Lecture 24- Epilepsy Flashcards

1
Q

What are ADNFLE and EIMFS?

A

-de novo mutations causing epilepsy

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2
Q

What is ADNFLE?

A
  • age of onset= 7 years old
  • cognitive dysfunction= mild
  • motor function= normal
  • response to antiepilepsy drugs= 50%
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3
Q

What is EIMFS?

A
  • 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
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4
Q

What are the mutations in?

A
  • KCNT1 also called Slack protein

- the mutations are part of the KCNT1 channel

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5
Q

What is the Slack channel function?

A
  • Activates in respond to increase in intracellular Na+
  • Mediates K+ outward current
  • Contributes to hyperpolarization after action potential firing
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6
Q

What do the KCNT1 mutations do about the Slack current?

A

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

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7
Q

What does gain of function correlate with?

A

-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

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8
Q

What is quinidine?

A
  • 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
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9
Q

Could quinidine be a potential therapeutic?

A

• Inhibit rodent Slack channels in expression systems

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

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10
Q

What does quinine do?

A

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

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11
Q

What is the case 1?

A

• 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

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12
Q

What is the case 2?

A

-also successful

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