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

Area of Science:

• Neuroscience
• Genetics
• Channelopathies

Background:

• The CACNA1A gene encodes the Cav2.1 (P/Q type) neuronal calcium channel, crucial for neuronal excitability.
• Pathogenic variants in CACNA1A are associated with diverse neurological disorders, including epilepsy, ataxia, and developmental delay.
• Status epilepticus and apnea are recognized complications, raising concerns for Sudden Unexpected Death in Epilepsy (SUDEP).

Purpose of the Study:

• To investigate the genetic and functional basis of a novel CACNA1A variant in a patient with severe neurological symptoms.
• To assess the risk of SUDEP in individuals with CACNA1A-associated epilepsy.

Main Methods:

• Clinical data collection from a pediatric patient with global developmental delay, congenital ataxia, and recurrent seizures.
• Genetic testing to identify variants in the CACNA1A gene.
• Functional analysis of the identified CACNA1A variant to determine its impact on channel function.

Main Results:

• A novel de novo missense variant (c.5398T>A, p.Phe1800Ile) in the CACNA1A gene was identified in the patient.
• Functional studies confirmed a gain-of-function mechanism for the identified variant, leading to increased channel activity.
• The patient presented with global developmental delay, congenital ataxia, recurrent seizures, status epilepticus, and life-threatening apnea, indicating a high SUDEP risk.

Conclusions:

• The novel CACNA1A variant contributes to a severe phenotype including epilepsy and apnea.
• Patients with CACNA1A-associated epilepsy face an elevated risk of SUDEP.
• Preventive strategies and discussions with caregivers are crucial for managing SUDEP risk in these patients.