hospital Tübingen, Tübingen, Germany.
- Neurogenetics Group, University of Antwerp, Antwerp, Belgium.
- Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
- Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.
- Department of Medical Genetics, Institute of Human Genetics, University of Tübingen, Tübingen, Germany.
- CeGaT GmbH, Tübingen, Germany.
- Department of Psychiatry, University of Tübingen, Tübingen, Germany.
- Department of Pediatric Neurology, University Children’s Hospital, Tübingen, Germany.
- Department of Orthopaedics and Trauma-Surgery, Medical University Vienna, Vienna, Austria.
- Division of Child Neurology, University Childrens Hospital Zurich, Zurich, Switzerland.
- Department of Pediatric and Adult Movement Disorders and Neuropsychiatry, Institute of Neurogenetics, University of Lübeck, Germany.
- Department of Neuropediatrics, Klinikum Kassel, Germany.
- Department for Social Pediatrics, Kinderhospital Osnabrück, Germany.
- Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Department of Neurology, University Hospital Ghent, Ghent, Belgium.
- Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
- Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.
- CIBERNED, Center for Networked Biomedical Research into Neurodegenerative Diseases, Madrid, Spain.
- Neuroscience Area, Institute Biodonostia, and Department of Neurosciences, University of Basque Country EHU-UPV, San Sebastián, Spain.
- Neurometabolic Diseases Laboratory, Institut d’Investigació Biomedica de Bellvitge IDIBELL, Hospital Duran i Reynals, Barcelona, 08908, Spain.
- Centre for Biomedical Research on Rare Diseases (CIBERER), Institute Carlos III, Madrid, Spain.
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
- Scientific Institute IRCCS E. Medea, Laboratory of Molecular Biology, 23842 Bosisio Parini, Lecco, Italy.
- Scientific Institute IRCCS E. Medea, Neuromuscular Unit, 23842 Bosisio Parini , Lecco, Italy.
- John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, FL33136 Miami, USA.
- Dr. John T. Macdonald Foundation, Department of Human Genetics, FL33136 Miami, USA.29CENTOGENE AG, Rostock, Germany.