Similar early characteristics but variable neurological outcome of patients with a de novo mutation of KCNQ2
- Mathieu Milh1, 2Email author,
- Nadia Boutry-Kryza3,
- Julie Sutera-Sardo1, 2,
- Cyril Mignot4, 5, 6,
- Stéphane Auvin7,
- Caroline Lacoste8,
- Nathalie Villeneuve2,
- Agathe Roubertie9, 10,
- Bénédicte Heron6,
- Maryline Carneiro9,
- Anna Kaminska11,
- Cécilia Altuzarra12,
- Gaëlle Blanchard13,
- Dorothée Ville13,
- Marie Anne Barthez14,
- Delphine Heron4, 5,
- Domitille Gras7,
- Alexandra Afenjar5, 6,
- Nathalie Dorison6,
- Dianne Doummar6,
- Thierry Billette de Villemeur5, 6,
- Isabelle An15,
- Aurélia Jacquette4,
- Perrine Charles4,
- Julie Perrier16,
- Bertrand Isidor17,
- Laurent Vercueil18,
- Brigitte Chabrol1, 2,
- Catherine Badens1, 8, 19,
- Gaétan Lesca3 and
- Laurent Villard1, 19
© Milh et al.; licensee BioMed Central Ltd. 2013
Received: 8 March 2013
Accepted: 15 May 2013
Published: 22 May 2013
Early 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.
We 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.
Out 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.
This 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.
KCNQ2 encodes a channel subunit carrying the neuronal Im current whose inherited mutations were first described in autosomal dominant benign familial neonatal epilepsy (BFNE, OMIM#121200) [1–3]. Patients affected by a BFNE displayed stormy phase of motor seizures during the neonatal period, lasting 2 to 6 weeks in average. Interictal EEG was normal or slightly modified . Subsequently, seizure frequency quickly decreased and the vast majority of patients became seizure free before the age of three months . Motor and cognitive outcome were usually normal. Recently, de novo mutations of KCNQ2 have been described in early onset epileptic encephalopathies (EOEEs; OMIM#613720) [6–8]. EOEEs are a group of devastating epilepsies beginning before three months of age, with frequent seizures and abnormal interictal EEG leading to a rapid deterioration of motor, cognitive and sensori-neuronal functions. Patients carrying de novo KCNQ2 mutations displayed abnormal interictal EEG that could reveal multifocal spikes or a suppression-burst pattern, and all had poor neurological outcome [7, 8]. This dramatic form of KCNQ2-related epilepsy, with very poor neurological outcome, was unexpected. In order to assess the importance of KCNQ2 screening for the molecular diagnosis of early onset epilepsies, and mostly to describe the outcome of the sporadically mutated patients, we have analyzed a cohort of 71 patients with an early onset, severe epilepsy, without any familial history of epilepsy.
This study was approved by CPP Sud Méditerannée (Comité de protection des personnes). Seventy one patients were included in a cohort of subjects who displayed an early onset epileptic encephalopathy. All the patients or their parents gave their informed consent to join the cohort. Inclusion in the cohort was decided according to the following criteria; (1) epilepsy onset within the first 3 months of age; (2) abnormal interictal EEG (3) brain MRI without obvious cortical malformation or hypoxic lesion; (4) normal metabolic screening (exclusion of nonketotic hyperglycinemia, hyperammonemia, urea cycle defect, organic aciduria, hyperlactacidemia, pyridoxine-dependent and pyridoxal-dependent seizures); (5) No mutation of STXBP1, a major gene involved in early onset epileptic encephalopathy with or without suppression-burst ; (6) No mutation of ARX  in male patients (n=35); (7) patients must be regularly followed till now. All the girls that displayed early onset epileptic spasms and/or tonic seizures without any suppression-bursts were tested for CDKL5 (n=36). The epilepsy began during the neonatal period for 47/71 patients, the EEG showed a suppression-burst or discontinuous traces in 33 of them (Groupe A), and multifocal spikes in the remaining 14 (Groupe B). Epilepsy began between 1 and 3 months for the 24 patients of groupe C. The 18 coding exons (including alternative exons) of KCNQ2 were sequenced. Primer sequences are available upon request. The identified mutations were numbered according to the KCNQ2 reference sequence NM_172107.2.
Results and discussion
KCNQ2 mutations and main features of the patients
Seizure onset (days)
Initial seizure type
Development (age at evaluation)
Clonic and tonic. Multiple seizures daily.
2 weeks: seizure offset.
Poor eye contact, poor head control (9 months). Normal HC.
Myoclonic jerks. No erratic myoclonus.
0-3 months: myoclonic jerks.
Deceased at 17 months.
Bursts of polyspikes generalized or in the in central regions.
No eye contact, no head control. HC : 41cm.
3–6 months: reflex audiogenic seizures.
