Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Abstract

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Ca_v2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca²⁺ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Ca_v2.2 in normal human neurodevelopment.

Keywords: CACNA1B; developmental and epileptic encephalopathy (DEE); epilepsy; epilepsy-dyskinesia.

Figure 1

Molecular Genetic Investigation and Electroencephalogram Features of Affected Individuals with Bi-allelic CACNA1B Variants (A) Segregation of CACNA1B c.3665del variant in family A shows all three affected children to be homozygous for the variant and parents to be heterozygous carriers of this variant. (B) In family B, the two affected individuals carried the two rare variants, c.3573_3574del and c.4857+1G>C. The mother is heterozygous for one of the variants. (C) For family C, the affected child is homozygous for the c.1147 C>T variant. Parental samples were not available. (D–G) EEG traces from affected individuals. An EEG of individual A-II:3 shows epileptic encephalopathy at age 3.75 years (D), with bilateral high-amplitude spike and wave discharges with spasm (arrow), and at age 4.75 years (E), with bilateral continuous high-amplitude spike and wave discharges that were maximal over central regions. An EEG of individual B-II:2 at age 9 years (HF filter, 70 Hz; sensitivity, 15 μV/mm; timebase, 30 mm/s) shows a burst suppression pattern in sleep (F) and fairly continuous, high-amplitude, multi-focal spike and wave activity that was maximal over central regions during wakefulness (G).

Figure 2

Schematic Representation of Ca_v2.2, Showing Location of CACNA1B Variants The structure of Ca_v2.2 consists of four homologous repeats (domains I–IV), each containing six transmembrane α-helices (S1–S6) and a p loop between S5 and S6. The S5 and S6 helices and the p loop represent the pore domain of the channel (green). The fourth segment (S4) of each domain is the voltage sensor for activation. Gene variants identified in families A, B, and C are indicated in red (these are loss-of-function variants). The previously reported heterozygous missense variant associated with myoclonus dystonia is highlighted in yellow. Abbreviations are as follows: Gβγ, G protein βγ subunit; P, binding site of PKC; PKC, protein kinase C.