Queen Square Centre for Neuromuscular Diseases

Muscle Channelopathies

Professor Michael G Hanna

25.3.17

What is a skeletal muscle channelopathy?

Muscle and nerves communicate by electrical signals

Electrical signals are made by the movement of positively and negatively charged ions in and out of cells

The ions can only move through dedicated ion channels

Dysfunction disturbs muscle membrane excitability

Genetic disorders

Episodic

Myotonia and paralysis

• Two main symptoms

• Paralysis = an inexcitable muscle

– Muscles are very weak or paralysed

• Myotonia = an overexcited muscle

– Muscle keeps contracting and become “stuck”

• Myotonia congenita – CLCN1

• Paramyotonia congenita – SCN4A

• Hyperkalaemic periodic paralysis – SCN4A

• Hypokalaemic periodic paralysis – 80% CACNA1S

– 10% SCN4A

• Andersen-Tawil Syndrome – KCNJ2 (+KCNJ5)

• Thyrotoxic periodic paralysis – KCNJ18

MYOTONIA

PARALYSIS

POTASSIUM CHANNELS

CHLORIDE CHANNELS

SODIUM CHANNELS

CALCIUM CHANNELS

Sodium and chloride channels

Na+ channels open

Depolarisation due to Na+ entry

Na+ channels close K+ channels open

Repolarisation due to K+ exit

K+ channels close

Cl-

-

+

What is myotonia?• Clinically: delayed muscle relaxation after forced

contraction

• Muscle are “stuck”, “stiff”, “cramp”

Electrophysiologically: spontaneous depolarisations of the muscle membrane

In what conditions do you see myotonia?

• Myotonic dystrophy type 1 (DM1)– Cardiac, cataracts, frontal balding, endocrine

• Myotonic dystrophy type 2 (DM2)– Cardiac, cataracts, endocrine

• Non-dystrophic myotonia (hyperPP)– No systemic features

• Myopathies - Pompes

• Schwartz-Jampel syndrome (neuromyotonia)

• Brody’s disease (pseudomyotonia)

Myotonia Congenita

• CLCN1 Gene – CLC-1 Channel

• Loss of function

• Dominant or recessive

• Most common

Na+ channels open

Depolarisation due to Na+ entry

Na+ channels close K+ channels open

Repolarisation due to K+ exit

K+ channels close

Cl-

-

+

Myotonia Congenita

• Age of onset variable – up to 40s

• Myotonia = stiff or stuck muscles

• Difficulty starting to move or with sudden movement – may fall

• “warm up” once I’m moving I’m ok

• Legs>arms or face

• +/- transient muscle weakness – usually improves with repetition (recessive > dominant)

• Myopathy

Paramyotonia Congenita

Na+ channels open

Depolarisation due to Na+ entry

Na+ channels close K+ channels open

Repolarisation due to K+ exit

K+ channels close

Cl-

-

+

SCN4A gene – alpha sub-unit Nav1.4 channel

Dominant

Paramyotonia Congenita• Onset first decade• Myotonia worse with repetition• COLD!!!• Exercise• Eyes + face/jaw+hands > legs• Dysphagia, respiratory rare• Episodic weakness/paralysis (hyperPP) – may last

hours• Hypertrophy• Myopathy

Investigations

• History and Clinical exam

• Blood tests: Potassium, CK, TFTs, WCC enzymes, vacuolated lymphocytes

• ECG

• Neurophysiology – short exercise test

• MRI scan

• Genetic tests – SCN4A/CLCN1 (DM1/2)

EMG - Myotonia

Clinical Neurophysiology tests

2. Long & short exercise tests

Record from ADM

Stimulate ulnar

nerve

Record a series of CMAPs before

and after exercising the muscle:

EMG - Myotonia Congenita

0

20

40

60

80

100

120

0 10 30 50 70 80 100 120 140 150 170 190 210

Time

CM

AP

am

plid

tue

an

d a

rea

(%

Bas

elin

e)

EMG – Paramyotonia Congenita

0

20

40

60

80

100

120

140

0 10 30 50 70 80 100 120 140 150 170 190 210

Time

CM

AP

am

plid

tue

and

ar

ea (

% B

asel

ine)

