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Presenter: Dr.Nikhil Panpalia
Guide: Dr.K.R.Naik
What is congenital myasthenic
syndrome??
 Inherited disorder of neuromuscular transmission associated with
abnormal weakness and fatiguability on exertion.
 The prevalence of CMS is estimated at one in 500 000 in Europe, and CMSs
are much more uncommon than autoimmune myasthenia
 Acetylcholinesterase deficiency was the first CMS identified, based on
the lack of the enzyme at neuromuscular junctions
 In the experience of Engel’s group, postsynaptic CMSs are three times
more frequent than acetylcholinesterase deficiency and 10 times more
frequent than presynaptic
Is CMS the same as myasthenia gravis?
 No.
 An autoimmune condition like rheumatoid arthritis,
which can affect both children and adults.
 Myasthenia gravis causes the body to produce proteins
that block and destroy some of their receptors, making
messaging from nerves to muscles less effective.
 Myasthenia gravis can be treated with steroids,
immunosuppressive drugs and thymectomy (surgical
removal of the thymus gland).
Basic anatomy and physiology NMJ
Synaptic space
Transmitter quantum
 Amount of Ach released from single synaptic vesicles.
 Electrophysiologically measurable parameters of
quantal release –
mnp
mnumber of quantum realeased
n number of readily releasable quanta
p probablity of release
Events after release of Ach
action potential  opening voltage-gated Ca2+ channels
↑Ca2+ permeability
Ca2+
Ca2+
channel
Presynaptic
terminal
Action
potential
Ca2+
Ca2+
channel
↑Ca2+  calcium calmodulin protein kinase phosphorylates
synapsin releases Ach from synaptic vesicles by exocytosis
ACh
Presynaptic
terminal
Na+
Synaptic cleft
Na+
ACh
Receptor
molecule
 ACh binding to Ach receptors  opening ligand-gated Na+
channels.
↑Na+ permeability depolarization action potential
generation in the postsynaptic membrane
Na+
Action
potential
Action
potential
Na+
ACh
receptor
site
Acetylcholinesterase
Acetic
acid
CholineACh
Ach →acetic acid + choline
▲
Ach-Esterase
Presynaptic
terminal
Synaptic
vesicle
ACh
Acetic
acid
Choline
CholineACh
in the presynaptic terminal
Choline + acetic acid → Ach → Synaptic vesicles
CHAT
VACht
Structure of AchE
 Acetylcholinesterase (AchE) is an
enzyme, which hydrolyses the
neurotransmitter acetylcholine.
 The active site of AChE is made up of
two subsites, both of which are critical to
the breakdown of ACh.
 The anionic site serves to bind a molecule
of ACh to the enzyme. Once the ACh is
bound, the hydrolytic reaction occurs at a
second region of the active site called the
esteratic subsite.
 Here, the ester bond of ACh is broken,
releasing acetate and choline. Choline is
then immediately taken up again by the
high affinity choline uptake system on the
presynaptic membrane.
15
MEPP , MEPC & EPP
 Single quantum Deporalization and current flow  MEPP
and MEPC
 MEPP Number and conductance per channel opened,
resistance of muscle fibre and functional state of AchE
 MEPC number of channel opening and the current per
channel flowing
 EPP nonlinear summation of individual quanta produces a
large deporalization which is EPP.
SAFETY MARGIN OF NM
TRANSMISSION
 Difference between the depolarization caused by EPP
and depolarization required to activate the Na
Channel.
