Progressive Ataxia with Hemiplegic Migraines: a Phenotype of CACNA1A Missense Mutations, Not CAG Repeat Expansions
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SHORT REPORTS
Progressive Ataxia with Hemiplegic Migraines: a Phenotype of CACNA1A Missense Mutations, Not CAG Repeat Expansions Kevin R. Duque 1 & Luca Marsili 1 Marcelo A. Kauffman 3
&
Andrea Sturchio 1 & Abhimanyu Mahajan 1 & Aristide Merola 2 & Alberto J. Espay 1 &
Accepted: 27 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract We report a 52-year-old woman presenting with autosomal dominant progressive cerebellar ataxia and familial hemiplegic migraine type 1 whose genetic evaluation, negative for spinocerebellar ataxia (SCA) types 1, 2, 3, and 6, revealed instead a heterozygous pathogenic missense mutation in CACNA1A (NM_001127221:c.1748G > A:p.Arg583Gln). A systematic literature review showed that Arg583Gln is associated predominantly with progressive ataxia combined with episodic disorders (overwhelmingly hemiplegic migraine) whereas Thr666Met, the other most common CACNA1A missense mutation, with a combination of progressive ataxia and episodic disorders in half the cases and episodic disorders only in the other half. While uncertainties remain in the genotype-phenotype correlation of all CACNA1A mutations, the accumulated evidence suggests that that the co-occurrence of hemiplegic migraine and autosomal dominant progressive cerebellar ataxia should guide the clinician to test for CACNA1A missense mutation rather than CAG expansions or truncating mutations. Keywords CACNA1A . Cerebellar ataxia . Migraine with aura . Whole exome sequencing . Gait analysis . Case report
Introduction Autosomal dominant cerebellar ataxias (ADCA) are a genetically heterogeneous group of disorders characterized by progressive or episodic impairment of balance and coordination [1]. Separately, hemiplegic migraine is a subtype of migraine with aura (MA) with episodic motor weakness [2]. Individuals with both progressive ADCA and hemiplegic migraine (mainly familial, FHM) Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12311-020-01185-9) contains supplementary material, which is available to authorized users. * Luca Marsili [email protected] 1
Department of Neurology and Rehabilitation Medicine, Gardner Family Center for Parkinson’s Disease and Movement Disorders, University of Cincinnati, 260 Stetson Street, Cincinnati, OH 45219, USA
2
Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
3
Consultorio y Laboratorio de Neurogenética, Centro Universitario de Neurología José María Ramos Mejía, Buenos Aires, Argentina
have been linked with missense mutations in either CACNA1A or, less often, SLC2A1 genes [3, 4]. Many different CACNA1A missense mutations have been reported and showed a sizeable phenotypic variability. A better genotype-phenotype characterization might guide the interpretation of results of functional studies and help to select appropriate patients for future gene-targeted disease-modifying clinical trials. Here, we report a woman who carried an Arg583Gln CACNA1A missense mutation
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