MRI in non-dystrophic myotonia

Morrow et al, Neuromuscular Disorders, 2013

Management

Exacerbating Factors

• Temperature

• Food

• Exercise

+ + + + + +

- - - - - -

- - - - - -

+ + + + + +

Activation

Inactivation

Depolarisation

Closed Open

Extracellular

Intracellular

Pharmacological Therapy Myotonia

Sodium channel blockers

X

Antiepilepticsphenytoincarbamazepinelamotrigine

Antiarrythmicsprocainamidemexiletineflecainidepropafenone

• 7 centres, 4 countries

• Mexiletine 200mg TDS vs placebo

• Four weeks crossover with one week washout

• Primary endpoint = self reported stiffness

Period 1

means

Period 2 means

Mexiletine 2.53 1.60

Placebo 4.21 5.27

Difference -1.58 -3.68

P value <0.001 0.04

Statland….Matthews…Hanna. JAMA 2012 October 3; 308(13):1357-1365

Mexiletine Audit Patient Demographics

Female Male TOTAL Male/female

Hyper PP 2 2 4 1.00

PMC & MC 2 0 2 0.00

PMC 6 5 11 0.83

SCM 1 5 6 5.00

SCN4A 11 12 23 1.09

MC Dom 5 6 11 1.20

MC Rec 6 20 26 3.33

MC 0 3 3

CLCN1 11 29 40 2.64

Mean length of follow up 4.8 years, median 3.3, range 0.7 to 17.8 years.

Mexiletine adverse effects

0

5

10

15

20

25

30

35

40

45

% o

f P

atie

nts

Re

po

rtin

g Sy

mp

tom

• 52% reported one or more adverse effect

• Dyspepsia most common, 16 required medical therapy, 4 had to stop Mexiletine because of symptoms

• 6 of 9 who had stopped because of SE previously found it effective & tolerable on retrial with slow dose titration

Mexiletine Safety

• No Serious adverse patient events

• No change in ECG parameters off mexiletine or at highest dose at which ECG recorded.

• 16 patients referred to cardiology with concerns over initiating or continuing Mexiletine therapy

– All advised to start or continue Mexiletine

Implications for Practice

• Mexiletine is a safe long term treatment for patients with non-dystrophic myotonia

• Patients with chloride channel myotonia likely to require higher dose of mexiletine for efficacy.

• Slow dose titration of 50 to 100mg per week up to either 200mg TDS or resolution of symptoms recommended.

• Dyspeptic therapy often needed to enable adequate dose titration of Mexiletine.

Implications for Practice

• Baseline ECG and cardiac history

• Repeat ECG after initial dose titration complete (approximately 2 weeks after stabilised at effective dose)

• Repeat ECG if significant dose change

• Repeat ECG if any concern over cardiac symptom and consider referral to Cardiology

• If mexiletine dose unchanged, no new cardiac symptoms, interacting medications or other related patient concerns than routine annual monitoring ECG not indicated.

• Mexiletine guidelines available

http://www.cnmd.ac.uk/our_services/clinical_services/Muscle/Muscle_Channelopathy_Tabs/Options/edit/tab_preview

0

2

4

6

8

10

12

14

16

Pain Weakness Stiffness Fatigue

0

2

4

6

8

10

12

14

16

Pain Weakness Stiffness Fatigue

No. of patients

Most prominent symptom

Severity of pain

19 NDM patients

3/19 pain most prominent symptom

16/19 some pain

100% SCN4A reported pain

50% CLCN1 reported pain

Pain without stiffness was common

2 studies:

pain more common in SCN4A than

CLCN1

57-82% of those with SCN4A muts

(Trip et al,JNNP 2009, Trivedi et al,

Brain, 2013)

Pain

Myotonia and anaesthetics

• May be worsened by anaesthetic agents

• Precipitating agents include suxamethonium, anticholinesterase agents and opioids

• Myotonia may make intubation and ventilation impossible “myotonic crisis”

• Treatment is with Na+ channel blockers (e.g. lidocaine)

Pregnancy and birth

• Fertility normal

• Symptoms may worsen in pregnancy?

• No more assisted deliveries than average?

• Some babies can be floppy and need extra help to feed

• Anaesthetic considerations

Neonatal hypotonia – sodium channel

Sex APGAR Onset of hypotonia

Impairment of sucking

Desaturation Kalaemia Motor devpt

Family 1 F NA Birth Day 1, bottle fed unable to breastfeed

No Na Delayed walking 19/12

Family2 F NA Birth No –hypotonialimited to limbs

No NA Delayed walking22/12

Family 3 F 10 Day 1 -hrs after birth

NG tube Day 1 –cyanosis

5.1 then normal

Normal

M 10 Day 1 –when bathed

Day 1 – no Rx reported

No Normal NA

Family 4 M NA Day 1 Day 1 – no Rx reported

No NA Normal

M 10 Day 1 –hrsafter birth

NG tube Day 2-6, nasal oxygen

Normal NA

• Intermittent stridor from birth or within a few hrs of birth

• Difficult/prolonged feeding common

• GORD and laryngomalacia not uncommonly diagnosed

• Episodic stridor with laryngospasm, general stiffness with hypoxia and cyanosis requiring ICU support from 0-3 months

