Muscle channelopathies

MUSCLE CHANNELOPATHIES

IMRAN RIZVI

Department of Neurology

KGMU; Lko

Introduction

• The muscle channelopathies are a group of rare inherited

diseases caused by mutations in muscle ion channels.

• Ion channels: membrane-bound proteins.

• Ion channels regulate ion flow into and out of cells.

• Thus they are integral to the fundamental processes of

electrical signaling and excitation within the nervous

system.

Classification of ion channels

• Ion channels are classified as Voltage gated or ligand

gated.

• Voltage gated ion channels activates by change in

membrane potential.

• Ligand gated ion channels responds to specific

neurotransmitter (Ach, GABA).

Basic structure

• Similar basic structure.

• Large pore-forming subunit, which is located within the

membrane.

• Pore forming unit = α subunit.

• Variable number of accessory subunits (β,ϒ) are present

around pore forming subunit.

• α subunit typically determines ion selectivity and mediate

the voltage sensing function of the channel.

Basic structure of ion channel

Functions of major ion channels

• Sodium channels: membrane excitability.

• Calcium channels: couple membrane excitation to muscle

contraction.

• Chloride channel: stabilizing the resting membrane

potential and help in membrane repolarization after

excitation.

• Potassium channel: membrane repolarization

Cherian, et al.: Muscle channelopathies. Ann Indian Acad Neurol 2008;11:20-7

Muscle Channelopathies Channel Disease Gene

Calcium channel Hypokalemic periodic paralysis CACNA1S

Chloride channel Myotonia congenita: Thomsen’s (AD) andBecker’s (AR)

CLCN1

Sodium channel Hyperkalemic periodic paralysisHypokalemic periodic paralysis 2Paramyotonia congenitaPotassium aggravated myotonia

SCN4A

Potassium channel Andersen’s syndrome KCNJ2

Clinical characteristics of muscle channelopathies

• Autosomal Dominant inheritance

• Episodic weakness/ muscle stiffness.

• Return to asymptomatic state.

• Exacerbation by environmental factors like fasting,

fatigue, carbohydrate rich diet etc.

• Response to carbonic anhydrase inhibitors.

Statland J et al. Neurol Clin 32 (2014) 801-15.

Muscle channelopathies

Non dystrophic myotonia

Myotonia congenita Paramyotonia congenita Potassium aggravated

myotonia

Periodic paralysis

Hypokalemic PP Hyperkalemic PP Andersen-Tawil

Non Dystrophic Myotonia

• Myotonia: Delayed muscle relaxation after voluntary or

evoked muscle contraction.

• NDM are clinically distinct from myotonic dystrophy as

there is absence of progressive muscle weakness and

systemic features.

• NDM comprise of myotonia congenita, paramyotonia

congenita and sodium channel myotonias.

Matthews E et al. Brain 2010: 133; 9–22

• Prevalence of NDM is approximately 1/100,000.

• Major presenting feature of NDM is muscle stiffness due

to myotonia.

• Other features can be transient weakness, muscle

hypertrophy, fatigue and pain.•

Myotonia Congenita

• MC can be inherited as AD or AR trait.

• AD= Thomsen Disease.

• AR= Becker Myotonia

• AD was first described in 1876 by Danish physician Julius

Thomsen; who suffered from disease himself.

• MC is the most common inherited skeletal muscle

channelopathy.

Matthews E et al. Brain 2010: 133; 9–22

Clinical features of MC

• Age of onset: first decade (Thomsen), 10-14 years

(Becker)

• The most common complaint is muscle stiffness due to

myotonia.

• Forceful movements abruptly initiated after several

minutes of rest causes most pronounced stiffness.

• Patients classically have a hypertrophic and muscular

build.

• Myotonia displays Warm Up phenomenon.

• Myotonia decreases or vanishes when repeating the

same movement several time. (DD= PMC)

• Myotonia can affect all skeletal muscles but it is most

prominent in legs.

• Patients with AR form experience transient bouts of

muscle weakness after a period of rest. (improves with

exercise)

• Muscle hypertrophy and disease severity are greater in

AR form of disease.Statland JM. Continuum (Minneap Minn) 2013;19(6):1598–1614.

Genetics/ pathophysiology

• Myotonia congenita is due to mutation in chloride channel

gene (CLCN-1).

