The genotype-phenotype correlations of the CACNA1A-related neurodevelopmental disorders: a small case series and literature reviews

Miriam Kessi; Baiyu Chen; Nan Pang; Lifen Yang; Jing Peng; Fang He; Fei Yin

doi:10.3389/fnmol.2023.1222321

The genotype-phenotype correlations of the CACNA1A-related neurodevelopmental disorders: a small case series and literature reviews

Front Mol Neurosci. 2023 Jul 24:16:1222321. doi: 10.3389/fnmol.2023.1222321. eCollection 2023.

Authors

Miriam Kessi^{1

2

3}, Baiyu Chen^{1

2

3}, Nan Pang^{1

2

3}, Lifen Yang^{1

2

3}, Jing Peng^{1

2

3}, Fang He^{1

2

3}, Fei Yin^{1

2

3}

Affiliations

¹ Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China.
² Hunan Intellectual and Developmental Disabilities Research Center, Pediatrics, Changsha, China.
³ Clinical Research Center for Children's Neurodevelopmental Disabilities of Hunan Province, Xiangya Hospital, Central South University, Changsha, China.

Abstract

Background: Genotype-phenotype correlations of the CACNA1A-related neurodevelopmental disorders such as global developmental delay (GDD)/intellectual disability (ID), epileptic encephalopathy (EE), and autism spectrum disorder (ASD) are unknown. We aimed to summarize genotype-phenotype correlations and potential treatment for CACNA1A-related neurodevelopmental disorders.

Methods: Six children diagnosed with CACNA1A-related neurodevelopmental disorders at Xiangya Hospital, Central South University from April 2018 to July 2021 were enrolled. The PubMed database was systematically searched for all reported patients with CACNA1A-related neurodevelopmental disorders until February 2023. Thereafter, we divided patients into several groups for comparison.

Results: Six patients were recruited from our hospital. Three cases presented with epilepsy, five with GDD/ID, five with ataxia, and two with ASD. The variants included p.G701R, p.R279C, p.D1644N, p.Y62C, p.L1422Sfs*8, and p. R1664Q [two gain-of-function (GOF) and four loss-of-function (LOF) variants]. About 187 individuals with GDD/ID harboring 123 variants were found (case series plus data from literature). Of those 123 variants, p.A713T and p.R1664* were recurrent, 37 were LOF, and 7 were GOF. GOF variants were linked with severe-profound GDD/ID while LOF variants were associated with mild-moderate GDD/ID (p = 0.001). The p.A713T variant correlated with severe-profound GDD/ID (p = 0.003). A total of 130 epileptic patients harboring 83 variants were identified. The epileptic manifestations included status epilepticus (n = 64), provoked seizures (n = 49), focal seizures (n = 37), EE (n = 29), absence seizures (n = 26), and myoclonic seizures (n = 10). About 49 (42.20%) patients had controlled seizures while 67 (57.80%) individuals remained with refractory seizures. Status epilepticus correlated with variants located on S4, S5, and S6 (p = 0.000). Among the 83 epilepsy-related variants, 23 were recurrent, 32 were LOF, and 11 were GOF. Status epilepticus was linked with GOF variants (p = 0.000). LOF variants were associated with absence seizures (p = 0.000). Six patients died at an early age (3 months to ≤5 years). We found 18 children with ASD. Thirteen variants including recurrent ones were identified in those 18 cases. GOF changes were more linked to ASD.

Conclusion: The p.A713T variant is linked with severe-profound GDD/ID. More than half of CACNA1A-related epilepsy is refractory. The most common epileptic manifestation is status epilepticus, which correlates with variants located on S4, S5, and S6.

Keywords: CACNA1A; autism spectrum disorder; epilepsy; genotype–phenotype correlations; global developmental delay; intellectual disability.