KCNQ3-related disorders are associated with a spectrum of disorders ranging from self-limiting (familial) neonatal/infantile epilepsy at the mild end to neonatal epilepsy with developmental delay (developmental and epileptic encephalopathy) at the severe end. Neonatal or infantile seizures are the main features, but patients without neonatal seizures are described. The disease characteristics are mainly defined by the type of variant one has in KCNQ3, although some variability exists even among individuals carrying the same variant.
Self-limiting (familial) neonatal epilepsy (S(F)NE) is caused by loss of function variants (the potassium channel works less than normal) and is characterized by seizures starting between the first and the eighth day of life. During a seizure there is asymmetric stiffening of the body (tonic), sometimes followed by jerking (clonic), and this may occur multiple times a day. Changes in breathing pattern or hart rate are also described. 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 learning disability have been described.
Self-limiting (familial) infantile epilepsy (S(F)IE) is caused by loss of function variants (the potassium channel works less than normal) and is characterized by seizures starting in the first year of life. Seizure semiology is typically focal, that can generalize causing diffuse stiffening of the body with jerks of the limbs, head deviation, or motor arrest with unconsciousness and skin turning blue or purple (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) is characterized by neonatal epilepsy with mild to moderate developmental delay and is caused by two loss-of-function variants (the potassium channel works even less than seen in S(F)NE). 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 with language problems and motor impairment. Additionally, cortical visual impairment is described in some. Brain MRI is often normal.
KCNQ3-encephalopathy without neonatal epilepsy is mostly associated with (R230H, R230C, R230S, and R227Q) gain-of function variants (potassium channel is open more than it should be). Patients have developmental delay and autistic features. Although most patients have epileptic disturbances on (sleep-)EEG, seizures are not always present, and if they occur, start after the neonatal period.
KCNQ3