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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