[Epub ahead of print]

De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia.

Liedewei Van de Vondel, Jonathan De Winter, Danique Beijer, Giulia Coarelli, Melanie Wayand, Robin Palvadeau, Martje G. Pauly, Katrin Klein, Maren Rautenberg, Léna Guillot‐Noël, Tine Deconinck, Atay Vural, Sibel Ertan, Okan Dogu, Hilmi Uysal, Vesna Brankovic, Rebecca Herzog, Alexis Brice, Alexandra Durr, Stephan Klebe, Friedrich Stock, Almut Turid Bischoff, Tim W. Rattay, María‐Jesús Sobrido, Giovanna De Michele, Peter De Jonghe, Thomas Klopstock, Katja Lohmann, Ginevra Zanni, Filippo M. Santorelli, Vincent Timmerman, Tobias B. Haack, Stephan Züchner, Rebecca Schüle, Giovanni Stevanin, Matthis Synofzik, A. Nazli Basak, Jonathan Baets,
Movement Disorders. 2022-02-12; :
DOI: 10.1002/mds.28959

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De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and
Cerebellar Ataxia.

Van de Vondel L(1)(2), De Winter J(1)(2)(3), Beijer D(1)(2)(4), Coarelli G(5),
Wayand M(6)(7), Palvadeau R(8), Pauly MG(9)(10), Klein K(11), Rautenberg M(11),
Guillot-Noël L(5), Deconinck T(12), Vural A(13), Ertan S(13), Dogu O(14), Uysal
H(15), Brankovic V(16), Herzog R(9), Brice A(5), Durr A(5), Klebe S(17), Stock
F(18), Bischoff AT(19), Rattay TW(6)(7), Sobrido MJ(20)(21), De Michele G(22), De
Jonghe P(2)(3), Klopstock T(19)(23)(24), Lohmann K(10), Zanni G(25), Santorelli
FM(26), Timmerman V(2)(27), Haack TB(11)(28), Züchner S(4); PREPARE Consortium,
Schüle R(6)(7), Stevanin G(5)(29), Synofzik M(6)(7), Basak AN(8), Baets

Author information:
(1)Translational Neurosciences, Faculty of Medicine and Health Sciences,
University of Antwerp, Antwerp, Belgium.
(2)Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of
Antwerp, Antwerp, Belgium.
(3)Neuromuscular Reference Centre, Department of Neurology, Antwerp University
Hospital, Antwerp, Belgium.
(4)Dr John T. Macdonald Foundation Department of Human Genetics, John P. Hussman
Institute for Human Genomics, University of Miami Miller School of Medicine,
Miami, FL, USA.
(5)Sorbonne University, ICM-Paris Brain Institute, INSERM, CNRS, APHP, Pitié
Salpêtrière Hospital, Paris, France.
(6)Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain
Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany.
(7)German Center for Neurodegenerative Diseases (DZNE), University of Tübingen,
Tübingen, Germany.
(8)Koc University, School of Medicine, Suna and Inan Kirac Foundation, Istanbul,
(9)Department of Neurology, University Hospital Schleswig Holstein, Lübeck,
(10)Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
(11)Institute of Medical Genetics and Applied Genomics, University of Tuebingen,
Tübingen, Germany.
(12)Center of Medical Genetics, University of Antwerp and Antwerp University
Hospital, Edegem, Belgium.
(13)School of Medicine, Department of Neurology, Koc University, Istanbul,
(14)Department of Neurology, School of Medicine, Mersin University, Mersin,
(15)Department of Neurology, School of Medicine, Akdeniz University, Antalya,
(16)Clinic for Child Neurology and Psychiatry, University of Belgrade, Belgrade,
(17)Department of Neurology, University Hospital Essen, Essen, Germany.
(18)Institute of Human Genetics, University Hospital Essen, Essen, Germany.
(19)Department of Neurology, Friedrich-Baur-Institute, LMU Munich, Munich,
(20)Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER),
Santiago de Compostela, Spain.
(21)Neurogenetics Research Group, Instituto de Investigación Sanitaria (IDIS),
Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
(22)Department of Neurosciences and Reproductive and Odontostomatological
Sciences, Federico II University, Naples, Italy.
(23)German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
(24)Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
(25)Unit of Neuromuscular and Neurodegenerative Disorders, Department of
Neurosciences, Bambino Gesù Children’s Hospital, Rome, Italy.
(26)Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy.
(27)Peripheral Neuropathy Research Group, Department of Biomedical Sciences,
University of Antwerp, Antwerp, Belgium.
(28)Centre for Rare Diseases, University of Tübingen, Tübingen, Germany.
(29)Paris Sciences Lettres Research University, Ecole Pratique des Hautes Etudes,
Paris, France.

BACKGROUND: Pathogenic variants in SPTAN1 have been linked to a remarkably broad
phenotypical spectrum. Clinical presentations include epileptic syndromes,
intellectual disability, and hereditary motor neuropathy.
OBJECTIVES: We investigated the role of SPTAN1 variants in rare neurological
disorders such as ataxia and spastic paraplegia.
METHODS: We screened 10,000 NGS datasets across two international consortia and
one local database, indicative of the level of international collaboration
currently required to identify genes causative for rare disease. We performed in
silico modeling of the identified SPTAN1 variants.
RESULTS: We describe 22 patients from 14 families with five novel SPTAN1
variants. Of six patients with cerebellar ataxia, four carry a de novo SPTAN1
variant and two show a sporadic inheritance. In this group, one variant
(p.Lys2083del) is recurrent in four patients. Two patients have novel de novo
missense mutations (p.Arg1098Cys, p.Arg1624Cys) associated with cerebellar
ataxia, in one patient accompanied by intellectual disability and epilepsy. We
furthermore report a recurrent missense mutation (p.Arg19Trp) in 15 patients with
spastic paraplegia from seven families with a dominant inheritance pattern in
four and a de novo origin in one case. One further patient carrying a de novo
missense mutation (p.Gln2205Pro) has a complex spastic ataxic phenotype. Through
protein modeling we show that mutated amino acids are located at crucial
interlinking positions, interconnecting the three-helix bundle of a spectrin
CONCLUSIONS: We show that SPTAN1 is a relevant candidate gene for ataxia and
spastic paraplegia. We suggest that for the mutations identified in this study,
disruption of the interlinking of spectrin helices could be a key feature of the
pathomechanism. © 2022 International Parkinson and Movement Disorder Society.

© 2022 International Parkinson and Movement Disorder Society.

DOI: 10.1002/mds.28959
PMID: 35150594

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