CACNA1E encephalopathy: a new calcium channel disease

The calcium connection. Pathogenic variants in genes encoding voltage-gated ion channels have long been known to cause neurological disorders in people. Dravet syndrome, caused by pathogenic variants in the neuronal sodium channel-encoding gene SCN1A, is one of the most common channelopathies. Although sodium and potassium channels play an established role in childhood-onset epilepsies, the role of voltage-gated calcium channels has been less clear. We have known for over a decade that disease-causing variants in CACNA1A cause a spectrum of neurological disorders, including developmental and epileptic encephalopathies. But evidence of a role for other neuronal calcium channels in epilepsy has been sparse until now. Our publication in the American Journal of Human Genetics now explores the phenotype and functional consequences of de novo variants in CACNA1E, representing a new and unexpectedly frequent disease entity.
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The two faces of KCNA2 – a novel epileptic encephalopathy

Delayed rectifier. The discovery of de novo mutations in ion channel genes as a cause for genetic epilepsies continues. In a recent publication in Nature Genetics, we have identified de novo mutations in KCNA2 as a novel cause of epileptic encephalopathies associated with ataxia. Interestingly, even within a single gene, two different phenotypes seem to be emerging. Continue reading

Dravet Syndrome and rare variants in SCN9A

How monogenic is monogenic? Dravet Syndrome is a severe epileptic encephalopathy starting in the first year of life. More than 80% of patients have mutations or deletions in SCN1A, which makes Dravet Syndrome a relatively homogeneous genetic epilepsy. In addition to SCN1A, other genetic risk factors for Dravet Syndrome have been suggested, and current, large-scale studies including EuroEPINOMICS-RES are studying the genetic basis of the minority of Dravet patients negative for SCN1A. A recent paper in Epilepsia now suggests that a significant fraction of patients with Dravet Syndrome also carry rare variants in SCN9A in addition to the mutations in SCN1A. Is a mutation in SCN1A not sufficient to result in Dravet Syndrome, but needs additional genetic modifiers? Continue reading

“Meta-channelopathies” – RBFOX1 deletions and human epilepsy

Man is built to seize. When Hughlings Jackson made this famous comment pertaining to the inherent hyperexcitability of the human brain in response to a wide range of different stimuli, he probably didn’t anticipate the mechanisms of splicing regulation. Our CNS is actively protected from hyperexcitability through directed splicing of ion channel mRNA. Now, a recent study in Epilepsia finds that these mechanisms may be dysfunctional in human epilepsy. Continue reading

Seizures beget seizures through splicing in flies

The dynamic genome. Up to 95% of human genes undergo a process called alternative splicing. For these genes, several exons are present, which can be used alternatively or can be omitted. Accordingly, a single pre-mRNA can result in a variety of different proteins with different properties. For key players such as voltage-dependent sodium channels, it is therefore interesting to know which role alternative splicing plays in epilepsy. However, the splicing landscape of human sodium channels is complicated and difficult to investigate. Therefore, a model system is required where simple questions can be asked. A recent study now reveals interesting findings related to sodium channel splicing and seizure in the fruit fly.  Continue reading