KCNQ3-related disorders are associated with a spectrum of neurological phenotypes ranging from self-limiting (familial) neonatal/infantile epilepsy at the mild end to developmental and epileptic encephalopathy at the severe end. The large majority of patients present with neonatal seizures, but patients without neonatal seizures are described.
Self-limiting (familial) neonatal epilepsy (S(F)NE) due to heterozygous loss-of-function variants is characterized by seizures starting between the first and the eighth days of life. Seizure semiology is typically characterized by asymmetric tonic posturing, sometimes evolving to clonic jerking. Apneic episodes or autonomic changes are often associated. Seizures generally disappear between the first and 12th month of life. Sodium-channel blockers are considered as first-line treatment and seizures are usually treatment-responsive. Brain imaging is normal. Patients have a favorable long-term prognosis, and psychomotor development and clinical neurological examination are usually normal, although some patients with prolonged neonatal seizures, seizure recurrence later in life, and variable degrees of cognitive impairment, even within a family, have been described.
Self-limiting (familial) infantile epilepsy (S(F)IE) due to heterozygous loss-of-function variants is characterized by seizures starting in the first year of life. Seizure semiology is typically focal, but can generalize causing diffuse hypertonia with jerks of the limbs, head deviation, or motor arrest with unconsciousness and cyanosis. Seizures generally disappear between the first and second year of life. Sodium-channel blockers are considered as first-line treatment and seizures are usually treatment-responsive. Brain imaging is normal. Patients have a favorable long-term prognosis, and psychomotor development and clinical neurological examination are usually normal.
KCNQ3-Developmental and epileptic encephalopathy (KCNQ3-DEE) due to biallelic loss-of-function variants is characterized by neonatal epilepsy with mild to moderate developmental delay. Epilepsy emerges during the first week of life. After several months to years, seizures disappear, and EEG significantly ameliorate, although seizure recurrence is described. Despite this apparent positive evolution in terms of seizures, the developmental process is definitively altered and leads to a mild to moderate neurological impairment. Cortical visual impairment is described in some patients. Brain MRI is generally normal.
KCNQ3-encephalopathy without neonatal epilepsy due to de novo gain-of function variants (mainly R230H, R230C, R230S, and R227Q variants). Patients have autistic features and global developmental delay. Most children are able to walk but have prominent language impairment. Although EEG shows frequent sleep-activated multifocal epileptiform discharges, most patients do not have seizures. If they occur, seizures start after the neonatal period. Brain MRI is normal or shows non-specific abnormalities.
KCNQ3