Overview of new CMS classification
and implications for treatment
Warning
• None of these drugs are licensed for use in CMS
• They should not be taken without
recommendation from an neurologist with
expertise in CMS
NERVE
acetylcholine
choline
ChAT
c
acetylcholine
receptor
Na+
Na+
NERVE
MUSCLE
JUNCTION
Na+
Na+
MUSCLE
PRESYNAPTIC
SYNAPTIC
POSTSYNAPTIC
MUSCLE
PRESYNAPTIC
SYNAPTIC AChE deficient (COLQ mutation)
POSTSYNAPTIC
MUSCLE
PRESYNAPTIC
POSTSYNAPTIC
MUSCLE
NERVE
MuSK
AChR
PTB
Rapsyn
glycosylation genes
DOK-7
Glycosylation pathway
glysosylation pathway adds sugar molecules onto a protein
glycosylation of AChR → insertion into the post-synaptic membrane
ALG2
ALG14
GFPT1
DPAGT1
insert in
membrane
AChR
Mutations that cause CMS:
Upper arm and upper leg weakness
Eyes: normal
Face usually strong
Later onset (2yrs on) common
EMG and biopsy: muscle disorder
>22 Genes: >300 Mutations
Fast CS
Slow CS
AChR
epsilon
DOK7
COLQ
Mike Oldridge,
Tracy Lester
(NCG service)
RAPSN
GLYCOSYLATION
others
AChR deficiency (ε)
Other rare subtypes
COLQ
Fast channel
Rapsyn
Defects of Glycosylation
Slow channel
DOK-7
PRE
SYNAPTIC
CHAT
COLQ
(AGRIN)
POST
Abnormal function of AChR
AChR deficiency

e

Slow channel
Fast channel
AChR ε subunit
RAPSYN
 
DOK7
(MUSK)
Glycosylation defects ( GMPPB, GFPT1, DPAGT1, ALG2,14),

e

 
NERVE
ACh breakdown enzyme
COLQ
AChR
MuSK
PTB
Stabilises
NMJ
Rapsyn
glycosylation genes
DOK-7
Nerve terminal
AGRIN
ACh
MUSK
Rapsyn
Dok-7
stabilises
Disorders affecting
amount message
Reduced message Too much message
Slow channel
CHAT
COLQ
AChR epsilon
RAPSYN
Fast channel
Glycosylation defects
Disorders affecting
stability and structure
DOK7
(MUSK, AGRIN)
Fast Channel Syndrome
AChR single channel recordings of fast channel mutation
Adult
Normal
6 pA
Adult FCS
50 ms
Nerve terminal
ACh
Rapsyn
Dok-7
excess
destabilises
stabilises
Slow Channel Syndrome
normal
Single channel recordings of
slow channel mutant AChR
(Claire Newland)
Overstimulation of muscle → damage
takes time to develop hence delay in onset
Normal NMJ
www.wikipedia.com
SCS NMJ
Engel AG, Lambert EH, Mulder DM, et al.. Ann
Neurol 1982;11:553-569.
COLQ mutations:
AChE def  excess ACh  overstimulation
Na+
Na+
Na+
Na+
MUSCLE
Treatments
Increase acetylcholine (ACh) for too little message
Pyridostigmine (Mestinon)
3,4-DAP (Firdapse)
Blockers of AChR open channels slow channel syndrome
Fluoxetine (Prozac)
Quinidine
Post-synaptic membrane stabilisation
Ephedrine
Salbutamol (Albuterol)
NERVE
Pyridostigmine/
mestinon → stops
breakdown of ACh
Na+
Na+
Na+
Na+
MUSCLE
NERVE
3,4-DAP
Prolongs the nerve
firing
ACh
MUSCLE
Side effects
Pyridostigmine/Mestinon
Occasionally gastric: abdominal pain and diarrhoea
(probantheline)
3,4-DAP
tingling in hands and feet (mouth)
stimulant, hyperactivity, sleep impairment
(? epileptic fits)
Slow channel syndrome
Open Channel Blockers:
• Fluoxetine
• Quinidine
Nerve terminal
Salbutamol
Ephedrine
ACh
receptor
Rapsyn
Dok-7
stabilises
stabilises
Ephedrine and Salbutamol
Stabilises the nerve muscle junction
Gradual reversal of damage over months
Side effects
faster heart rate, high blood pressure, heart rhythm abnormalities, reduced
sleep and stimulation, muscle cramps,
Salbutamol
muscle cramps
Ephedrine
high blood pressure,
Disorders affecting
synaptic function
Reduced message
AChR epsilon
RAPSYN
Fast channel
Glycosylation defects
CHAT
Disorders affecting
synaptic structure and stability
Too much message
Slow channel
fluoxetine
quinidine
pyridostigmine/mestinon
3,4-DAP
COLQ
ephedrine
salbutamol
DOK7 ephedrine
MUSK salbutamol
AGRIN
Nerve terminal
Salbutamol
Ephedrine
pyridostigmine
ACh
receptor
Rapsyn
Dok-7
excess
destabilises
stabilises
stabilises
Disorders affecting
synaptic function
Reduced message
AChR epsilon
RAPSYN
Fast channel
Glycosylation defects
CHAT
Disorders affecting
synaptic structure and stability
Too much message
Slow channel
fluoxetine
quinidine
COLQ
pyridostigmine/mestinon
3,4-DAP
weak on high dose pyridostigmine
? ephedrine or salbutamol
ephedrine
salbutamol
DOK7 ephedrine
MUSK salbutamol
AGRIN
Thankyou