• This gene is located on chromosome 7q35.

• This mutation causes decreased sarcolemmal chloride

conductance.

• This causes repeated depolarization of sarcolemma;

hence leading to muscle hyper excitability and clinical

myotonia.

Investigations • Routine sensory and motor NCS are normal.

• Needle EMG: myotonic discharges are seen. Producing

characteristic dive bomber or reviving engine sound.

• MUAPs are characteristically normal.

• Short exercise test: produces a drop in CMAP amplitude

immediately after exercise; which recovers rapidly over 1-

2 minutes.

• CK levels may be slightly elevated.

Fournier E, et al. Ann Neurol 2004;56:650-61.

Short exercise test in MC

Myotonic discharges

Comparison of features of Thomsen and Becker’s.Thomsen Becker’s

Inheritance AD AR

Age of onset First decade 10-14 years

Myotonia distribution UL> LL LL>> UL

Episodic weakness None Common, develops oninitiation of movementbut transient andimproves rapidly

Muscle hypertrophy + ++

Warm up phenomenon present Present

Myotonia coldsensitivity

None or minimal None or minimal

Paramyotonia congenita

• First described by Eulenburg in 1886.

• He described syndrome of muscle stiffness and episodic

weakness profoundly exacerbated by cold and exercise.

• Three characteristic features

Paradoxical myotonia

Cold induced myotonia

Weakness after prolonged cold exposure.

Clinical features of PMC

• Age of presentation: infancy; within first decade.

• Facial, tongue and hand muscles are predominantly

affected.

• Muscle stiffness increases by repeated or prolonged

muscle contraction. (DD=MC)

• Infant is noted to have prolonged eye closure after

crying/sleeping.

• Patient can c/o difficulty in eye opening after sneezing.

• Muscle stiffness is also triggered by exposure to cold.

• c/o difficulty in swimming in cold water; difficulty in

swallowing ice cream.

• Cold also induces weakness which can take hours to

normalize despite rewarming.

• Muscle hypertrophy is less common as compared to MC.

Matthews E et al. Neurology 2008b; 70: 50–3.

Investigations in PMC

• Routine motor and sensory NCS is normal.

• EMG: Myotonic discharges. MUAPs will be normal.

• Muscle cooling will increase myotonia which is

pathognomic of PMC. Cooling will also cause dense

fibrillation potential to appear.

• As the muscle cools down below 20 C all myotonic

discharges disappear completely giving way to paralysis.

• Short exercise test: produces a drop in CMAP amplitude

post exercise; the recovery is delayed to often 60 minutes.

• The short exercise test after cooling may further enhance

drop in amplitude; recovery is also delayed after cooling.

Genetics of PMC

• Autosomal dominant.

• Point mutation in the SCN4A gene on chromosome 17q.

• Mutation in this gene causes defect in sodium channel

deactivation.

Sodium channel myotonia• Also known as potassium aggravated myotonia.

• Autosomal dominant inheritance.

• Mutation in SCN4A gene located on chromosome 17q.

• This mutation causes disturbance in fast inactivation of

sodium channels.

• Three clinical variants

Myotonia fluctuans

Myotonia permanens

Actezolamide responsive myotonia.

Clinical features

• Patients presents with generalized stiffness due to

myotonia.

• Myotonia aggravates after potassium ingestion.

• No worsening of symptoms with cold.

• Patients do not experience episodic weakness.

• Delayed onset myotonia after exercise. (10-30 min)

Mankodi, et al. Neurology India 2008;56:298-304.

• Myotonia fluctuans: myotonia fluctuates in severity; is

aggravated by potassium ingestion and prolonged

exercise.

• Myotonia permanens: most serious form; severe and

protracted myotonia which can impair respiration.

• Actezolamide responsive myotonia: painful myotonia that

responds to carbonic anhydrase inhibitors.

Investigations

• Sensory and motor NCS: normal

• EMG: myotonic discharges

• Muscle cooling: no effect

• Short exercise test: no significant change of CMAPs from

baseline.

• CPK levels may be elevated by 2-3 folds.

