AUTHOR=Kessi Miriam , Chen Baiyu , Pang Nan , Yang Lifen , Peng Jing , He Fang , Yin Fei 

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

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=16

YEAR=2023

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2023.1222321

DOI=10.3389/fnmol.2023.1222321

ISSN=1662-5099

ABSTRACT=<sec id="sec1"><title>Background</title><p>Genotype–phenotype correlations of the <italic>CACNA1A</italic>-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 <italic>CACNA1A</italic>-related neurodevelopmental disorders.</p></sec><sec id="sec2"><title>Methods</title><p>Six children diagnosed with <italic>CACNA1A</italic>-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 <italic>CACNA1A</italic>-related neurodevelopmental disorders until February 2023. Thereafter, we divided patients into several groups for comparison.</p></sec><sec id="sec3"><title>Results</title><p>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 (<italic>p</italic> = 0.001). The p.A713T variant correlated with severe-profound GDD/ID (<italic>p</italic> = 0.003). A total of 130 epileptic patients harboring 83 variants were identified. The epileptic manifestations included status epilepticus (<italic>n</italic> = 64), provoked seizures (<italic>n</italic> = 49), focal seizures (<italic>n</italic> = 37), EE (<italic>n</italic> = 29), absence seizures (<italic>n</italic> = 26), and myoclonic seizures (<italic>n</italic> = 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 (<italic>p</italic> = 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 (<italic>p</italic> = 0.000). LOF variants were associated with absence seizures (<italic>p</italic> = 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.</p></sec><sec id="sec4"><title>Conclusion</title><p>The p.A713T variant is linked with severe-profound GDD/ID. More than half of <italic>CACNA1A</italic>-related epilepsy is refractory. The most common epileptic manifestation is status epilepticus, which correlates with variants located on S4, S5, and S6.</p></sec>