Lecture 24- Epilepsy Flashcards
What are ADNFLE and EIMFS?
-de novo mutations causing epilepsy
What is ADNFLE?
- age of onset= 7 years old
- cognitive dysfunction= mild
- motor function= normal
- response to antiepilepsy drugs= 50%
What is EIMFS?
- age of onset= 3 to 6 months of age
- cognitive dysfunction= severe
- motor function= developmental arrest
- no response to antiepilepsy drugs
- • EIMFS is a more severe form of epilepsy than ADNFLE
- • So far, genetic background or environmental factors cannot explain the clinical heterogeneity
What are the mutations in?
- KCNT1 also called Slack protein
- the mutations are part of the KCNT1 channel
What is the Slack channel function?
- Activates in respond to increase in intracellular Na+
- Mediates K+ outward current
- Contributes to hyperpolarization after action potential firing
What do the KCNT1 mutations do about the Slack current?
-increase Slack current
• Both ADNFLE and EIMFS mutations increase Slack current response
• KCNT1 mutations cause gain of function
What does gain of function correlate with?
-gain of function correlates with disease severity
• Pooling individual mutations across syndromes to remove genetic background “noise”
• Gain of function: EIMFS (5-fold) ADNFLE (3-fold)
• Disease severity: EIMFS > ADNFLE
What is quinidine?
- Cinchona bark extract used by Quechua people of Peru to stop cold induced shivering. Major commercial plant in Europe and eventually reaching the British colonies in the 19th century as a fortuitous treat for malaria
• Amongst other alkaloids, the bark contains quinine, the anti-malarial and quinidine, an anti-arrhythmic
• Quinidine
– FDA approved, indicated for abnormal heart rhythms
– Blocks Na+ channels
– Side effects and toxicity well characterized
Could quinidine be a potential therapeutic?
• Inhibit rodent Slack channels in expression systems
-• Will quinidine inhibit human Slack and rescue channel function?= yes! it decreases the firing
What does quinine do?
-Quinidine reverses effects of KCNT1 mutations
• Quinidine effectively inhibits human Slack current
• Returned most ADNFLE mutants to WT level
• EIMFS mutants are partially reversed
What is the case 1?
• Female 11 years old
• At 2.5 years age presented with 40 seizures per day and regressed to
non-ambulatory non-verbal state
• After one day of quinidine 19 mg/kg/d, seizures dropped to 2/d at 12 mg/kg/day seizures were 3/d
• Improved bladder control, alertness, head control, sitting for first time
What is the case 2?
-also successful