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FAHN/SPG35 : a narrow phenotypic spectrum across disease classifications

(2019) BRAIN. 142(6). p.1561-1572
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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
SPG35, FAHN, FA2H, imaging biomarker, hereditary spastic paraplegia: HEREDITARY SPASTIC PARAPLEGIA, FATTY-ACID 2-HYDROXYLASE, IRON ACCUMULATION, COMPLICATED FORM, MUTATIONS, FA2H, NEURODEGENERATION, PARAPARESIS, DISORDERS, DIAGNOSIS

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MLA
Rattay, TW et al. “FAHN/SPG35 : a Narrow Phenotypic Spectrum Across Disease Classifications.” BRAIN 142.6 (2019): 1561–1572. Print.
APA
Rattay, T., Lindig, T., Baets, J., Smets, K., Deconinck, T., Söhn, A., Hörtnagel, K., et al. (2019). FAHN/SPG35 : a narrow phenotypic spectrum across disease classifications. BRAIN, 142(6), 1561–1572.
Chicago author-date
Rattay, TW, T Lindig, J Baets, K Smets, T Deconinck, AS Söhn, K Hörtnagel, et al. 2019. “FAHN/SPG35 : a Narrow Phenotypic Spectrum Across Disease Classifications.” Brain 142 (6): 1561–1572.
Chicago author-date (all authors)
Rattay, TW, T Lindig, J Baets, K Smets, T Deconinck, AS Söhn, K Hörtnagel, KN Eckstein, S Wiethoff, J Reichbauer, M Döbler-Neumann, I Krägeloh-Mann, M Auer-Grumbach, B Plecko, A Münchau, B Wilken, M Janauschek, AK Giese, Jan De Bleecker, E Ortibus, M Debyser, A Lopez de Munain, A Pujol, MT Bassi, MG D’Angelo, P De Jonghe, S Züchner, P Bauer, L Schöls, and R Schüle. 2019. “FAHN/SPG35 : a Narrow Phenotypic Spectrum Across Disease Classifications.” Brain 142 (6): 1561–1572.
Vancouver
1.
Rattay T, Lindig T, Baets J, Smets K, Deconinck T, Söhn A, et al. FAHN/SPG35 : a narrow phenotypic spectrum across disease classifications. BRAIN. 2019;142(6):1561–72.
IEEE
[1]
T. Rattay et al., “FAHN/SPG35 : a narrow phenotypic spectrum across disease classifications,” BRAIN, vol. 142, no. 6, pp. 1561–1572, 2019.
@article{8618343,
  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.},
  author       = {Rattay, TW and Lindig, T and Baets, J and Smets, K and Deconinck, T and Söhn, AS and Hörtnagel, K and Eckstein, KN and Wiethoff, S and Reichbauer, J and Döbler-Neumann, M and Krägeloh-Mann, I and Auer-Grumbach, M and Plecko, B and Münchau, A and Wilken, B and Janauschek, M and Giese, AK and De Bleecker, Jan and Ortibus, E and Debyser, M and Lopez de Munain, A and Pujol, A and Bassi, MT and D'Angelo, MG and De Jonghe, P and Züchner, S and Bauer, P and Schöls, L and Schüle, R},
  issn         = {0006-8950},
  journal      = {BRAIN},
  keywords     = {SPG35,FAHN,FA2H,imaging biomarker,hereditary spastic paraplegia: HEREDITARY SPASTIC PARAPLEGIA,FATTY-ACID 2-HYDROXYLASE,IRON ACCUMULATION,COMPLICATED FORM,MUTATIONS,FA2H,NEURODEGENERATION,PARAPARESIS,DISORDERS,DIAGNOSIS},
  language     = {eng},
  number       = {6},
  pages        = {1561--1572},
  title        = {FAHN/SPG35 : a narrow phenotypic spectrum across disease classifications},
  url          = {http://dx.doi.org/10.1093/brain/awz102},
  volume       = {142},
  year         = {2019},
}

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