Channelopathies

Question 1

Channelopathies

Answer 1

Related to Na+, Ca2+, K+, and Cl- channels
Normally, the inside of the neuron is negative compared to the outside
With cell depolarization, Na and Ca enter into the cell, making it more positive
With hyperpolarization, K+ leaves the cell and Cl- enters the cell

Question 2

Myotonia congenita

Answer 2

Three types
Thompson - AD, in infancy, mild myotonia and hypertrophy
Becker’s - AR, onset at 4-12 yo, more severe myotonia, muscle hypertrophy, “Herculean” phenotype
Myotonia levior: AD, later onset, mild myotonia, no muscle hypertrophy
Extreme muscle stiffness due to delay relaxation
“Warm up”, stiffness subsides with repeated muscle contraction
Allelic in CLCN1, a muscle CL channel

Question 3

Paramyotonia congenital

Answer 3

AD, Na channel mutations, allelic with the periodic paralyses
Similar to MC, failure of relaxation after muscle contraction
BUT
Temperature sensitive stiffness, may experience periodic paralysis
Provoked by cold
No “warm up” phenomenon. In fact, myotonia worsens with repeated muscle action
Typically more limited to forearm and facial muscles

Question 4

Hypokalemic periodic paralysis

Answer 4

AD, reduced penetrance, more common in males 3:1
Ca (type 1) and Na (type 2) channel mutations
Onset at any age, typically second decade
Can be provoked by low K, carbohydrate load (can trigger it via glucose load in clinical testing), alcohol, heavy exercise, cold, and emotional stressors
Attacks typically begin in AM, proximal>distal affect, respiratory muscles not affected, low serum K during attack, may have elevated CK
Weakness persists for hours with mild residual weakness for days

Type 1 is the dihydropiridine receptor (CACNA1S)

Tx: avoid triggers; carbonic anhydrase inhibitors such as acetazolamide and potassium-sparing diuretics are also useful in treating this condition.

Question 5

Hyperkalemic period paralysis

Answer 5

AD, highly penetrant
Na channel mutation (like hypoK PP type 1 and paramyotonia congenita) - SCN4A
Provoked by high K (provocative testing with administration of K), rest after heavy exercise, fasting, (hot and cold temperatures)
Onset commonly in infancy or childhood
Attacks one on quick, milder, briefer than hypoK variety <1 hr, serum K is typically normal
Residual weakness not typical

Treatment is focused on avoiding triggers. During attacks, glucose can be provided, and as prophylactic therapy, thiazide diuretics can be used.

Question 6

Episodic ataxia with myokymia

Answer 6

KCNA1 (K channel)

Question 7

Episodic ataxia with nystagmus

Answer 7

CACNA1A (Ca channel)

Question 8

Familial hemiplegic migraine Type 1 vs Type 2

Answer 8

Type 1: CACNA1A (Ca channel)
Type 2: ATP1A2 (Na/K pump)

SCN1A

Question 9

Benign familial neonatal convulsions

Answer 9

KCNQ2/KCNQ3 both K channels

Question 10

Severe myoclonic epilepsy of infancy aka Dravnet

Answer 10

SCN1A, Na channels
Also implicated in familial hemiplegic migrianes

Question 11

Generalized epilepsy with febrile seizures

Answer 11

SCNB2, SCNA1: Na channels

Maybe SCN2B SCN1A typ-o from powerpoint :/

Question 12

AD noturnal frontal lobe epilepsy

Answer 12

CHBRNA4, CHBRN2 - nicotinic acetylcholine receptors

Question 13

Sodium channelopathies

Answer 13

SCN4A - periodic paralysis
SCN1A/2A/1B - epilepsy
SCN5A - cardia arrhythmia

Question 14

Calcium channelopathies

Answer 14

Periodic paralysis CACNA1S
Migraine/episodic ataxia CACNA1A
Epilepsy multiple

Question 15

Potassium channel-patties

Answer 15

Periodic paralysis KCNE3
Cardiac arrhythmia multiple
Benign familial neonatal convulsions KCNQ2/KCNQ3
Anderson/Tawil KCNJ2

Question 16

Myotonia congenita

Answer 16

3 types
-Thompsen - AD, in infancy, mild (painless) myotonia and hypertrophy but no weakness
-Becker’s - AR, onset at 4-12 yo, more severe myotonia with associated weakness, muscle hypertrophy, “Herculean” phenotype
-Myotonia levior: AD, later onset, mild myotonia, no muscle hypertrophy
Extreme muscle stiffness due to delay relaxation
“Warm up”, stiffness subsides with repeated muscle contraction
Allelic in CLCN1, a muscle CL channel
The main manifestation is myotonia, which is an impaired muscle relaxation as seen when the patients cannot relax their handgrip after grasping an object, and also manifested on percussion, leading to contraction and delayed relaxation. Myotonic potentials can be detected on EMG. Propofol and depolarizing neuromuscular blocking agents may aggravate the myotonia, and patients may have prolonged recovery. Mexiletine is the treatment of choice.

Question 17

Paramyotonia congenita

Answer 17

AD, Na channel mutations, allelic with the periodic paralyse
Similar to MC, failure of relaxation after muscle contraction
BUT Temperature sensitive stiffness, may experience periodic paralysis provoked by cold. No “warm up” phenomenon. In fact, myotonia worsens with repeated muscle action
Typically more limited to forearm and facial muscles

This patient has paramyotonia congenita, which is an autosomal dominant channelopathy caused by a mutation in the sodium channel gene SCN4A. The manifestations are similar to those of myotonia congenita; however, unlike in myotonia congenita, in paramyotonia congenita, there is no “warm-up” phenomenon. Rather, repeated exercise accentuates myotonia, which is most clearly appreciated in the eyelids. Hence the name is derived from “para”-doxical reaction to exercise. Exposure to cold worsens the myotonia and may precipitate weakness, also in contrast to myotonia congenita. Percussion myotonia is rare, but can be seen after exposure to cold. EMG after cold exposure can also demonstrate fibrillation potentials followed by electrical inexcitability.

Question 18

Hypokalemic periodic paralysis

Answer 18

AD, reduced penetrance, more common in males 3:1
Ca (type 1) and Na (type 2) channel mutations
Onset at any age, typically second decade
Can be provoked by low K, carbohydrate load (can trigger it via glucose load in clinical testing), alcohol, heavy exercise, cold, and emotional stressors
Attacks typically begin in AM, proximal>distal affect, respiratory muscles not affected, low serum K during attack, may have elevated CK
Weakness persists for hours with mild residual weakness for days
Type 1 is the dihydropiridine receptor (CACNA1S)
Tx: avoid triggers; carbonic anhydrase inhibitors such as acetazolamide and potassium-sparing diuretics are also useful in treating this condition

Question 19

>Hyperkalemic period paralysis

Answer 19

AD, highly penetrant
Na channel mutation (like hypoK PP type 1 and paramyotonia congenita) - SCN4A
Provoked by high K (provocative testing with administration of K), rest after heavy exercise, fasting (hot and cold temperatures)
Onset commonly in infancy or childhood
Attacks are often quick, milder, briefer than hypoK variety <1 hr, serum K is typically normal
Residual weakness not typical
Treatment is focused on avoiding triggers.
During attacks, glucose can be provided, and as prophylactic therapy, thiazide diuretics can be used.