KCNQ2-related disorders are associated with different phenotypes ranging from self-limiting (familial) neonatal epilepsy at the mild end to developmental and epileptic encephalopathy at the severe end. Neonatal seizures are the main features, but patients without neonatal seizures are described.
Self-limiting (familial) neonatal epilepsy (S(F)NE) is characterized by seizures starting between the first and eight day of life. Seizures have an asymmetric tonic semiology, sometimes followed by clonic jerks (sequential seizures), and may occur multiple times a day. Apneic episodes or autonomic changes are also described. Seizures generally disappear between the first and 15th 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 (10-15%), and variable degrees of learning disabilities, even within a family, have been described.
KCNQ2-Developmental and epileptic encephalopathy (KCNQ2-DEE) due to loss-of-function variants is the most common cause of neonatal epilepsy with moderate to severe developmental delay. Epilepsy emerges during the first week of life (often during the first 24 houres of life) with frequent seizures with a prominent tonic component and with or without autonomic features, sometimes progressing to clonic jerking. This stormy phase of tonic seizures associated to an abnormal (excessive sharp waves and discontinuity) EEG pattern lasts 2 to 15 weeks and usually gives place to a calmer period of rare seizures and significant amelioration of the EEG. Despite this apparent positive evolution in terms of seizures, the developmental process is definitively altered and leads to a severe and global neurological impairment. The vast majority of patients have no informative language, autistic behavior, visual impairment, gastro-intestinal problems (for example gastrostomy tube dependent), and significant motor impairment such as spastic tetraparesis, ataxia, global hypotonia or dystonia. However, some individuals are able to walk independently and use a few words. Brain MRI can either be normal or shows temporary T2 hyperintensities in deep nuclear structures (e.g., basal ganglia, thalamus).
KCNQ-encephalopathy without neonatal epilepsy is associated with gain-of function variants. Patients have developmental delay and variable degree of intellectual disability with or without autistic features. Intellectual disability ranges from profound impairment with central hypoventilation to moderate impairment. Although most patients have epileptic disturbances on (sleep-)EEG, seizures are not always present, and if they occur, starting after the neonatal period.
Some patients carrying KCNQ2 gain-of-function variants (mainly R201C, R201H, and V175L variants) present with neonatal non-epileptic myoclonus, central hypoventilation, and suppression-burst EEG. They have prominent developmental delay and are hypotonic at birth. The non-epileptic myoclonus is triggered by tactile or acoustic stimuli. Some patients develop infantile spasms at a few months of age as the EEG pattern evolves to hypsarrhythmia. Prognosis is poor; central hypoventilation and risk for aspiration pneumonia often create a need for respiratory support and gastrostomy tube placement. Brain MRI shows a thin corpus callosum, progressive volume loss and hypomyelination.
Other patients carrying KCNQ2 gain-of-function variants (mainly R198Q variants) present with infantile spasms (without previous neonatal seizures) and hypsarrhythmia on EEG between 4 and 6 months of age. Subsequently, severe developmental delay and intellectual disability manifest. Brain MRI shows mild cerebral volume loss.
Myokymia (peripheral nerve hyperexcitability) is rarely associated with KCNQ2-related disorders, and can be caused by KCN2-DEE pathogenic variants.
KCNQ2