KCNQ2-related disorders are caused by a change in the genetic material (pathogenic variants) in the KCNQ2 gene located on chromosome 20. KCNQ2 encodes for voltage gated potassium channel subunits which are widely expressed in the nervous system. These subunits form channels to generate the M-current (IKM). This current suppresses repetitive transmission of electrical signals (neuronal firing). In this way, it has a critical role in controlling neuronal excitability.
Pathogenic variants in KCNQ2 represent one of the most common causes of childhood-onset genetic epilepsies, with an incidence in young population of 1 per 17000 live births. Most disease-causing KCNQ2 variants cause the potassium channel to be closed more than it should be (loss-of-function) and have been associated with a broad spectrum of neonatal-onset epilepsy with or without developmental delay. KCNQ2 variants that open the potassium channel more than it should be (gain-of-function) are mainly characterized by developmental delay and autistic features without neonatal seizures. More rarely, patients with myokymia (muscle twitching), self-limiting infantile seizures or infantile spasms are described. In addition, behavioral disorders, like autism spectrum disorders or attention deficit hyperactivity disorder, are frequently associated with KCNQ2-related disorders.
Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother.
Pathogenic variants are inherited by an autosomal dominant mode. This means that one of the two KCNQ2 copies with a variant is enough to cause the disease. Mildly affected patients associated with self-limiting neonatal seizures without developmental delay often inherited the variant from a parent. In contrast, almost all severely affected individuals with developmental delay have a new, spontaneous mutation and is not inherited (de novo).
KCNQ2