FAHN/SPG35: a narrow phenotypic spectrum across disease classifications

Tim W. Rattay, Tobias Lindig, Jonathan Baets, Katrien Smets, Tine Deconinck, Anne S. Söhn, Konstanze Hörtnagel, Kathrin N. Eckstein, Sarah Wiethoff, Jennifer Reichbauer, Marion Döbler-Neumann, Ingeborg Krägeloh-Mann, Michaela Auer-Grumbach, Barbara Plecko, Alexander Münchau, Bernd Wilken, Marc Janauschek, Anne Katrin Giese, Jan L. De Bleecker, Els OrtibusMartine Debyser, Adolfo Lopez de Munain, Aurora Pujol, Maria Teresa Bassi, Maria Grazia D'Angelo, Peter De Jonghe, Stephan L Zuchner, Peter Bauer, Ludger Schöls, Rebecca Schüle

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1561-1572
Number of pages12
JournalBrain : a journal of neurology
Volume142
Issue number6
DOIs
StatePublished - Jun 1 2019

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Mixed Function Oxygenases
Fatty Acids
Hair
Hereditary Spastic Paraplegia
Sebum
Exotropia
Dysarthria
Glycosphingolipids
Cerebellar Ataxia
Mutation
Focal Adhesions
Globus Pallidus
Muscle Spasticity
Dystonia
Corpus Callosum
Movement Disorders
Demyelinating Diseases
Deglutition Disorders
Myelin Sheath
Endoplasmic Reticulum

Keywords

  • FA2H
  • FAHN
  • hereditary spastic paraplegia
  • imaging biomarker
  • SPG35

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Rattay, T. W., Lindig, T., Baets, J., Smets, K., Deconinck, T., Söhn, A. S., ... Schüle, R. (2019). FAHN/SPG35: a narrow phenotypic spectrum across disease classifications. Brain : a journal of neurology, 142(6), 1561-1572. https://doi.org/10.1093/brain/awz102

FAHN/SPG35 : a narrow phenotypic spectrum across disease classifications. / Rattay, Tim W.; Lindig, Tobias; Baets, Jonathan; Smets, Katrien; Deconinck, Tine; Söhn, Anne S.; Hörtnagel, Konstanze; Eckstein, Kathrin N.; Wiethoff, Sarah; Reichbauer, Jennifer; Döbler-Neumann, Marion; Krägeloh-Mann, Ingeborg; Auer-Grumbach, Michaela; Plecko, Barbara; Münchau, Alexander; Wilken, Bernd; Janauschek, Marc; Giese, Anne Katrin; De Bleecker, Jan L.; Ortibus, Els; Debyser, Martine; Lopez de Munain, Adolfo; Pujol, Aurora; Bassi, Maria Teresa; D'Angelo, Maria Grazia; De Jonghe, Peter; Zuchner, Stephan L; Bauer, Peter; Schöls, Ludger; Schüle, Rebecca.

In: Brain : a journal of neurology, Vol. 142, No. 6, 01.06.2019, p. 1561-1572.

Research output: Contribution to journalArticle

Rattay, TW, Lindig, T, Baets, J, Smets, K, Deconinck, T, Söhn, AS, Hörtnagel, K, Eckstein, KN, Wiethoff, S, Reichbauer, J, Döbler-Neumann, M, Krägeloh-Mann, I, Auer-Grumbach, M, Plecko, B, Münchau, A, Wilken, B, Janauschek, M, Giese, AK, De Bleecker, JL, Ortibus, E, Debyser, M, Lopez de Munain, A, Pujol, A, Bassi, MT, D'Angelo, MG, De Jonghe, P, Zuchner, SL, Bauer, P, Schöls, L & Schüle, R 2019, 'FAHN/SPG35: a narrow phenotypic spectrum across disease classifications', Brain : a journal of neurology, vol. 142, no. 6, pp. 1561-1572. https://doi.org/10.1093/brain/awz102
Rattay TW, Lindig T, Baets J, Smets K, Deconinck T, Söhn AS et al. FAHN/SPG35: a narrow phenotypic spectrum across disease classifications. Brain : a journal of neurology. 2019 Jun 1;142(6):1561-1572. https://doi.org/10.1093/brain/awz102
Rattay, Tim W. ; Lindig, Tobias ; Baets, Jonathan ; Smets, Katrien ; Deconinck, Tine ; Söhn, Anne S. ; Hörtnagel, Konstanze ; Eckstein, Kathrin N. ; Wiethoff, Sarah ; Reichbauer, Jennifer ; Döbler-Neumann, Marion ; Krägeloh-Mann, Ingeborg ; Auer-Grumbach, Michaela ; Plecko, Barbara ; Münchau, Alexander ; Wilken, Bernd ; Janauschek, Marc ; Giese, Anne Katrin ; De Bleecker, Jan L. ; Ortibus, Els ; Debyser, Martine ; Lopez de Munain, Adolfo ; Pujol, Aurora ; Bassi, Maria Teresa ; D'Angelo, Maria Grazia ; De Jonghe, Peter ; Zuchner, Stephan L ; Bauer, Peter ; Schöls, Ludger ; Schüle, Rebecca. / FAHN/SPG35 : a narrow phenotypic spectrum across disease classifications. In: Brain : a journal of neurology. 2019 ; Vol. 142, No. 6. pp. 1561-1572.
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