A novel pathogenic CACNA1A variant causing episodic ataxia type 2 (EA2) spectrum phenotype in four family members and a
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LETTER TO THE EDITORS
A novel pathogenic CACNA1A variant causing episodic ataxia type 2 (EA2) spectrum phenotype in four family members and a novel combined therapy Josef Penkava1 · S. Ledderose2 · S. Chahrokh‑Zadeh3 · A. Munzig3 · zu Eulenburg1 · D. Huppert1 · M. Strupp1,4 · S. Becker‑Bense1 Received: 17 April 2020 / Revised: 18 August 2020 / Accepted: 26 August 2020 © The Author(s) 2020
Dear Sirs, Episodic ataxias (EAs) are rare neurological disorders characterized by recurrent episodes of cerebellar ataxia with an imbalance of stance and gait, limb ataxia, dysarthria, and nystagmus, often triggered by physical or emotional stress, or alcohol and accompanied by nausea and vomiting (for review see [1, 2]). Currently, there are at least seven known subtypes of EA. Among them, EA1 and EA2 are clinically most relevant [2]. EA2 has its onset typically in adolescence, but some cases with a late onset have been reported [3]. EA2 episodes generally last between minutes and hours, and are accompanied by migraine-like cephalgia in around 50% of patients [4]. EA 2 patients frequently develop slowly progressive interictal ataxia and distinct central ocular motor dysfunctions, e.g., mainly gaze-evoked or downbeat nystagmus [4, 5]. EA2 is an inherited autosomal-dominant channelopathy, caused by pathogenic variants affecting the CACNA1A gene on chromosome 19p13, which encodes the alpha-1A subunit of the P/Q-type voltage-gated calcium channel (Cav2.1) [1, 6]. The latter is found ubiquitously in the nervous system with high expression levels in cerebellar Purkinje cells [7, 8]. EA2 shares molecular pathologic similarities with spinocerebellar ataxia type 6 (SCA6), familial * Josef Penkava [email protected]‑muenchen.de 1
German Center for Vertigo and Balance Disorders (DSGZ), Ludwig-Maximilians-Universität München, Campus Großhadern, Marchioninistr. 15, 81377 Munich, Germany
2
Department of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany
3
Center for Human Genetics and Laboratory Diagnostics (CHGLD), Martinsried, Germany
4
Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
hemiplegic migraine (FHM) and epileptic encephalopathy, also carrying mutations in the CACNA1A gene. Typically, cases of FHM present with missense mutations, SCA6 with a C-terminal polyglutamine expansion and EA2 harbors point mutations resulting in premature stop codons as well as small or large deletions, insertions and missense mutations [2]. During the last decades, an increasing number of CACNA1A variants have been described. Here, we report on a female patient with a novel pathogenic CACNA1A variant and give insights into the heterogeneous phenotypes within her family. A 47-year-old white Caucasian female presented to our tertiary outpatient center with recurrent attacks of postural imbalance (no vertigo sensu stricto, no nausea or vomiting) with the feeling of falling forward, and an associated holocephalic headache that began around the age of 15 years. The attacks occurred daily, mo
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