Lecture 24- Epilepsy

Question 1

What are ADNFLE and EIMFS?

Answer 1

-de novo mutations causing epilepsy

Question 2

What is ADNFLE?

Answer 2

• age of onset= 7 years old
• cognitive dysfunction= mild
• motor function= normal
• response to antiepilepsy drugs= 50%

Question 3

What is EIMFS?

Answer 3

• 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

Question 4

What are the mutations in?

Answer 4

• KCNT1 also called Slack protein

- the mutations are part of the KCNT1 channel

Question 5

What is the Slack channel function?

Answer 5

• Activates in respond to increase in intracellular Na+
• Mediates K+ outward current
• Contributes to hyperpolarization after action potential firing

Question 6

What do the KCNT1 mutations do about the Slack current?

Answer 6

-increase Slack current
• Both ADNFLE and EIMFS mutations increase Slack current response
• KCNT1 mutations cause gain of function

Question 7

What does gain of function correlate with?

Answer 7

-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

Question 8

What is quinidine?

Answer 8

• 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

Question 9

Could quinidine be a potential therapeutic?

Answer 9

• Inhibit rodent Slack channels in expression systems

-• Will quinidine inhibit human Slack and rescue channel function?= yes! it decreases the firing

Question 10

What does quinine do?

Answer 10

-Quinidine reverses effects of KCNT1 mutations
• Quinidine effectively inhibits human Slack current
• Returned most ADNFLE mutants to WT level
• EIMFS mutants are partially reversed

Question 11

What is the case 1?

Answer 11

• 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

Question 12

What is the case 2?

Answer 12

-also successful