Rare CACNA1A mutations leading to congenital ataxia
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INVITED REVIEW
Rare CACNA1A mutations leading to congenital ataxia Mercè Izquierdo-Serra 1 & José M. Fernández-Fernández 1
&
Mercedes Serrano 2,3
Received: 27 March 2020 / Revised: 5 May 2020 / Accepted: 6 May 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Human mutations in the CACNA1A gene that encodes the pore-forming α1A subunit of the voltage-gated CaV2.1 (P/Q-type) Ca2+ channel cause multiple neurological disorders including sporadic and familial hemiplegic migraine, as well as cerebellar pathologies such as episodic ataxia, progressive ataxia, and early-onset cerebellar syndrome consistent with the definition of congenital ataxia (CA), with presentation before the age of 2 years. Such a pathological role is in accordance with the physiological relevance of CaV2.1 in neuronal tissue, especially in the cerebellum. This review deals with the report of the main clinical features defining CA, along with the presentation of an increasing number of CACNA1A genetic variants linked to this severe cerebellar disorder in the context of Ca2+ homeostasis alteration. Moreover, the review describes each pathological mutation according to structural location and known molecular and cellular functional effects in both heterologous expression systems and animal models. In view of this information in correlation with the clinical phenotype, we take into consideration different pathomechanisms underlying the observed motor dysfunction in CA patients carrying CACNA1A mutations. Present therapeutic management in CA and options for the development of future personalized treatment based on CaV2.1 dysfunction are also discussed. Keywords Congenital ataxia . Cerebellar atrophy . Permanent ataxia . Early-onset cerebellar signs . CACNA1A gene . CaV2.1 (P/Q-type) voltage-dependent calcium channel
Introduction The term congenital ataxia (CA) is applied to children with early evidence and symptoms of ataxia caused by cerebellar disease. However, the infant affected by a cerebellar disease does not show the typical signs of cerebellar syndrome, which can be detected later in life, due to the immaturity of the
This article is part of the special issue on Channelopathies: from mutation to diseases in Pflügers Archiv—European Journal of Physiology * José M. Fernández-Fernández [email protected] * Mercedes Serrano [email protected] 1
Laboratori de Fisiologia Molecular, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, C/ Dr. Aiguader, 88, 08003 Barcelona, Spain
2
Neuropediatric Department, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, 08950 Barcelona, Spain
3
U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, 08002 Barcelona, Spain
central nervous system and the chronology of motor development. This may delay clinical suspicion as the predominant signs at that moment are unspecific: muscular hypotonia, weak deep tendon reflexes, and delayed motor milestones. Since clear signs of a cerebel
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