Congenital Myasthenic
Syndromes
Shahriar Nafissi, MD
Associate Professor of Neurology
Tehran University of Medical Sciences
Physiology
The Neuromuscular Junction
Action
Presynaptic potential
channel terminal
Ca2+
Ca2+
action potential  opening voltage-gated Ca2+ channels
↑Ca2+ permeability
Ca2+
Presynaptic
Ca2+
terminal
channel
ACh
↑Ca2+
 Ach release from synaptic vesicles
Synaptic cleft
Na+
ACh
Na+
Receptor
molecule
 ACh binding to Ach receptors  opening ligand-gated Na+
channels.
Na+
Action
potential Na+
Action
potential
↑Na+ permeability depolarization action potential
generation in the postsynaptic membrane
ACh
Choline Acetic
acid
ACh
receptor
site
Acetylcholinesterase
Ach
→acetic acid + choline
▲
Ach-Esterase
Presynaptic
terminal
ACh
Acetic
acid
Synaptic
vesicle
Choline
ACh
Choline
in the presynaptic terminal
Choline + acetic acid → Ach → Synaptic vesicles
Structural Reality
By John Heuser and Louise Evans
University of California, San Francisco
Ligand- Gated Ion Channel
2α + β + ε + δ
Congenital Myasthenic Syndromes
• Group of diseases caused by genetic
defects affecting neuromuscular
transmission
• Heterogeneous inheritance and
pathophysiology
Classification
• Presynaptic Defect
– Choline Acetyl Transferase deficiency
– Paucity of synaptic vesicles
– Lambert-Eaton like CMS
• Synaptic Defect
– Endplate ACh Esterase deficiency
• Postsynaptic Defects
–
–
–
–
–
–
Kinetic abnormality of AChR
AChR deficiency
Rapsyn
Dok-7
SCN4A
MuSK
• No identified Defect
percentage of CMS subtypes in
different centers
Diagnostic Clues in CMS
• Weakness/fatigability of limbs and
oculobulbar muscles
• Early onset (since neonatal period)
• Positive family history
• EDX findings (RNS, SFEMG)
• Response to anti-cholinesterases
• Absence of anti-AChR, MuSK , VGCC
antibodies
Diagnostic Difficulties
• Diagnostic problems
–
–
–
–
–
–
Late onset (in adult)
No response to anticholinesterases
No family history
Episodic symptoms
No ophthalmoplegia or cranial involvement
Decrement may not be present in all muscles, or
present only intermittently
• Misdiagnosed as
– congenital myopathy
– Seronegative MG (late onset)
– Metabolic myopathies
R ABD POLL BR EVIS
Ampl (mV) over Study
5.0
2.5
0.0
1
24 Yo, referred as congenital myopathy
Responsive to Mestinon
2
3
4
Electrodiagnosis
• Decrement after 2-3 HZ RNS
– Absent in ChAT def., Na-Channel CMS,
Some cases of Rapsyn
• If negative, try higher frequencies
• Try conditioning with 5 minutes 10HZ
stimulation
• Single-Fiber EMG
Electrodiagnostic clues
• Repetitive CMAP after single stimulus
• Low amplitude CMAP with significant
increment after high frequency RNS
• Response to Tensilon test
Presynaptic Syndromes
Choline-Acetyl Transferase
deficiency (ChAT def.)
• ± neonatal hypotonia, gradually improve
• Attacks of apnea, bulbar paralysis
precipitated after infection, fever,
excitement
• No symptoms or mild-myasthenic symptoms
between attacks
• Reduced number of attacks with increasing
age
• Treatment:
– AchE Inh. for myasthenic symptoms and
prophylaxis
– IM AchE Inh. Injection on crisis
Synaptic Defect
Endplate ACh Esterase deficiency
AChEsterase
Clinical Features
• Myasthenic symptoms since birth or
early childhood
• delayed milestones
• Weakness facial, axial, limb±
ophthalmoplegia
• Fatigable lordosis and scoliosis
• Finger extensor weakness
• Slow pupillary light response
•11 yo, weak since infancy with ptosis, restricted EOM,
sluggish pupillary reflex, lordosis
•Worsening with Mestinon, some response to pseudoephedrine
Decrement after 3 HZ RNS
Repetitive CMAP after
single stimuli
Catalytic
Subunits
Collagen Tail
Formed by triple-helical association
of three collagen strands (ColQ)
Therapy
• AchE inhibitors ineffective
• Increased muscarinic side effects
• Some improve with ephedrine or
pseudo-ephedrine
20 yo, Ptosis since infancy
Delayed walking, Ophthalmoparesis
generalized weakness
No reponse to mestinon, 3,4-DAP,
Quinidine, fluoxetine
Improved with ephedrine
Mutation found in ColQ
L ABD DIG MIN (UL)
1.1
1.2
1.3
Ampl (mV) over Study
1.4
10
1.5
1.6
5
1.7
2
0
1.8
1.9
1
2
3
4
5
1
3
5
4
1.10
30ms 2mV
16 yo, Lordotic gait from
beginning, WCB from 11
No ptosis or ophthalmoparesis
proximal > distal
Diagnosed as DMD
AChRAb negative
Worse with Mestinon
R ABD POLL BREVIS
1.1
1.2
1.3
1.4
1.5
1.6
2
1.7
1.8
1.9
1
5
3
1.10
30ms 500µV
4
R ULNAR - ADM
R MEDIAN - APB
2
2
1
3
5
4
Wrist 1
30ms 5mV 16mA
14-33% decrement
1
Wrist 1
30ms 1mV 20mA
Repetitive CMAP
2
2
1
3
4
5
B.Elbow 2
30ms 5mV 16mA
1
3
El bow 2
30ms 1mV 20mA
Post-Synaptic Syndromes
Post-Synaptic Syndromes
• Kinetic abnormalities of AChR
– Slow-Channel Syndrome
– Fast Channel Syndrome
• Low-Expressor AChR
Deficiency
• Rapsyn Deficiency
• Sodium-Channel Myasthenia
• Dok-7 Synaptopathy
Slow-Channel Syndrome
• Autosomal Dominant
• Selective weakness of cervical, scapular,
finger ext.,
• Eye movements: spared or mildly affected
• Early onset: gradually progressive
• Late onset and mild
• Fluctuating
• Severely affected muscles become
atrophic
• EMG
– Repetitive CMAP after single stimuli
– Decrement only in weak muscles
• Pathogenesis
– Prolonged AChR opening ↑ cations and
Ca++ Ca++ excess activation of
protease, lipase, free radicals endplate myopathy
– Depolarization block
Family M.