6–12 months: epileptic spasms.
>12 months: myoclonic jerks.
Tonic, pallor, Multiple seizures daily.
0-24 months: multiple daily focal seizures. 2–5 years: 1 seizure/week. 7 years: epilepsy offset.
Poor eye contact. Global hypotonia, unable to sit (2 years)
Tonic and hypotonic. Epileptic spasms.
2 months: seizure free. Erratic intermittent myoclonus.
Poor eye contact, no head control, global hypotonia (14 years). Normal HC.
Right temporal, asymptomatic seizures.
Tonic and tonic-clonic, cyanosis.
2-6 weeks: Tonic and tonic-clonic seizures in clusters. 2 m: seizure stop
Poor activity. Prolonged periods of flatness of the traces. Generalized spikes predominating on the left hemisphere. Then suppression-burst.
Good eye contact. Sitting, hand use (10 months). Walking (22 months).
No speech (4 y) Normal HC
Left and right clonic jerks, facial cyanosis.
3 months: Seizure offset.
Poor head control, unable to sit, no voluntary movement, no language (2 years).
Isolated access of cyanosis. Then recurrent hypertonic posture.
7 months: epileptic spasms.
Eye contact. Strabismus.
No sit, no speech (11 y).
Multiple focal seizures: tonic contractions of one or several limbs, cyanosis.
2–9 years: seizure-free.
> 9 years: monthly GTC seizures.
2 months: multifocal seizures. 4 months: rhythmic jerks. 3 years: tonic seizures, cyanosis. 3-11y: Persistence of tonic seizures, cyanosis.
Bursts of multifocal spikes and periods of poorness of the activity.
Unable to sit, poor use of hands. No language. Feeding difficulties (gastrostomy, 11 years)
0-6 months: multiple focal seizures. 6–24 months: epileptic spasms. Seizure free since then.
Poor eye contact. Global hypotonia, unable to sit (10 years)
Tonic and/or clonic, Multiple seizures daily.
>4 months: myoclonic jerks
Burst of asynchronous spikes and sharp waves. Periods of discontinuity with flatness of the traces without classical suppression burst.
Poor eye contact. Global hypotonia, poor head control, pyramidal signs (6 months)
Tonic, cyanosis, Multiple seizures daily.
0-19 days: multiple seizures. 6-18 m: no seizure. 18 m- 11y: several episodes of CTGC or PS with secondary generalization.
Left or right spikes on a moderately abnormal background.
Walking (18 months). Poor language, autistic features (11 years)
Partial motor seizure with asymmetric tonic extension of one limb. Bilateral clonic seizures. Apnea.
1 month: seizure free.
Slight peripheral hypertonia (3 months). Good outcome, walking (18 months), normal language (5 years)
Hemi corporeal, left or right.
0-11 months: partial clonic seizures. Then seizure offset.
Independent walking (4 y). No language (6.5 y). Normal HC 52.5 cm
Many motor seizures during the neonatal period. 2 m: Seizure stop. AED withdrawn at 4 years.
Asymmetrical suppression-burst with multifocal slow waves, left frontal and right occipital spikes. Periods of generalized flattening.
Sitting (3 y) hand stereotypies. Unable to walk/stand, stereotypies, pyramidal signs. Poor language. Normal HC (16 y).
Myoclonic jerks, Multiple seizures daily.
0-3 months: myoclonic jerks. 3 months: seizure offset. Therapy stopped at 6 months.
Sit (2 y). No walking, 2–3 words. Understands simple orders. Strabismus, nystagmus (3 y)
Bilateral tonic clonic And right clonic
0-3 y: active epilepsy, motor seizures 3-10 y: seizure free 10-20 y: monthly focal seizures
Slow waves with asynchronous bilateral spikes and intermittent flattening
First steps (18 m). Few words (3 y) Able to read but cannot write, limited communication skills, marked bradypsychia, hand stereotypies (26 y)
Data on initial evaluation and treatment, EEG evolution and brain MRI
Term. Clinical examination at birth
Treatment during the first month
EEG evolution (age)
Brain MRI (age)
Full term. Hypotonia. No eye contact. BW: 3000 g HC: 35 cm
1 m: Continuous with rare posterior spikes and fast rhythms
Day 7: Normal, absence of any signal abnormality. 2 y: Discrete global brain atrophy, thin corpus callosum
6 m: slow background, rare focal spikes.
34 GW Fetal distress, apnea, movements disorder BW: 2,040 g HC: 30 cm
MDZ, PHB, B6, TPM, VGB
0-7 m: Suppression-burst >7 m: Hypsarythmia
D13: absence of any signal abnormality. 3 m: Absence of signal abnormality
Full term Failure. to thrive. Feeding difficulties BW: 3,770 g HC: 37.5 cm
PHB, B6, PHT, VGB, TPM, CLB.
