Delineating SPTAN1 associated phenotypes: From isolated epilepsy to encephalopathy with progressive brain atrophy

Steffen Syrbe, Frederike L. Harms, Elena Parrini, Martino Montomoli, Ulrike Mütze, Katherine L. Helbig, Tilman Polster, Beate Albrecht, Ulrich Bernbeck, Ellen Van Binsbergen, Saskia Biskup, Lydie Burglen, Jonas Denecke, Bénédicte Heron, Henrike O. Heyne, Georg F. Hoffmann, Frauke Hornemann, Takeshi Matsushige, Ryuki Matsuura, Mitsuhiro KatoG. Christoph Korenke, Alma Kuechler, Constanze Lämmer, Andreas Merkenschlager, Cyril Mignot, Susanne Ruf, Mitsuko Nakashima, Hirotomo Saitsu, Hannah Stamberger, Tiziana Pisano, Jun Tohyama, Sarah Weckhuysen, Wendy Werckx, Julia Wickert, Francesco Mari, Nienke E. Verbeek, Rikke S. Møller, Bobby Koeleman, Naomichi Matsumoto, William B. Dobyns, Johannes R. Lemke, Kerstin Kutsche, Domenica Battaglia, Renzo Guerrini

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


De novo in-frame deletions and duplications in the SPTAN1 gene, encoding the non-erythrocyte aII spectrin, have been associated with severe West syndrome with hypomyelination and pontocerebellar atrophy. We aimed at comprehensively delineating the phenotypic spectrum associated with SPTAN1 mutations. Using different molecular genetic techniques, we identified 20 patients with a pathogenic or likely pathogenic SPTAN1 variant and reviewed their clinical, genetic and imaging data. SPTAN1 de novo alterations included seven unique missense variants and nine in-frame deletions/duplications of which 12 were novel. The recurrent three-amino acid duplication p.(Asp2303-Leu2305dup) occurred in five patients. Our patient cohort exhibited a broad spectrum of neurodevelopmental phenotypes, comprising six patients with mild to moderate intellectual disability, with or without epilepsy and behavioural disorders, and 14 patients with infantile epileptic encephalopathy, of which 13 had severe neurodevelopmental impairment and four died in early childhood. Imaging studies suggested that the severity of neurological impairment and epilepsy correlates with that of structural abnormalities as well as the mutation type and location. Out of seven patients harbouring mutations outside the α/β spectrin heterodimerization domain, four had normal brain imaging and three exhibited moderately progressive brain and/or cerebellar atrophy. Twelve of 13 patients with mutations located within the spectrin heterodimer contact site exhibited severe and progressive brain, brainstem and cerebellar atrophy, with hypomyelination in most. We used fibroblasts from five patients to study spectrin aggregate formation by Triton-X extraction and immunocytochemistry followed by fluorescence microscopy. aII/bII aggregates and αII spectrin in the insoluble protein fraction were observed in fibroblasts derived from patients with the mutations p.(Glu2207del), p.(Asp2303-Leu2305dup) and p.(Arg2308-Met2309dup), all falling in the nucleation site of the α/β spectrin heterodimer region. Molecular modelling of the seven SPTAN1 amino acid changes provided preliminary evidence for structural alterations of the A-, B- and/or C-helices within each of the mutated spectrin repeats. We conclude that SPTAN1-related disorders comprise a wide spectrum of neurodevelopmental phenotypes ranging from mild to severe and progressive. Spectrin aggregate formation in fibroblasts with mutations in the α/β heterodimerization domain seems to be associated with a severe neurodegenerative course and suggests that the amino acid stretch from Asp2303 to Met2309 in the α20 repeat is important for α/β spectrin heterodimer formation and/or αII spectrin function.

Original languageEnglish (US)
Pages (from-to)2322-2336
Number of pages15
Issue number9
StatePublished - Sep 1 2017
Externally publishedYes

Bibliographical note

Funding Information:
7th Framework Programme (FP7) under the project DESIRE grant N602531 (to R.G.); a grant from the Dietmar-Hopp-Stiftung (23011236 to S.S.), Practical Research Project for Rare/Intractable Diseases (27280301 to M.K. and 26310501 to N.M.) from Japan Agency for Medical Research and development, AMED; and the Federal Ministry of Education and Research (BMBF), Germany (FKZ: 01EO1501 to H.O.H.).

Funding Information:
This work was supported by a grant of the Deutsche Forschungsgemeinschaft (KU 1240/10-1 to K.K.); the EU

Publisher Copyright:
© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.


  • Epileptic encephalopathy
  • Hypomyelination
  • Myoclonic epilepsy
  • Pontocerebellar atrophy
  • West syndrome


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