What Is a Skeletal Muscle Channelopathy?

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 CHLORIDE CHANNELS • Myotonia congenita – CLCN1

• Paramyotonia congenita – SCN4A MYOTONIA SODIUM CHANNELS • Hyperkalaemic periodic paralysis – SCN4A

• Hypokalaemic periodic paralysis – 80% CACNA1S CALCIUM CHANNELS – 10% SCN4A PARALYSIS

• Andersen-Tawil Syndrome – KCNJ2 POTASSIUM 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” - Nerve action potential Cl_ - + - + + + Motor nerve K+ + Na+ Na+ Muscle membrane Ach Motor end plate T-tubule Nav1.4 Ach receptors Cav1.1 and RYR1

Muscle action potential Calcium

MuscleRelaxed contraction muscle 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

POTASSIUM POTASSIUM

• Hyperkalaemic • Hypokalaemic • Any time • Night/early morning • Mins to hours • Hours to days • High potassium foods • Carbohydrates

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

120

100

Baseline) 40

0 CMAPamplidtue (% and area 0 10 30 50 70 80 100 120 140 150 170 190 210

Time EMG – Paramyotonia Congenita

140 120 100 80 60 40

area (% Baseline) (% area 20

CMAP amplidtue and and amplidtue CMAP 0 0 10 30 50 70 80 100 120 140 150 170 190 210 Time EMG – Periodic Paralysis

McManis long exercise test

200

150

100

50 (% of of (% baseline)

CMAP CMAP Amplitude and Area 0 1 3 5 1 3 5 8 12 16 20 24 28 32 36 40 44

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 Pharmacological Therapies Myotonia • Anti-arrhythmic drugs – Mexiletine – Flecainide Magnesium • Anti-epileptic drugs – Carbamazepine – Topiramate, Lamotrigine Mexiletine

• Mexiletine is a safe long term 50 treatment for patients with non- 45 dystrophic myotonia 40 35

• Patients with chloride channel 30

myotonia may require a higher 25

dose of mexiletine for efficacy. 20

• Slow dose titration of 100mg per 15 %of Patients ReportingSymptom week may help to reduce side 10 effects 5 • Indigestion therapy may be 0 needed Acetazolamide Risk of kidney stones

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