Mammadova D, Kraus C, Leis T, Popp B, Zweier C, Reis A, Trollmann R (2024)
Publication Type: Journal article
Publication year: 2024
Book Volume: 15
Article Number: 1458109
DOI: 10.3389/fneur.2024.1458109
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.
APA:
Mammadova, D., Kraus, C., Leis, T., Popp, B., Zweier, C., Reis, A., & Trollmann, R. (2024). Intrafamilial neurological phenotypic variability due to either biallelic or monoallelic pathogenic variants in CACNA1A. Frontiers in Neurology, 15. https://doi.org/10.3389/fneur.2024.1458109
MLA:
Mammadova, Dilbar, et al. "Intrafamilial neurological phenotypic variability due to either biallelic or monoallelic pathogenic variants in CACNA1A." Frontiers in Neurology 15 (2024).
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