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@ARTICLE{Rattay:140899,
      author       = {Rattay, Tim W and Lindig, Tobias and Baets, Jonathan and
                      Smets, Katrien and Deconinck, Tine and Söhn, Anne S and
                      Hörtnagel, Konstanze and Eckstein, Kathrin N and Wiethoff,
                      Sarah and Reichbauer, Jennifer and Döbler-Neumann, Marion
                      and Krägeloh-Mann, Ingeborg and Auer-Grumbach, Michaela and
                      Plecko, Barbara and Münchau, Alexander and Wilken, Bernd
                      and Janauschek, Marc and Giese, Anne-Katrin and De Bleecker,
                      Jan L and Ortibus, Els and Debyser, Martine and Lopez de
                      Munain, Adolfo and Pujol, Aurora and Bassi, Maria Teresa and
                      D'Angelo, Maria Grazia and De Jonghe, Peter and Züchner,
                      Stephan and Bauer, Peter and Schöls, Ludger and Schüle,
                      Rebecca},
      title        = {{FAHN}/{SPG}35: a narrow phenotypic spectrum across disease
                      classifications.},
      journal      = {Brain},
      volume       = {142},
      number       = {6},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2020-07221},
      pages        = {1561-1572},
      year         = {2019},
      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.},
      keywords     = {Child / Cohort Studies / Demyelinating Diseases: genetics /
                      Female / Heredodegenerative Disorders, Nervous System:
                      genetics / Humans / Male / Mixed Function Oxygenases:
                      genetics / Mutation: genetics / Pedigree / Phenotype /
                      Retrospective Studies / Spastic Paraplegia, Hereditary:
                      classification / Spastic Paraplegia, Hereditary: genetics},
      cin          = {AG Gasser 1 / Tübingen Pre 2020 / AG Maetzler},
      ddc          = {610},
      cid          = {I:(DE-2719)1210000 / I:(DE-2719)6000018 /
                      I:(DE-2719)5000024},
      pnm          = {345 - Population Studies and Genetics (POF3-345) / 344 -
                      Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-345 / G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31135052},
      pmc          = {pmc:PMC6536916},
      doi          = {10.1093/brain/awz102},
      url          = {https://pub.dzne.de/record/140899},
}