title: Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene.
abstract: Episodic ataxia type 1 (EA1) is an autosomal dominant K(+) channelopathy which manifests with short attacks of cerebellar ataxia and dysarthria, and may also show interictal myokymia. Episodes can be triggered by emotional or physical stress, startle response, sudden postural change or fever. Here we describe a 31-year-old man displaying markedly atypical symptoms, including long-lasting attacks of jerking muscle contractions associated with hyperthermia, severe migraine, and a relatively short-sleep phenotype. A single nucleotide change in KCNA1 (c.555C>G) was identified that changes a highly conserved residue (p.C185W) in the first transmembrane segment of the voltage-gated K(+) channel Kv1.1. The patient is heterozygous and the mutation was inherited from his asymptomatic mother. Next generation sequencing revealed no variations in the CACNA1A, CACNB4, KCNC3, KCNJ10, PRRT2 or SCN8A genes of either the patient or mother, except for a benign variant in SLC1A3. Functional analysis of the p.C185W mutation in KCNA1 demonstrated a deleterious dominant-negative phenotype where the remaining current displayed slower activation kinetics, subtle changes in voltage-dependence and faster recovery from slow inactivation. Structural modeling also predicts the C185W mutation to be functionally deleterious. This description of novel clinical features, associated with a Kv1.1 mutation highlights a possibly unrecognized relationship between K(+) channel dysfunction, hyperthermia and migraine in EA1, and suggests that thorough assessments for these symptoms should be carefully considered for all patients affected by EA1.
authors: Section of Physiology and Biochemistry, Department of Experimental Medicine, School of Medicine, University of Perugia Perugia, Italy ; Section of Neurophysiology and Biophysics, Istituto Euro-Mediterraneo di Scienza e Tecnologia Palermo, Italy.
authors: Maria C
authors: MC
authors: D'Adamo
authors: Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University Munich, Germany ; German Network for Mitochondrial Disorders (mitoNET) Ludwigshafen, Germany ; DZNE - German Center for Neurodegenerative Diseases Munich, Germany.
authors: Constanze
authors: C
authors: Gallenmüller
authors: Section of Physiology and Biochemistry, Department of Experimental Medicine, School of Medicine, University of Perugia Perugia, Italy.
authors: Ilenio
authors: I
authors: Servettini
authors: Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University Munich, Germany.
authors: Elisabeth
authors: E
authors: Hartl
authors: Clarendon Laboratory, Department of Physics, University of Oxford Oxford, UK.
authors: Stephen J
authors: SJ
authors: Tucker
authors: Department of Human Genetics, Ruhr-University Bochum Bochum, Germany.
authors: Larissa
authors: L
authors: Arning
authors: Center for Genomics and Transcriptomics (CeGaT) GmbH Tübingen Tübingen, Germany.
authors: Saskia
authors: S
authors: Biskup
authors: Department of Supercomputing Applications and Innovation, CINECA (Consorzio Inter-Universitario per il Calcolo Automatico) Rome, Italy.
authors: Alessandro
authors: A
authors: Grottesi
authors: Section of Physiology and Biochemistry, Department of Experimental Medicine, School of Medicine, University of Perugia Perugia, Italy.
authors: Luca
authors: L
authors: Guglielmi
authors: Department of Pharmacy, University of Bari Bari, Italy.
authors: Paola
authors: P
authors: Imbrici
authors: Neurology IV - Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute "Carlo Besta" Milan, Italy.
authors: Pia
authors: P
authors: Bernasconi
authors: Section of Neurophysiology and Biophysics, Istituto Euro-Mediterraneo di Scienza e Tecnologia Palermo, Italy ; Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta Msida, Malta.
authors: Giuseppe
authors: G
authors: Di Giovanni
authors: Department of Chemistry, Biology and Biotechnology, University of Perugia Perugia, Italy.
authors: Fabio
authors: F
authors: Franciolini
authors: Department of Chemistry, Biology and Biotechnology, University of Perugia Perugia, Italy.
authors: Luigi
authors: L
authors: Catacuzzeno
authors: Section of Physiology and Biochemistry, Department of Experimental Medicine, School of Medicine, University of Perugia Perugia, Italy ; Section of Neurophysiology and Biophysics, Istituto Euro-Mediterraneo di Scienza e Tecnologia Palermo, Italy.
authors: Mauro
authors: M
authors: Pessia
authors: Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University Munich, Germany ; German Network for Mitochondrial Disorders (mitoNET) Ludwigshafen, Germany ; DZNE - German Center for Neurodegenerative Diseases Munich, Germany ; German Center for Vertigo and Balance Disorders Munich, Germany.
authors: Thomas
authors: T
authors: Klopstock
keywords: C185W; Shaker potassium channels; episodic ataxia type 1; hyperthermia; migraine; sleep
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