De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

Abstract

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the a 1-subunit of the voltage-gated Ca V 2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed Ca V 2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

Whole‐exome sequencing in adult patients with developmental and epileptic encephalopathy: It is never too late

“…Topiramate, an ASM acting on the Ca V 2.3 channel, was adopted 13 for the patient carrying a CACNA1E variant. Valproate was discontinued in patient carrying RARS2 disease-causative variants, due to its deleterious effect on mitochondrial diseases and compounds with antioxidant effect are currently being administered.…”

The Genomics Research and Innovation Network: creating an interoperable, federated, genomics learning system

“…The work resulted in the first description of epilepsy due to missense variants in GABRG2, 27 and the first description of de novo variants of CACNA1E as a cause of severe developmental and epileptic encephalopathies. 28 In addition, the harmonized GRIN IRB protocol enabled contribution to the largest genetic studies in the field, including the most recent genome-wide association study (GWAS) by the International League Against Epilepsy (ILAE) 29 and a large burden analysis performed on more than 17,000 individuals with epilepsy. The GRIN support for these contributions removed institutional barriers for data sharing and provided infrastructure for effective patient recruitment and phenotyping.…”

Analisis Molekular dan Karakteristik Hidrogen Sianida (HCN)

“…Asam sianida akan larut dalam air (109; 110) , senyawa ini didalam air akanmembentuk ion CNdan ion H + .Senyawa dengan rumus kimia HCN cairan tak bewarna dan sangat beracun. Asam sianida memiliki bentuk molekul (115) linear (116)(117)(118)(119)(120) dengan momen dipol (121) Densitas (94; 125; 126) disebut juga dengan kerapatan merupakan massa per satuan volume suatu zat (211)(212)(213) pada suhu (127; 128) tertentu dan tidak hanya ditentukan gaya interaksi antar molekul (231)(232)(233)(234)(235) .Senyawa asam sianida memiliki sifat melarut sempurna pada air , dan sedikit larut dalam etanol. Ada beberapa faktor yang memengaruhi kelarutan suatu senyawa diantaranya sifat dari zat terlarut (solute) (139)(140)(141)(142)(143) dan pelarut (144) (solvent) (94; 129; 132; 145; 146) dimana zat terlarut yang bersifat polar (214)(215)(216) akan mudah larut dalam solvent (243)(244)(245)(246) atau yang disebut pelarut yang bersifat polar, begitupun sebaliknya, disini berlaku asas like dissolve like.…”