 All congenital or acquired cause of neuromuscular
transmission have been shown to sub threshold EPP
for activating Na or Na channel unresponsiveness to
EPP
Saturating disc model of NM
transmission
 MEPPs are believed to be the depolarization of the muscle membrane caused by
the action of the acetylcholine released by a single synaptic vesicle which
spontaneously fused with the presynaptic membrane – this is the vesicle
hypothesis
 Quantal nature of the small EPPs
Fusion of no vesicles = no EPP
Fusion of one vesicle = MEPP (0.5mV)
Fusion of three vesicles = EPP with an amplitude 3x the MEPP (1.5mV)
 10-20% of 10,000 molecules of ACh released by a single vesicle bind to AChE in the
cleft
 the remaining NT binds to AChR in a patch of about 0.3m m2 in area = the disk of
AChR saturated with agonist NT
 Saturated disk model: vesicle releases enough ACh to bind all AChE and AChR in 0.1
ms
Congenital Myasthenic Syndromes
 Congenital Myasthenic Syndromes are inherited
disorders of neuromuscular transmission.
 CMS was recognized 1st time in late 1970’s and early
1980’s after recognization of auto immune origin of
myasthenia gravis
 During the past decade various divergent types of CMS
were identified
 Various classifications were done but Mayo clinic and
European neuromuscular centre classification was
mostly accepted
Frequencies of identified mutations
 Mutations in AChR subunits,
55%
 Low-expressor in e subunit,
34%
 Low expressor in other AChR
subunits, 3%
 Slow channel mutations, 12%
 Fast channel mutations, 6%
 Rapsyn, 15%
 ColQ, 15%
 Dok-7, 9%
 ChAT, 6%
 Nav1.4, Plectin, Agrin, MuSK,
Laminin b2 <1%
 If clinical data provides no
clues for targeted mutation
analysis, search for mutations
in descending order as listed
 Screen for common mutations
in RAPSN and DOK7
 Search for common mutations
in ethnic groups (e.g,
e1267delG)
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
Investigations of Endplate Diseases
 Clinical
- History, examination, response to Tensilon or 3,4-DAP
- EMG: repetitive nerve stimulation, SFEMG
- Serologic tests: AChR and MuSK antibodies, tests for
botulism
 Muscle biopsy studies: morphology
- Cytochemical localization of AChR, AChE, immune deposits
- AChR per endplate (125I-a-bungarotoxin)
- Quantitative EM, immuno-EM
 Muscle biopsy studies: electrophysiology
- Microelectrode studies: MEPP, MEPC, EPP, m, n, p
- Single-channel patch-clamp recordings
 Mutation analysis and expression studies
Pre-Synaptic Syndromes
Presynaptic Syndromes
 Choline Acetyltransferase Deficiency
 Paucity of synaptic vesicles and reduced quantal
release
 Lambert-Eaton-Like syndrome
 Other syndromes associated with reduced quantal
release
Choline Acetyltransferase
Deficiency
 Recognized 3 decades ago
 Previously it was called as Familial Infantile
Myasthenia
 Distinguishing features are sudden and expected
dyspnea and bulbar weakness CMS with episodic
apnea (CMS-EA)
 Impaired vesicular packaging and resynthesis of Ach.
Choline Acetyltransferase
Deficiency
 Clinical Features
 Most cases in infancy
 Sudden unexpected episodes of dyspnea and bulbar
weakness culminating in apnea (CMS-EA)
 Some patients had hypotonia, bulbar and respiratory
weakness at birth requiring ventilator
 Others develop symptoms during childhood
precipitated by cold or infection.
 After age of 10 symptoms less severe and there is
no loss of muscle bulk nor permanent myopathy
 Phenotypic heterogenity may be seen in
kinships.
 With increase in age exacerbation are less severe.
Choline Acetyltransferase
Deficiency
 Fig 66-1
Choline Acetyltransferase
Deficiency
 Electrophysiology
1. Decremental response seen in weak muscles.
2. SFEMG similar to MG
3. Weakness induced by exercise and RNS at 10 Hz.
4. Decrement can be corrected by edrophinium.
 End plate studies
1. Number of AChRs/end plate and postsynaptic structure
normal
2. Synaptic vesicles smaller in rested muscle
3. MEPP and EPP normal at rest but decreases with 10 Hz
stimulation with slow recovery over 10 to 15 mins.
Molecular study….
