Leu226Trp CACNA1A variant associated with juvenile myoclonic epilepsy with and without intellectual disability

Alehabib, Elham; Kokotović, Tomislav; Ranji-Burachaloo, Sakineh; Tafakhori, Abbas; Ramsheh, Samira Molaei; Esmaeilizadeh, Zahra; Darvish, Hossein; Movafagh, Abolfazl; Nagy, Vanja

doi:10.1016/j.clineuro.2021.107108

Cited by 5 publications

(1 citation statement)

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“…There were 83 variants reported to relate to epilepsy ( Imbrici et al, 2004 ; Kors et al, 2004 ; Rajakulendran et al, 2010 ; Zangaladze et al, 2010 ; Yamazaki et al, 2011 ; Damaj et al, 2015 ; Byers et al, 2016 ; Reinson et al, 2016 ; Du et al, 2017 ; Lv et al, 2017 ; Epperson et al, 2018 ; Hayashida et al, 2018 ; Kothur et al, 2018 ; Lee et al, 2018 ; Angelini et al, 2019 ; Jiang et al, 2019 ; Yamamoto et al, 2019 ; Gauquelin et al, 2020 ; Gudenkauf et al, 2020 ; Mitta et al, 2020 ; Stendel et al, 2020 ; Zhang et al, 2020 ; Ho et al, 2021 ; Le Roux et al, 2021 ; Stubberud et al, 2021 ; Verriello et al, 2021 ; Alehabib et al, 2022 ; Bolte et al, 2022 ; Hommersom et al, 2022 ; Krygier et al, 2022 ; Li et al, 2022 ; Lipman et al, 2022 ; Niu X. et al, 2022 ; Niu Y. et al, 2022 ) as shown in Supplementary Table 2 . The majority of the variants were missense (77.20%) followed by nonsense (8.80%) as shown in Figure 1A .…”

Section: Resultsmentioning

confidence: 99%

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

Kessi¹,

Chen²,

Pang³

et al. 2023

Front. Mol. Neurosci.

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BackgroundGenotype–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.MethodsSix 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.ResultsSix 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.ConclusionThe 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.

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