CACNA1A, encoding the pore-forming α1 subunit of P/Q-type voltage-gated calcium channels, is crucial for normal neurological function. These channels are involved in processes such as neurotransmitter release at synapses, which is essential for proper neuronal communication [3].

Pathogenic variants in CACNA1A have been associated with a wide range of neurological phenotypes. These include episodic ataxia type 2, familial hemiplegic migraine, spinocerebellar ataxia 6, as well as developmental delay, epilepsy, paroxysmal dystonia, and neuropsychiatric disorders [1]. In a study of 18 patients with CACNA1A mutations, different electro-clinical phenotypes were observed, often associated with permanent cerebellar dysfunction and moderate to severe global developmental delay/intellectual deficiency. Gain-of-function (GOF) variants were related to intractable seizures, early and recurrent status epilepticus, and hemiplegic accesses, while loss-of-function (LOF) variants were associated with refractory early-onset absence seizures [2].

In conclusion, CACNA1A is essential for normal neuronal function, especially in processes related to synaptic transmission. Studies of CACNA1A-related disorders have shown its significance in a variety of neurological diseases. Understanding the role of CACNA1A through functional studies, including those potentially involving gene knockout or conditional knockout mouse models, can provide insights into the pathogenesis of these disorders, which may aid in developing more targeted treatment strategies [1,2,3].

References:

1. Lipman, Amy R, Fan, Xiao, Shen, Yufeng, Chung, Wendy K. 2022. Clinical and genetic characterization of CACNA1A-related disease. In Clinical genetics, 102, 288-295. doi:10.1111/cge.14180. https://pubmed.ncbi.nlm.nih.gov/35722745/

2. Le Roux, Marie, Barth, Magalie, Gueden, Sophie, Riant, Florence, Van Bogaert, Patrick. 2021. CACNA1A-associated epilepsy: Electroclinical findings and treatment response on seizures in 18 patients. In European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 33, 75-85. doi:10.1016/j.ejpn.2021.05.010. https://pubmed.ncbi.nlm.nih.gov/34102571/

3. Hommersom, Marina P, Doorn, Nina, Puvogel, Sofía, Nadif Kasri, Nael, van Bokhoven, Hans. . CACNA1A haploinsufficiency leads to reduced synaptic function and increased intrinsic excitability. In Brain : a journal of neurology, 148, 1286-1301. doi:10.1093/brain/awae330. https://pubmed.ncbi.nlm.nih.gov/39460936/