This document summarizes current research on KCNQ2 mutations and KCNQ2 encephalopathy. It discusses how KCNQ2 mutations were discovered in patients with benign familial neonatal seizures (BFNS) in 1998. More recently, de novo KCNQ2 mutations have been found to cause KCNQ2 encephalopathy, an early-onset epileptic encephalopathy associated with intellectual disability. These mutations have a dominant negative effect on channel function. Retigabine, a potassium channel opener, shows promise in treating seizures caused by KCNQ2 encephalopathy. Further research is needed to better understand genotype-phenotype correlations, treatment responses, functional consequences of mutations, and potential therapies.
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1. KCNQ2 discovery and research:
what do we know and where to go
Dr. Sarah Weckhuysen, MD, PhD
Neurogenetics Group, VIB-Department of Molecular Genetics
University of Antwerp, Belgium
7. Causes of epilepsy
Idiopathic(Genetic)
Stroke
MR/CP
Head trauma
Brain tumor
Infection
Others
From: Annegers JF. The Epidemiology of epilepsy. In: Elaine Wyllie.
The Treatment of Epilepsy.
13. 1998: KCNQ2 mutations in Benign
Familial Neonatal Seizures (BFNS)
• Mostly familial
• Seizures onset between 2 - 8 days, remission
within first months of life
• Investigations normal
• Psychomotor development normal
15. Where the story starts
KCNQ2 screening offered for neonatal
seizures in diagnostic unit
◦ 2010: 1 patient: refractory seizures and
psychomotor regression
Literature
◦ 4 case reports of patients with neonatal
seizures and intellectual disability
(Dedek et al 2003, Borgatti et al 2004, Schmitt et al 2005,
Steinlein et al. 2007)
16. Methods
• KCNQ2 and KCNQ3 screening in 80
patients with unexplained neonatal or
early onset epileptic encephalopathy
• Onset of seizures < 3 months
• Slowing of psychomotor development
• Metabolic screening normal
• Imaging: no explanation
• Genetic screening for relevant genes normal
Weckhuysen et al, Ann. Neurol. 2012
17. Results
No KCNQ3 mutations
7 novel KCNQ2 mutations in 8/80 patients (10%)
Inheritance
Heterozygous
Almost all mutations de novo
1 mosaic father with benign neonatal seizures
Weckhuysen et al, Ann. Neurol. 2012
18.
19.
20. September 2014
◦ 62 patients with KCNQ2 encephalopathy
described in literature
44 different mutations
23. KCNQ2 encephalopathy
• 10% of patients with neonatal epileptic
encephalopathy of unknown etiology
• KCNQ2 encephalopathy mutations
Novel: not reported in BFNS
• Inheritance
de novo
1 mosaic father with benign seizures
24. KCNQ2 encephalopathy
• Neonatal onset
1 patient onset at 5 months
• Seizure type at onset
Motor seizures, prominent tonic component
Often autonomic features: apnea, desaturation, bradycardia
• Dramatic onset, multiple sz daily
• Abnormalities on EEG
• Range of severity of intellectual disability
43. Functional
What are the consequences of
different KCNQ2 mutations
◦ Potassium channel function
◦ Excitability of neurons
◦ Brain functioning
◦ Brain structure
Reversal of mutational effect
◦ Retigabine and other drugs
◦ Gene therapy
◦ Time frame
47. Neurogenetics group -
epilepsy
◦ Rik Hendrickx
◦ Tine Deconinck
◦ Jolien Roovers
◦ Tania Djémié
◦ Katia Hardies
◦ Arvid Suls
◦ Peter De Jonghe
SPECIAL THANKS TO:
Parents and patients with
KCNQ2 mutations
All collaborators and treating
physicians of patients with
KCNQ2 mutations
Notas del editor
1h
FIGUUR!
After 2007: silence
Mutations affecting the pore region of the Kv7.2 channels showed a striking loss-of-function. Up: when expressed in Xenopus laevis oocytes, they yielded almost no currents. Below: In these experiments the injected amont of the WT was the same when it was expressed alone (left) or together with each of these mutations (right), but in the presence of mutations the WT currents were dramatically reduced, revealing that the mutant channels exerted a strong dominant-negative effect on the WT channel. The dominant-negative effect is known only for a few Kv7.2 mutations associated with neonatal seizures and is not as pronounced.
Doxycycline during the first 1–3 weeks of life
=> normal KCNQ channels during early development, blocked channels thereafter
To analyse the functional impact of Kv7.2 Mutations, they were expressed in Xenopus laevis oocytes and currents were recorded using a fully automated two-microelectrode voltage clamp system. Currents were elicited by 2.5 s long depolarizing steps from a holding potential at -80 to +60 mV, in 10 mV steps. Representative current traces are shown on the right.
