Muscle Channel Patient Day 2019

Dr Emma Matthews

The Team• Professor Michael Hanna • Emma Matthews • Doreen Fialho - neurophysiology• Natalie James – clinical nurse specialist• Sarah Holmes - physiotherapy• Richa Sud - genetics• Roope Mannikko – electrophysiology• Iwona Skorupinska – research nurse• Louise Germain – research nurse• Kira Baden- service manager• Jackie Kasoze-Batende– NCG manager• Jean Elliott – NCG senior secretary• Karen Suetterlin, Vino Vivekanandam• – research fellows

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

If the channel doesn’t work properly, you have a “channelopathy”

Ion channels

• Myotonia congenita – CLCN1

• Paramyotonia congenita – SCN4A

• Hyperkalaemic periodic paralysis – SCN4A

• Hypokalaemic periodic paralysis – 80% CACNA1S

– 10% SCN4A

• Andersen-Tawil Syndrome – KCNJ2

MYOTONIA

PARALYSIS

POTASSIUM CHANNELS

CHLORIDE CHANNELS

SODIUM CHANNELS

CALCIUM CHANNELS

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”

Muscle action potential

Calcium

Na+

Nav1.4

Ach

Cav1.1 and RYR1

Relaxed muscleMuscle contraction

Ach receptors

Motor nerve

Muscle membrane

T-tubule

Nerve action potential

Motor end plate

+

++

++Cl_ -

-

-

Na+

K+

Myotonia Congenita

• Myotonia = stiff or stuck muscles

• Difficulty starting to move

• “warm up” once I’m moving I’m ok

• Legs>arms or face

• Falls

• +/- Muscle weakness – usually improves with repetition

Paramyotonia Congenita• Myotonia

• COLD!!!

• It gets worse the more I do it

• Eyes + face + hands > legs

• Weakness/paralysis

Periodic Paralysis

• Hypokalaemic

• Night/early morning

• Hours to days

• Carbohydrates

• Hyperkalaemic

• Any time

• Mins to hours

• High potassium foods

POTASSIUM POTASSIUM

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

Investigations

• History and Clinical exam

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

• ECG

• Neurophysiology (electrical tests)

• MRI scan

• Genetic tests

EMG Myotonia

EMG - Myotonia Congenita

0

20

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120

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

Time

CM

AP

am

plid

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an

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(%

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elin

e)

EMG – Paramyotonia Congenita

0

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

Time

CM

AP

am

plid

tue

an

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area

(%

Bas

elin

e)

EMG – Periodic Paralysis

McManis long exercise test

0

50

100

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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

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asel

ine

)

CMAP amp CMAP area

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

• Anti-arrhythmic drugs

– Mexiletine

– Flecainide

• Anti-epileptic drugs

– Carbamazepine

– Topiramate, Lamotrigine

Pharmacological Therapies Myotonia

Magnesium

Mexiletine

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

• Patients with chloride channel myotonia may require a higher dose of mexiletine for efficacy.

• Slow dose titration of 100mg per week may help to reduce side effects

• Indigestion therapy may be needed

0

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% o

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tom

Acetazolamide

Kidney Stones: A Global Picture of Prevalence, Incidence, and Associated Risk Factors Rev Urol. 2010 Spring-Summer; 12(2-3): e86–e96.

Risk of kidney stones