Similar early characteristics but variable neurological outcome of patients with a de novo mutation of KCNQ2

Abstract

BackgroundEarly onset epileptic encephalopathies (EOEEs) are dramatic heterogeneous conditions in which aetiology, seizures and/or interictal EEG have a negative impact on neurological development. Several genes have been associated with EOEE and a molecular diagnosis workup is challenging since similar phenotypes are associated with mutations in different genes and since mutations in one given gene can be associated with very different phenotypes. Recently, de novo mutations in KCNQ2, have been found in about 10% of EOEE patients. Our objective was to confirm that KCNQ2 was an important gene to include in the diagnosis workup of EOEEs and to fully describe the clinical and EEG features of mutated patients.MethodsWe have screened KCNQ2 in a cohort of 71 patients with an EOEE, without any brain structural abnormality. To be included in the cohort, patient’s epilepsy should begin before three months of age and be associated with abnormal interictal EEG and neurological impairment. Brain MRI should not show any structural abnormality that could account for the epilepsy.ResultsOut of those 71 patients, 16 had a de novo mutation in KCNQ2 (23%). Interestingly, in the majority of the cases, the initial epileptic features of these patients were comparable to those previously described in the case of benign familial neonatal epilepsy (BFNE) also caused by KCNQ2 mutations. However, in contrast to BFNE, the interictal background EEG was altered and displayed multifocal spikes or a suppression-burst pattern. The ongoing epilepsy and development were highly variable but overall severe: 15/16 had obvious cognitive impairment, half of the patients became seizure-free, 5/16 could walk before the age of 3 and only 2/16 patient acquired the ability to speak.ConclusionThis study confirms that KCNQ2 is frequently mutated de novo in neonatal onset epileptic encephalopathy. We show here that despite a relatively stereotyped beginning of the condition, the neurological and epileptic evolution is variable.

A Kv7.2 mutation associated with early onset epileptic encephalopathy with suppression‐burst enhances Kv7/M channel activity

“…We recently identified the mutation p.V175L located in S3 region of Kv7.2 in a patient with EOEE. 9 Herein we show that this mutation increases Mchannel activity and does not affect channel distribution in neurons.…”

A Distinctive Ictal Amplitude-Integrated Electroencephalography Pattern in Newborns with Neonatal Epilepsy Associated with <b><i>KCNQ2</i></b> Mutations

“…Mutations in KCNQ2 , a gene encoding the voltage-gated potassium channel Kv7.2, were initially discovered in patients with BFNS [6], and later in infants with a neonatal form of epileptic encephalopathy . Mutations in this gene are frequently seen in patients or families with early-onset epilepsy [14] and are estimated to cause between 13 and 23% of all neonatal epileptic encephalopathies [7,8,9,11]. …”

“…Mutations in KCNQ2 , encoding the voltage-gated potassium channel Kv7.2, were first described in autosomal dominant benign familial neonatal seizures (BFNS) a self-limiting form of neonatal epilepsy with favorable outcome [6] . Recently, de novo mutations of KCNQ2 have been reported in children with refractory seizures and poor neurodevelopmental outcome [7,8,9]. KCNQ2-related epilepsies are characterized by recurrent seizures with onset during the first week after birth.…”

Epilepsy genetics: The ongoing revolution

“…STXBP1 mutations are, so far, the most frequent causes of OS/EOEE. In 2012, the finding that de novo mutations of KCNQ2 account for a significant proportion of patients with OS/EOEE was unexpected [69][70][71]. The epileptic features of these patients were comparable, at onset, to those with BFNE but their interictal EEG background displayed multifocal spikes or a suppression burst pattern.…”