Myotonia congenita Paramyotonia congenita Sodium channel myotonia

Inheritance AD= ThomsenAR= Becker

AD AD

Causative gene CLCN-1 SCN4A SCN4A

Myotonia distribution UL, LL, Face Upper limbs and face morethan lower limbs

Upper limbs, face andextraocular, more thanlower limbs

Myotonia coldsensitivity

None or minimal Yes—often dramatic None

Warm upphenomenon

Present Absent May be present

Paradoxical myotonia Absent Present Absent

Delayed onset myotoniaafter exercise

Absent Absent Present

Episodic muscleweakness

Can occur in AR.Transient at initiation of movement.

Common.After exposure to cold.Several hours.

None

Short exercise test Early decrement in CMAPwith rapid recovery

Gradual and persistentreduction in CMAPenhanced by cooling.

No significant changeof the CMAP frombaseline

Management of NDM

• For mild symptoms no specific treatment is needed.

• Patients should be advised regarding avoidance of

precipitating factors like cold, strenuous exercise or

ingestion of potassium rich food.

• The class IB anti-arrhythmic mexiletine is considered the

drug of choice.

Statland JM. Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial. JAMA 2012.

• Oral 200-mg mexiletine 3 times a day resulted in

improved patient-reported stiffness over 4 weeks of

treatment as compared to placebo.

• Mexiletine has pro-arrhythmic potential therefore ECG to

measure QT interval should be done.

• Other useful drugs are phenytoin, procainamide or

quinine; but they have unfavorable side effect profile.

Statland JM. Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial. JAMA 2012.

• Patients with sodium channel myotonia responds to

carbononic anhydrase inhibitors.

• Acetazolamide with starting dose 125 mg daily with

gradual titration up to 250 mg three times a day is found

be useful in decreasing severity of myotonia.

Mankodi, et al. Neurology India 2008;56:298-304.

Hypokalemic periodic paralysis

• HypoKPP is the most common PP.

• Prevalence: 1 in 100,000.

• Autosomal dominant inheritance.

• There is reduced penetrance in females (50%) in contrast

to the complete penetrance seen in males.

• Approximately one-third of cases may be new dominant

mutations.

Venance SL et al. Brain (2006), 129, 8–17

Clinical features

• Age of symptom onset: 1 or 2 decade.

• Usual time of attack: in the early morning or on awakening

in the night.

• Weakness can be generalized or focal.

• Facial and respiratory muscle are usually spared.

• Tendon reflexes are usually hypoactive.

• Typical attack lasts for few hours (occasionally days).


• Frequency of individual attacks can vary from daily to a

few episodes in a lifetime.

• Attacks often decrease in frequency after 40 years.

• Usual triggers: rest after vigorous exercise, carbohydrate-

rich meal on the previous day.

• Other triggers: viral illness, lack of sleep, menstruation

and specific medications (e.g. beta agonists,

corticosteroids and insulin).• Approximately two-thirds of the patients will develop

progressive fixed weakness later on in life.

Miller TM et al. Neurology 2004; 63: 1647–55.

Genetics

• Mutation in α subunit of skeletal muscle L-type calcium

channel gene CACN1AS. (chromosome 1q).

70 % of cases; HypoKPP 1.

• Mutation in α subunit of skeletal muscle sodium channel

gene SCN4A (chromosome 17q)

10-20 % of cases; HypoKPP 2.


HypoKPP 2• These pts differs from classical form in following aspects.

Myalgia following paralytic attacks.

Worsening of symptoms by acetazolamide.

Older age of onset.

Shorter duration of attacks.

Miller TM et al. Neurology 2004; 63: 1647–55.

Investigations

• Serum potassium concentration are usually low during an

attack. (K levels are normal in inter ictal period).

• ECG: T wave flattening, prominent U waves.

• Provocative testing (oral glucose load): not

recommended.

• NCS: during an attack CMAPs amplitude can be low.

• Motor and sensory NCS are normal between attacks.

• EMG: normal between attacks.

• During attacks there can be reduction in size and number

of MUAPs recruited.

• Fixed weakness: Myopathic MUAPs with early

recruitment.

• Prolonged exercise test: immediate increase in CMAP

amplitude, followed by a drop of about 50% in CMAP

amplitude over 20-40 minutes.

• Muscle biopsy: central vacuoles and chronic myopathic

changes.

Prolonged exercise test

Muscle biopsy in HypoKPP

Treatment• Lifestyle and dietary modification.• Acute pharmacological intervention.• Chronic pharmacological intervention.

• Eat frequent small meals to avoid large carbohydrate

loads.

