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ORIGINAL RESEARCH article

Front. Neurol.
Sec. Pediatric Neurology
Volume 15 - 2024 | doi: 10.3389/fneur.2024.1458109

Intrafamilial neurological phenotypic variability due to either biallelic or monoallelic pathogenic variants in CACNA1A

Provisionally accepted
Dilbar Mammadova Dilbar Mammadova 1Cornelia Kraus Cornelia Kraus 2Thomas Leis Thomas Leis 1Bernt Popp Bernt Popp 2Christiane Zweier Christiane Zweier 3Andre Reis Andre Reis 2Regina Trollmann Regina Trollmann 1*
  • 1 Division of Pediatric Neurology, Department of Pediatrics and Adolescent Medicine, University of Erlangen Nuremberg, Erlangen, Germany
  • 2 Institute of Human Genetics, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Bavaria, Germany
  • 3 Department of Human Genetics, Faculty of Medicine, University of Bern, Bern, Switzerland

The final, formatted version of the article will be published soon.

    Pathogenic heterozygous variants in CACNA1A are associated with familial hemiplegic migraine, episodic ataxia type 2 and spinocerebellar ataxia type 6, and more recently, neurodevelopmental disorders. We describe a severe, early-onset phenotype including severe muscular hypotonia, early-onset epileptic seizures, apnoea, optic atrophy and dysphagia in three siblings carrying compound heterozygous frameshift variants in CACNA1A. Two male patients died at the age of 5 or 14 months of suspected SIDS or severe developmental epileptic encephalopathy (DEE) with refractory seizures and apnoea.A male child (index patient) developed severe early-onset DEE including seizures and ictal apnoea at the age of 4 weeks. Another male child developed generalized epilepsy and mild intellectual impairment in late infancy, and his mother and his maternal uncle were identified as carriers of a known CACNA1A pathogenic variant (c.2602delG heterozygous, p.(Ala868Profs*24)) with a diagnosis of episodic ataxia type 2. This maternal pathogenic variant c.2602delG was detected in the index patient and child 2. Trio-Exome sequencing identified an additional heterozygous pathogenic variant in the CACNA1A gene, c.5476delC, p.(His1826Thrfs*30) in the index patient and child 2, which was inherited from the asymptomatic father.In conclusion, the novel compound heterozygosity for two frameshift pathogenic variants, maternally (c.2602delG, p.(Ala868Profs*24)) and paternally (c.5476delC, p.(His1826Thrfs*3)) is associated with a severe phenotype of early-onset DEE. This observation highlights the necessity of additional analyses to clarify unusual phenotypes even if a pathogenic variant has already been identified, and expands the clinical spectrum of CACNA1A-related disorders.

    Keywords: Early-onset epileptic encephalopathy, apneic spells, Optic Nerve atrophy, burst suppression, developmental epileptic encephalopathy, generalized epilepsy

    Received: 01 Jul 2024; Accepted: 09 Sep 2024.

    Copyright: © 2024 Mammadova, Kraus, Leis, Popp, Zweier, Reis and Trollmann. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Regina Trollmann, Division of Pediatric Neurology, Department of Pediatrics and Adolescent Medicine, University of Erlangen Nuremberg, Erlangen, Germany

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