Prolonged apnea in a boy with epilepsy and a novel gain-of-function missense CACNA1A variant indicating SUDEP risk

Simone Pelizzari¹Marta Campiglio¹Yousra El Ghaleb¹Tatjana Bierhals²Maja Hempel³Jonas Denecke⁴Bernhard E Flucher¹Jessika Johannsen^4*

• ¹Department of Physiology and Medical Physics, Innsbruck Medical University, Innsbruck, Tyrol, Austria
• ²Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
• ³Institute of Human Genetics, University Heidelberg, Heidelberg, Germany
• ⁴Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

The CACNA1A gene encodes the pore-forming subunit of the Cav2.1 (P/Q type) neuronal calcium channel and pathogenic variants cause a variety of neurological disorders including episodic and congenital ataxia, familial hemiplegic migraine, developmental delay and epilepsy. Multiple types of seizures have been described in affected patients, including status epilepticus as the first manifestation. In mice harboring the homozygous gain-of-function variant p.Ser218Leu, seizures leading to SUDEP triggered by brainstem spreading depolarization with subsequent apnea and cardiac arrest have been reported. Here, we report on a 9-year-old boy with global developmental delay and congenital ataxia who developed recurrent seizures and status epilepticus with prolonged, life-threatening apnea implying a high risk for SUDEP. Genetic testing showed a novel de novo missense variant in CACNA1A (c.5398T>A, p.Phe1800Ile). Functional analysis revealed a gain of channel function as the molecular pathomechanism. Therefore, an increased risk of SUDEP in patients with CACNA1-associated epilepsy seems reasonable and preventive strategies should be discussed with caregivers.