• Refrain from excessive exercise.

Treatment of acute attack

• Oral potassium 10-20 mEq every 15-30 minutes over 1-3

hours (not to exceed 200mEq in a 24 hour period).

• If the patient is not able to take orally IV potassium should

be given.

• IV potassium should be mixed with 5% mannitol.

• 35 mEq K with 1 L 5% mannitol @250ml/hour (not to

exceed 200mEq in a 24 hour period).


Prevention of attacks

• Prophylactic use acetazolamide decreases the frequency

and severity of attacks.

• Starting dose is 125mg/day; to be up titrated as needed

up to a maximum of 1000-1500mg/day in divided doses.

• Dichlorphenamide is another carbonic anhydrase inhibitor

that effectively prevents attacks. (50-200mg/day)

Tawil et al. Ann Neurol 2000; 47: 46–53.

Thyrotoxic periodic paralysis• TPP is seen most commonly in Asian men.

• Characterized by abrupt onset of hypokalemia and

paralysis.

• Patients present with acute onset of proximal symmetrical

ascending lower-extremity muscle weakness.

• Triggers: rest after exercise or high carbohydrate meals.

• Deep tendon reflexes are decreased or absent

• Hypokalemia results from an intracellular shift of K induced

by the thyroid hormone.

• Features s/o TPP are age>20 years, no family h/o of PP,

male sex, Asian origin.

• T/t: nonselective beta-blockade, correcting the underlying

hyperthyroid state, and replacing potassium.

• TPP is curable once a euthyroid state is achieved.


Hyperkalemic periodic paralysis

• Age of symptom onset: early childhood (first decade)

• Attacks of periodic weakness are short lived (1-4 hours)

• Weakness commonly occurs in the morning after

awakening from sleep.

• Provoking factors: rest after exercise, fasting, emotional

stress, cold, and potassium loading.

• Weakness usually is generalized but spares the facial and

respiratory muscles.

• Hyporeflexia is present during weakness.

• Clinical myotonia is seen in about 20% of cases.

(myotonia on EMG is more common)

• Eyelid myotonia is common.

• The frequency of attacks generally lessens in middle age.

• A large proportion of subjects with HyperKPP develop a

progressive proximal myopathy.

Genetics • Autosomal dominant.• Mutation in gene encoding α subunit of voltage gated

sodium channel (SCN4A)• Chromosome 17q

Investigations

• Serum potassium levels: may be elevated at the time of

weakness.

• K levels can be normal in about 50% of cases.

• NCS: normal between the attacks.

• Reduced CMAPs amplitude during attacks.

• EMG: reduction in size of MUAPs during attacks

• Myotonia in between attacks

• . Venance SL et al. Brain (2006), 129, 8–17

• Muscle cooling has no appreciable effect on the needle

EMG findings.

• Prolonged exercise test: immediate increase in the CMAP

amplitude, followed by a progressive drop in the CMAP

amplitude by about 50% over 20 to 40 minutes.

• Muscle biopsy: central vacuoles.

Treatment • Lifestyle modification:

Avoidance of K rich foods

Avoidance of drugs that can increase K (spironolactone)

Avoidance of fasting.

Diet high in carbohydrates.

Treatment of acute attacks

• Acute attacks are often mild and brief therefore not

requiring treatment.

• In severe attacks aim at lowering EC K levels

• Mild exercise

• Eating high sugar load (candy bar)

• Inhalation of β agonist (1–2 puffs of 0.1 mg salbutamol or

albuterol)

• IV calcium gluconate in very severe cases.

Prevention of attacks

• Acetazolamide: start at 125mg/day. Titrate as needed to

1000-1500mg/day.

• Thiazide diuretics.

• Dichlorphenamide was found to be useful in reducing the

frequency of attacks in a recent RCT.

Tawil et al. Ann Neurol 2000; 47: 46–53.

Andersen-Tawil Syndrome• Characterized by classic triad of

1.Periodic paralysis.

2.Ventricular arrhythmias.

3.Dysmorphic features.

• Age of symptom onset: 1-2 decade.• Episodic weakness is usually the first presenting

symptom.• Triggers for weakness: prolonged rest or rest following

exertion

Venance et al. Brain (2006), 129, 8–17

• Ictal K levels can be low, normal or elevated.

• permanent proximal weakness often develops later in the

course.