Slow channel
G153S
Intra familial
variability
for severity
mild
severe
• Pathology: tubular aggregates
• Genetics: mutation in AChR subunits
• D.D.:
•Polyneuropathy
•Motor Neuron Disease
•Radial palsy
•Mitochondrial disease
•Limb-Girdle MD
•Myotonic Dystrophy
•FSHD
Therapy
• AChE Inh. Ineffective or only
temporary improvement
• Probably accelerate progression by
cationic overload
• Long-lived open channel AChR blockers
– Quinidine 200 mg × 3-4/d
– Fluoxetine 80 mg/d
Ach Receptor Deficiency
ε/
Low-Expressor AChR mutations
• Reduced AChR expression to < 15%
• Mild to severe phenotype
• Most cases mutation in ε-subunit of
AchR fetal AchR harboring γsubunit is substituted
• Mutations in both alleles of a non-ε
subunit incompatible with life
• Most respond well to AChE Inh ± DAP
•18 yo, referred as MG for a
consult before rhinoplasty
•Has always been weak in
physical activity and if doing
so, fatigued very fast.
•Fluctuating ptosis and
diplopia.
•Stable and non-progressive
during these years and worse
in the evening
•Significant subjective and
objective improvement with
Mestinon
• Myasthenic symptoms since infancy
• Very good response to mestinon
• Both have been misdiagnosed as myasthenia
gravis and both thymectomised
• Mutation in CHRNE (
ε-subunit of AchR)
Rapsyn
Tyrosine kinase function :
AChR concentration and linkage to cytoskeleton
Rapsyn Deficiency
• Has a crucial role in concentrating AChR in
post-synaptic membrane
• Birth or neonatal ± Arthrogryposis
• Sometimes juvenile-adult onset
• Facial deformity: prognathism, malocclusion
• Severe masticatory weakness
• Ptosis without ophthalmoparesis
• Cervical, truncal, limb usually spared
• Stable and benign course
• EMG
– Decrement not present in all
– Single-Fiber EMG
• Partial to well response to AChE Inh
• Addition of 3,4-DAP sometimes
beneficial
DOK7 Synaptopathy
Dok-7 interacts with MuSK and is essential for postsynaptic specialization of the neuromuscular junction
DOK7 Synaptopathy
Clinical features
• Difficulty in walking developing after
normal motor milestones
• Proximal muscles weakness > distal
• Ptosis often present, EOM rarely involved
• EMG always abnormal
– decrement in amplitude and/or
– jitter and blocking on single-fiber studies
• No benefit from anticholinesterase,
sometimes worsened
• Responded to ephedrine
Clinical clues pointing to a
specific diagnosis
Endplate AChE deficiency
● Repetitive CMAPs
● Refractoriness to cholinesterase inhibitors
● Delayed pupillary light reflexes
Slow-channel CMS
● Repetitive CMAPs
● Selectively severe involvement of cervical and
wrist and finger extensor muscles in most cases
● Dominant inheritance in most cases
Clinical clues pointing …-2
Endplate choline acetyltransferase deficiency
● Recurrent apneic episodes
● No or variable myasthenic symptoms between acute
episodes
● EMG decrement at 2-3 Hz can be absent at rest but
appears after stimulation at 10 Hz for 5 min, then
disappears slowly.
Rapsyn deficiency
● Multiple congenital joint contractures
● Increased weakness and respiratory insufficiency
precipitated by intercurrent infections
● EMG decrement can be mild or absent.
Dok-7 myasthenia
● Proximal greater than distal limb weakness,
● mild ptosis, and normal ocular ductions in the majority
● May deteriorate on exposure to pyridostigmine
Standard pharmacotherapy
• ChAT deficiency: AChEI oral prophylaxis, parenteral use
in crisis
• Achesterase deficiency: avoid AChEI; try ephedrine
• AChR deficiency: AChEI; 3,4-DAP also helps in 30–50%
• Slow-channel CMS: quinidine or fluoxetine
• Fast-channel CMS: AChEI and 3,4-DAP
• Rapsyn deficiency: AChEI; some benefit further from
3,4-DAP
• Limb-girdle myasthenia: AChEI; some benefit from
ephedrine
• Dok-7: ephedrine ?