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

• Published in: Frontiers in molecular neuroscience Vol. 16; p. 1222321
• Main Authors: Kessi, Miriam, Chen, Baiyu, Pang, Nan, Yang, Lifen, Peng, Jing, He, Fang, Yin, Fei
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 24.07.2023; Frontiers Media S.A
• Subjects: Age; Ataxia; Autism; autism spectrum disorder; CACNA1A; Child development; Convulsions & seizures; Encephalopathy; Epilepsy; Genotype & phenotype; Genotypes; genotype–phenotype correlations; global developmental delay; Intellectual disabilities; intellectual disability; Literature reviews; Molecular Neuroscience; Mutation; Neurodevelopmental disorders; Patients; Phenotypes; Seizures; Statistical analysis; epilepsy; CACNA1A; autism spectrum disorder; global developmental delay; intellectual disability; genotype–phenotype correlations
• ISSN: 1662-5099; 1662-5099
• DOI: 10.3389/fnmol.2023.1222321

Genotype-phenotype correlations of the -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 -related neurodevelopmental disorders. Six children diagnosed with -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 -related neurodevelopmental disorders until February 2023. Thereafter, we divided patients into several groups for comparison. 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 ( = 0.001). The p.A713T variant correlated with severe-profound GDD/ID ( = 0.003). A total of 130 epileptic patients harboring 83 variants were identified. The epileptic manifestations included status epilepticus ( = 64), provoked seizures ( = 49), focal seizures ( = 37), EE ( = 29), absence seizures ( = 26), and myoclonic seizures ( = 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 ( = 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 ( = 0.000). LOF variants were associated with absence seizures ( = 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. The p.A713T variant is linked with severe-profound GDD/ID. More than half of -related epilepsy is refractory. The most common epileptic manifestation is status epilepticus, which correlates with variants located on S4, S5, and S6.