Clinical Characteristics for Families

KCNQ2-related disorders are associated with a spectrum of disorders ranging from self-limiting (familial) neonatal epilepsy at the mild end to neonatal epilepsy with developmental delay (developmental and epileptic encephalopathy) at the severe end. Neonatal 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 KCNQ2, although some variability exists even among individuals carrying the same variant.

Self-limiting (familial) neonatal epilepsy (S(F)NE) is caused by mild loss of function variants (the potassium channel works less than normal) and is characterized by seizures starting between the first and eight day of life. Seizures have an asymmetric stiffening of the body (tonic), sometimes followed by jerking (clonic), and may occur multiple times a day. Changes in breathing pattern or hart rate 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 mostly 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 disability have been described.

KCNQ2-Developmental and epileptic encephalopathy (KCNQ2-DEE) is the most common cause of neonatal epilepsy with moderate to severe developmental delay, and is caused by severe loss-of-function variants (the potassium channel works even less than seen in S(F)NE). Epilepsy emerges during the first week of life (often during the first 24 houres of life) with frequent seizures with a prominent stiffening of the body (tonic component) and with or without changes in breath pattern and hart rate, sometimes progressing to jerking (clonic). This stormy phase of tonic seizures associated to an abnormal EEG pattern lasts 2 to 15 weeks and usually gives place to a calmer period of more 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 global neurological impairment. The vast majority of patients have language problems, autistic behavior, visual impairment, gastro-intestinal problems (f.e. gastrostomy tube dependent), and significant motor impairment. However, some individuals are able to walk independently and use a few words.

KCNQ-encephalopathy without neonatal epilepsy is mostly associated with gain-of function variants (potassium channel is open more than it should be). Patients have developmental delay and variable degree of intellectual disability with or without autistic features. Intellectual disability ranges from profound impairment with respiratory distress to moderate impairment. Although most patients have epileptic disturbances on (sleep-)EEG, seizures are not always present, and if they occur, start after the neonatal period.

Some patients carrying KCNQ2 gain-of-function variants (mainly R201C, R201H, and V175L variants) present with non-epileptic irregular involuntary contraction of a muscle (myoclonus), respiratory distress, and altered pattern on EEG. They have prominent developmental delay and low muscle tone at birth. The non-epileptic myoclonus is triggered by tactile or acoustic stimuli. Some patients develop infantile spasms.

Other patients carrying KCNQ2 gain-of-function variants (mainly R198Q variants) have a normal start but present with infantile spasms between 4 and 6 months of age. Subsequently, developmental delay and intellectual disability manifest.

Myokymia (muscle twitching) is rarely associated with KCNQ2-related disorders, and presents at adolescent or adult age of some individuals that often had a history of neonatal seizures.