1-6 w: Asynchronous SB. 2-8 m: bilateral Bursts of central spikes 1-6 y: Bursts of rhythmic generalized spikes at 3 Hz
Day 3: T1 bilateral hypersignal of pallida, tegmentum, locus niger, hippocampi. Abnormal ADC in these regions. 2 y: T1 hypersignal of the same structures and diffuse T1 hypersignal of the white matter. Brain atrophy
Full term. Normal BW: 3,580 g HC: 37 cm
PHB, PHT, VPA
0-2 m: Suppression-burst. 2–12 m: hypsarythmia. >12 m: Frequent multifocal spikes
Day 7: Normal CT scan 2 y: Thin Corpus Callosum, absence of signal abnormality
Full term. Normal BW: 3,240 g HC: 34 cm
PHB, PHT, B6, VGB, VPA
0-2 m: Suppression-burst. 2–6 m: continuous, slow background, multifocal spikes. >6 m: Rare spikes in temporal and occipital lobes
Day 10: no signal abnormality.
Full term. Normal BW: 2,790 g HC: 34,5 cm
0-1 m: Suppression-burst. <1 m: Multifocal spikes, slow background
1 m: Normal
Full term. Normal BW: 3,180 g, HC: 36 cm
PHB, B6, PHT
0-1 m: Suppression-burst. 1–7 m: Continuous EEG, multifocal spikes 7–24 m: Hypsarythmic pattern. >24 m: Frequent spikes and spike wave in frontal regions
Day 4: Normal, absence of any signal abnormality
0-2 m: Bursts of multifocal spikes, periods of flatness. >2 m: Multifocal spikes, poor organization
1 y: No structural or signal abnormality.
At term. Hypotonia. No eye contact. BW: 3,450 g HC: 35 cm
PB, CZP, VGB
0-2 m: Suppression-burst 2–6 m: Slow background, rare generalized spike waves. 6–12 m: Hypsarythmic pattern. >12 m: Rare asynchronous frontal and temporal spikes
Day 10: Normal, absence of any signal abnormality
Full term. No eye contact BW: 3,120 g HC: 33 cm
PB, PHT, TPM, VGB, B6,
0-2 m: discontinuous EEG. >2 m: continuous, slow EEG with rare generalized spikes
Day 5: T1: symmetrical hypersignal of the pallida, caudate nuclei and hippocampi T2: bilateral hypersignal of the parietal occipital white matter
Full term. Hypotonia, hyporeactivity, failure to feed
PHB, PHT, VPA.
0-1 m: Left or right spikes on a moderately abnormal background. >1 m: Occipital or temporal spikes with left prominence with progressive migration on the central temporal region
1 m: normal
Full term. Normal BW and HC
0-2 m: Suppression-burst. 2–6 m: General slowing of the traces, no spike. 6 m-2 y: Rare spikes in the right central region, Normal background. >2 y: normal traces.
Day 7: T2 hyperintensity of the basal ganglia 2 y: Normal 3y: Normal
Full term. Fetal distress. BW, HC: ND
1 m: No structural abormality, no signal change
Full term. BW 3,750 g. Poor eye contact, trunk hypotonia with bouts of hypertonia
PHB, VGB, CBZ;
0-4 m: Asymmetrical suppression-burst 4-10 m: Left occipital spikes and slow waves 10 m-3 y: Normal background activity + posterior theta waves, No spike 3 y: Intermittent slow background, no spike >8 y: Normal
3 m: Normal
Oligoamnios Born at 30 Weeks (GA) BW: 1580 g HC: 29 cm
0-1 m: Suppression-burst >1 m: continuous traces (normal)
2 y: normal
Full term Global hypotonia, weak cry
0-1 m: absence of physiologic features, slow waves, spikes, brief flattening. 1–6 m: improvement of background activity, some generalized flattening episodes, left occipital slow waves. 6 m – 6 y: slow. background activity, rare spikes. 27 y: bilateral temporal slow waves. 30 y: normal background activity, bilateral fronto-temporal bursts of slow waves, photic stimulation-evoked slow spikes
17 y: slight T2 and FLAIR hyperintensity of thalami.
KCNQ2 is frequently found mutated de novo in early onset epileptic encephalopathies, especially if the epilepsy begins within the first week of life. Despite relatively stereotyped initial phenotype, the neurological and epileptic outcomes were highly variable, overall severe.
This work was supported by INSERM (Contrat d'Interface pour Hospitalier to MM), Programme Hospitalier de recherche Clinique, Aix Marseille Université and Assistance Publique Hôpitaux de Marseille (Contrat Hospitalier de Recherche Translationnelle to LV). We thank the Centre de Ressources Biologiques of La Timone Children’s Hospital for access to the biological samples used in this study.
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