Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Nov;188(11):3306-3311.
doi: 10.1002/ajmg.a.62960. Epub 2022 Sep 5.

Biallelic CACNA1A variants: Review of literature and report of a child with drug-resistant epilepsy and developmental delay

Vivien M Y Wong-Spracklen  1 , Anna Kolesnik  2 , Josefine Eck  2 , Saras Sabanathan  3 , Olivera Spasic-Boskovic  4 , Anna Maw  1 , Kate Baker  2   5
Affiliations
Review

Biallelic CACNA1A variants: Review of literature and report of a child with drug-resistant epilepsy and developmental delay

Vivien M Y Wong-Spracklen et al. Am J Med Genet A. 2022 Nov.

Abstract

Biallelic variants in CACNA1A have previously been reported in nine individuals (four families) presenting with epilepsy and cognitive impairments of variable severity and age-of-onset. Here, we describe a child who presented at 6 months of age with drug-resistant epilepsy and developmental delay. At 10 years of age, she has profound impairments in motor function and communication. MRI was initially unremarkable, but progressed to severe cerebellar atrophy by age 3 years. Next Generation Sequencing and panel analysis identified a maternally inherited truncating variant c.2042_2043delAG, p.(Gln681ArgfsTer100) and paternally inherited missense variant c.1693G>A, p.(Glu565Lys). In contrast to previously reported biallelic cases, parents carrying these monoallelic variants did not display clear signs of a CACNA1A-associated syndrome. In conclusion, we provide further evidence that biallelic CACNA1A variants can cause a severe epileptic and developmental encephalopathy with progressive cerebellar atrophy, and highlight complexities of genetic counseling in such situations.

Keywords: CACNA1A; biallelic; cerebellar atrophy; epileptic encephalopathy; intellectual disability; recessive.

PubMed Disclaimer

Conflict of interest statement

The authors declare that there is no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Child with biallelic CACNA1A variants, at age 9 years (published with parental permission)
FIGURE 2
FIGURE 2
Magnetic resonance imaging for child with biallelic CACNA1A variants. (a) Cranial MRI at 6 months of age. (b) Cranial MRI at 3 years of age. Both panels show T1‐weighted sagittal image and T2‐weighted axial images
See this image and copyright information in PMC

References

    1. Angelini, C. , Van Gils, J. , Bigourdan, A. , Jouk, P. S. , Lacombe, D. , Menegon, P. , Moutton, S. , Riant, F. , Sole, G. , Tournier‐Lasserve, E. , Trimouille, A. , Vincent, M. , & Goizet, C. (2019). Major intra‐familial phenotypic heterogeneity and incomplete penetrance due to a CACNA1A pathogenic variant. European Journal of Medical Genetics, 62(6), 103530. - PubMed
    1. Arteche‐Lopez, A. , Alvarez‐Mora, M. I. , Sanchez Calvin, M. T. , Lezana Rosales, J. M. , Palma Milla, C. , Gomez Rodriguez, M. J. , Gomez Manjon, I. , Blazquez, A. , Juarez Rufian, A. , Ramos Gomez, P. , Sierra Tomillo, O. , Hidalgo Mayoral, I. , Perez de la Fuente, R. , Posada Rodriguez, I. J. , Gonzalez Granado, L. I. , Martin, M. A. , Quesada‐Espinosa, J. F. , & Moreno‐Garcia, M. (2021). Biallelic variants in genes previously associated with dominant inheritance: CACNA1A, RET and SLC20A2. European Journal of Human Genetics, 29(10), 1520–1526. - PMC - PubMed
    1. Byers, H. M. , Beatty, C. W. , Hahn, S. H. , & Gospe, S. M., Jr. (2016). Dramatic response after lamotrigine in a patient with epileptic encephalopathy and a De NovoCACNA1A variant. Pediatric Neurology, 60, 79–82. - PMC - PubMed
    1. Constantino, J. N. (2012). Social responsiveness scale (SRS‐2) (2nd ed.). WPS.
    1. Damaj, L. , Lupien‐Meilleur, A. , Lortie, A. , Riou, E. , Ospina, L. H. , Gagnon, L. , Vanasse, C. , & Rossignol, E. (2015). CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms. European Journal of Human Genetics, 23(11), 1505–1512. - PMC - PubMed