• Bradycardia and LOC may accompany

• Muscle hypertrophy and myotonia from c.6 months

• Mild delay in motor development

• 2 fatalities– 1 posthumous diagnosis

– 1 MEX (no response to CBZ), died LRTI and resp arrest

• Good response to sodium channel blockers generally reported

• Other features: dysmorphic features, congenital hip dislocation and psychomotor delay

Severe Neonatal Episodic Laryngospasm

Gay et al. Am J Med Genet A 2008 Feb 1;146:380-383

Periodic Paralysis

• Hypokalaemic

• Night/early morning

• Hours to days

• Carbohydrates

• CACNA1S/SCN4A

• Hyperkalaemic

• Any time

• Mins to hours

• High potassium foods

• SCN4A

POTASSIUM POTASSIUM

MRC Centre for Neuromuscular

Disease

Modelling of sodium channel myotonia and paralysis

Gain of function; persistent inward sodium current

Sodium and calcium channels

Na+ channels open

Depolarisation due to Na+ entry

Na+ channels close K+ channels open

Repolarisation due to K+ exit

K+ channels close

Cl-

-

+

Hypokalaemic periodic paralysis

+ +

+ +

+

+ +

+ +

+

++

+ +

+ +

+ +

+ +

+

P loop

S5 and S6 pore forming

segments

EEEE

Voltage sensor

+ +

+ +

+

+ +

+ +

+

++

+ +

+ +

+ +

+ +

+

P loop

S5 and S6 pore forming

segments

EEEE+ +

+ +

+

+ +

+ +

+

++

+ +

+ +

+ +

+ +

+

P loop

S5 and S6 pore forming

segments

EEEEEEE

Voltage sensor

+ +

+ +

+ +

+ +

+ +

+ +

++

+ +

+ +

+ +

+ +

+

P loop

S5 and S6 pore forming

segments

AKED

IF M

+ +

+ +

+ +

+ +

+ +

+ +

++

+ +

+ +

+ +

+ +

+

P loop

S5 and S6 pore forming

segments

AAKKEED

IF M

6

5

3

2

1

4

Pore closed

66

55

33

22

11

44

Pore closed

6

5

4 32

1

4

Pore open

66

5

4 3322

11

4

Pore open

5.0

4.5

4.0

3.5

3.0

2.5

K+

Day 3 Day 4 Day 5

Day 6

Day 79am 10am 2pm 5pm

examination

tone

power

reflexes

sensation

NORMAL

NORMAL

NORMAL

NORMAL

5.0

4.5

4.0

3.5

3.0

2.5

K+

Day 3 Day 4 Day 5

Day 6

Day 79am 10am 2pm 5pm

examination

tone

power

reflexes

sensation

FLACCID

1-2/5, exc. EE 4/5

ABSENT, exc. tri

NORMAL

ECG – during weakness

U-wave

ECG – following recovery

Andersen et al. (Acta Paediat Scan 1971)

Andersen – Tawil Syndrome• Periodic paralysis• Cardiac conduction• Characteristic features

Investigations

• History and Clinical exam

• Blood tests: Potassium, CK, TFTs, Renal tests

• ECG

• Neurophysiology

• MRI scan

• Genetic tests

EMG – Periodic Paralysis

McManis long exercise test

0

50

100

150

200

0 1 3 5 1 3 5 8 12 16 20 24 28 32 36 40 44CM

AP

Am

plit

ud

e a

nd

Are

a

(% o

f b

asel

ine

)

CMAP amp CMAP area

HypoPP and Myopathy

Morrow et al, in preparation

Treatment

Exacerbating Factors

• Temperature

• Food

• Exercise

Pharmacological Therapies Periodic Paralysis

• Hypokalaemic Periodic Paralysis

– K supplements

– Acetazolamide

– Diuretics: Spirinolactone, Amiloride

• Hyperkalaemic periodic paralysis

– Acetazolamide

– Thiazide diuretics

Emergency Treatment

• Don’t forget TFTs!

• IV potassium replacement MUST be monitored with electrolytes and ECG

• Pregnancy

• Anaesthetic considerations

• Professor Michael Hanna • Emma Matthews - neurologist• Doreen Fialho - neurophysiology• Natalie James – CNS• Sarah Holmes - neurophysiotherapist• Karen Suetterlin & Matthew Evans – research fellows• Richa Sud & Samuel McCall - genetics• Roope Mannikko – electrophysiology• Sally-Ann de Souza - senior secretary• Jackie Kasozi-Batende – service manager• Trish Turner- neuromuscular manager• Mary Sweeney & Professor Henry Houlden - genetics

The Team