FAHN/SPG35: a narrow phenotypic spectrum across disease classifications
| Autor: | Jonathan Baets, Adolfo López de Munain, Maria Grazia D'Angelo, Tobias Lindig, Marion Döbler-Neumann, Rebecca Schüle, Jennifer Reichbauer, Anne S. Söhn, Martine Debyser, Alexander Münchau, Tim W. Rattay, Stephan Züchner, Barbara Plecko, Tine Deconinck, Peter De Jonghe, Maria Teresa Bassi, Ludger Schöls, Ingeborg Krägeloh-Mann, Katrien Smets, Marc Janauschek, Kathrin N. Eckstein, Anne-Katrin Giese, Konstanze Hörtnagel, Bernd Wilken, Jan De Bleecker, Els Ortibus, Sarah Wiethoff, Aurora Pujol, Michaela Auer-Grumbach, Peter Bauer |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Pathology medicine.medical_specialty Movement disorders genetics [Heredodegenerative Disorders Nervous System] Hereditary spastic paraplegia Neurodegeneration with brain iron accumulation genetics [Demyelinating Diseases] genetics [Mutation] Mixed Function Oxygenases White matter Cohort Studies 03 medical and health sciences 0302 clinical medicine Atrophy genetics [Spastic Paraplegia Hereditary] medicine Humans ddc:610 Child Retrospective Studies Dystonia classification [Spastic Paraplegia Hereditary] Cerebellar ataxia business.industry Spastic Paraplegia Hereditary Leukodystrophy Original Articles medicine.disease genetics [Mixed Function Oxygenases] 3. Good health Pedigree 030104 developmental biology medicine.anatomical_structure Phenotype Mutation Heredodegenerative Disorders Nervous System Female Neurology (clinical) Human medicine medicine.symptom business 030217 neurology & neurosurgery Demyelinating Diseases |
| Zdroj: | Brain Brain 142(6), 1561-1572 (2019). doi:10.1093/brain/awz102 |
| ISSN: | 0006-8950 |
| DOI: | 10.1093/brain/awz102 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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