• Patients can present with palpitation, syncope or rarely

cardiac arrest.

• ECG can show

Prolonged QTc

VPCs, ventricular bigeminy, polymorphic VT.

Bidirectional VT.

• Dysmorphic features can be any combination of

Short stature.

Low set ears.

Ocular hypertelorism.

Broad nasal root.

Small mandible.

Fifth-digit clinodactyly (abnormally bent or curved finger),

and syndactyly.

Tristani-Firouzi et al. J Clin Invest 2002; 110: 381–8.

Diagnostic criteria for ATS1. A clinically definite diagnosis requires 2 of the following 3

features

•PP

•Prolonged QTc or ventricular ectopy.

•The typical facies: low set ears, ocular hypertelorism, small

mandible, fifth digit clinodactyly, syndactyly.

2. Alternatively a diagnosis can be made with 1 of the

above feature and an affected family member meeting 2 of

3 features.

Genetics of ATS

• Autosomal dominant inheritance

• Mutation in KCNJ2 gene on 17q.

• This gene encodes for inwardly rectifying K channel.

• Potassium inward rectifier helps in maintaining

sarcolemma resting membrane potential.

Venance et al. Brain (2006), 129, 8–17

Treatment of ATS• Multidisciplinary team approach.

• A yearly ECG and Holter monitor are recommended.

• Consider for implantable defibrillator if patient is having symptomatic

ventricular arrhythmia.

• Drugs that prolong QTc should be avoided.

• If patients are hypokalemic during episodes of paralysis, potassium

supplementation can be used.

• carbonic anhydrase inhibitors can decrease the frequency or severity of

paralytic attacks.


Hypo KPP Hyper KPP ATS

Age at onset 1 or 2 decade. 1 decade 1 or 2 decade

Duration of attacks Hours to days Hours Hours to days

Myotonia No Yes No

Usual triggers Rest after exercise,carbohydrate load

Rest after exercise,K-rich foods

Prolonged restafter exercise

Ictal K Low High or normal Low/ normal/ high

Fixed proximal weakness

Yes Yes Yes

Cardiac arrhythmias No No Yes

Skeletal anomalies No No Yes

Response to K Improves weakness Aggravates weakness Depends on ictal K

Mutation CACNA1SSCN4A

SCN4A KCNJ2

Take home message• Muscle channelopathies can present as NDM or PP.• Myotonia congenita typically displays warm up

phenomenon.• Exposure to cold aggravates myotonia and weakness in

PMC.• TPP is an important DD of HypoKPP in our setup.• K levels can be normal in HyperKPP during attacks.• ATS is a triad of PP, Ventricular arrhythmias and

dysmorphic features.

THANK YOU

Which of the following is NOT a sodium channelopathy?A. Hyper KPP

B. PMC

C. Hypo KPP

D. MC

Which of the following is NOT correct?A. Chloride channel: MC

B. Sodium channel: PMC

C. Sodium channel: K aggravated myotonia

D. Potassium channel: Hypo KPP

Which of the following is true about MC?A. Myotonia decreases with exercise

B. Becker’s dis is AD

C. Myotonia is cold sensitive

D. Progressive weakness is seen commonly.

A 10 year old boy presented with myotonia; a short exercise test was performed which showed drop in CMAP amplitude post exercise which persisted for 1 hour, the most likely diagnosis is ?A. MC

B. PMC

C. Sodium channel myotonia

D. None of the above

All of the following are true regarding sodium channel myotonia EXCEPT?A. Myotonia aggravated by potassium load.

B. Episodic weakness on cold exposure.

C. Myotonia is not sensitive to cold.

D. Many pts respond to acetazolamide.

False regarding Hypo KPP?

A. Calcium channel mutation is MC.

B. Females show incomplete penetrance.

C. Many patients develop progressive myopathy later in the course.

D. AR inheritance.

Which of the following is not a classical feature of ATS?A. PP

B. Myotonia

C. Dysmorphic face

D. Ventricular arrythmias

Myotonia on needle EMG is seen in which of the following disorder?A. Hypo KPP

B. ATS

C. Hyper KPP

D. None of the above

ATS is which type of channelopathy?A. Sodium

B. Chloride

C. Calcium

D. potassium

Muscle channelopathies

Health & Medicine

Transcript of Muscle channelopathies