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

Syrbe S1, Harms FL2, Parrini E3, Montomoli M3, Mütze U1, Helbig KL4, Polster T5, Albrecht B6, Bernbeck U7, van Binsbergen E8, Biskup S9, Burglen L10,11, Denecke J12, Heron B11,13, Heyne HO14, Hoffmann GF1, Hornemann F15, Matsushige T16, Matsuura R17, Kato M18, Korenke GC19, Kuechler A6, Lämmer C20, Merkenschlager A15, Mignot C21,22, Ruf S23, Nakashima M24, Saitsu H25, Stamberger H26,27,28, Pisano T3, Tohyama J29, Weckhuysen S26,27,28, Werckx W30, Wickert J2,31, Mari F3, Verbeek NE8, Møller RS32,33, Koeleman B8, Matsumoto N24, Dobyns WB34,35, Battaglia D36, Lemke JR14, Kutsche K2, Guerrini R3,31.
  1. Department of General Paediatrics, Division of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
  2. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  3. Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children’s Hospital, University of Florence, Florence, Italy.
  4. Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
  5. Bethel Epilepsy Center – Krankenhaus Mara GmbH Bielefeld, Germany.
  6. Institut für Humangenetik, Universitaetsklinikum Essen, Universitaet Duisburg-Essen, Germany.
  7. Rems-Murr-Kliniken GmbH, Klinik für Kinder- und Jugendmedizin, Winnenden, Germany.
  8. Department of Genetics, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.
  9. CeGaT-Center for Genomics and Transcriptomics GmbH, Tuebingen, Germany.
  10. Centre de référence des Malformations et maladies congénitales du cervelet and Département de Génétique et embryologie médicales, AP-HP, GHUEP, Hôpital Trousseau 75012 Paris, France.
  11. GRC ConCer-LD, Sorbonne Universités, UPMC Univ 06, Paris, France.
  12. Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  13. AP-HP, Hôpital Trousseau, Service de Neurologie Pédiatrique; Paris, France.
  14. Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
  15. Department of Women and Child Health, Hospital for Children and Adolescents, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
  16. Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan.
  17. Division of Neurology, Saitama Children’s Medical Center, Saitama, Japan.
  18. Department of Pediatrics, Showa University School of Medicine, Hatanodai, Shinagawa-ku, Tokyo, Japan.
  19. Klinikum Oldenburg, Zentrum für Kinder- und Jugendmedizin, Klinik für Neuropaediatrie u. angeborene Stoffwechselerkrankungen, Oldenburg, Germany.
  20. St. Bernward Krankenhaus, Hildesheim, Germany.
  21. AP-HP, Département de Génétique and Centre de Référence Déficiences Intellectuelles de Causes Rares, Paris, France.
  22. GRC UPMC “Déficiences Intellectuelles et Autisme”, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
  23. Department of Pediatric Neurology and Developmental Medicine, University Children’s Hospital, Tübingen, Germany.
  24. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  25. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
  26. Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.
  27. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Belgium.
  28. Division of Neurology; Antwerp University Hospital, Antwerp, Belgium.
  29. Department of Pediatrics, Nishi-Niigata Chuo National Hospital, Niigata, Japan.
  30. Jessa Hospital, Hasselt, Belgium.
  31. IRCCS Stella Maris Foundation, Pisa, Italy.
  32. Danish Epilepsy Centre, Dianalund, Denmark.
  33. Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
  34. Departments of Pediatrics and Neurology, University of Washington, Seattle, Washington, USA.
  35. Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA.
  36. Child Neurology and Psychiatry Unit, Catholic University, Largo Gemelli 18, Rome, Italy.


De novo in-frame deletions and duplications in the SPTAN1 gene, encoding the non-erythrocyte αII 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. αII/βII 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.