 Impaired vesicular packaging and Ach resynthesis
 4 genes impicated:
1. Presynaptic high affinity choline transporter
2. CHAT
3. VAchT
4. Vesicular proton pump
5. Patients had no ANS and CNS involvement
suggested that selectively vulnerable to CHAT.
Choline Acetyltransferase
Deficiency
 Treatment
1. Anticholinesterase medications prophylactically and
during crisis found to be usefull
2. Long term apnea monitoring required in whom
CMS-EA suspected.
Paucity of synaptic vesicles and reduced
quantal release
 Only 1 patient reported till date
 Clinical and EMG finding similar to auto immune MG
 But onset was at birth, Anti- AChR antibodies
absent, no endplate AChR deficiency
 EM Revealed No Post synaptic abnormality
Paucity of synaptic vesicles and reduced
quantal release
 Decreased (20%) ACh Quanta (m) release by nerve
impulse due to decreased number of readily releasable
qaunta (n).
 Decreased density of synaptic vesicles by about 20% of
normal in unstimulated nerve terminals
 Patients symptom improved by pyrodistigmine.
Paucity of synaptic vesicles and reduced
quantal release
 Disorder stems from paucity of synaptic vesicles.
 Synaptic vessel protein in perikaryon of Ant horn cell
carried distally by kinesin assembled in nerve terminal
Packed to form Ach.
 Basic defects maybe due to-
1. Defect in formation of synaptic vesicles precursors in anterior
horn cells
2. Defect in axonal transport
3. Impaired assembly of mature vesicles
4. Impaired recycling
Paucity of synaptic vesicles and reduced
quantal release
Lambert-Eaton-Like syndrome
 At Mayo clinic, a 6 months old girl presented with
severe bulbar and limb weakness, hypotonia, areflexia
and respirator dependency since birth.
 EMG showed low amplitude CMAP which facilitated
500% on high frequency stimulation and 40%
decrement on low frequency.
 Amplitude of CMAP was abnormally small but
facilated several fold on tetanic stimulation.
Lambert-Eaton-Like syndrome
 EM revealed no defect in pre or post synaptic regions.
 AChR and synaptic vesicles were normal.
 MEPP amplitude was normal for muscle fiber size
 Quantal content of EPP at 1 Hz stimulation was less
than 10% and at 40Hz increased by 300%
Lambert-Eaton-Like syndrome
 EMG abnormality improved by 3,4-DAP but patient
remained weak.
 Molecular basis- ? presynaptic voltage gated calcium
channel or ? Vesicular release complex defect.
 Mutation analysis of CACNA1A gene revealed no
abnormality.
Other syndromes associated with reduced
quantal release
 Maselli et al reported 3 sporadic patients, 1 more than
5 years and 2 in early infancy.
 They had truncal or limb ataxia and 1 had horizontal
nystagmus with sparing of external occular muscles.
 EMG- decremental response at 2 Hz which did not
improve with high frequency
 No AChR deficiency
Other syndromes associated with reduced
quantal release
 EM-normal nerve terminal, normal no. of synaptic vesicles
with small double membrane
 In vitro microelectrode- decrease in no. of quanta released
at 1 Hz
 No mutation detected
 One patient responded to pyridostigmine and 3,4-DAP and
another mild response to pyridostigmine and ephedrine.
Synaptic Basal Lamina-
associated Syndrome
AChEsterase
Congenital End plate Acetylcholinesterase
deficiency
 Myasthenia refractory to AChE inhibitors.
 AChe was absent from endplate detected by
cytochemical and immunocytochemcal criteria.
Clinical Features
 Symptoms since birth (poor suck, cry, dyspnea)
 Delayed motor milestones
 Weakness of facial, cervical, axial and limb muscles
 Ophthalmoparesis in some pts with abnormally slow pupillary
reactions.
 Fixed scoliosis, severe weakness & atrophy of dorsal forearm &
intrinsic muscles of hand.
 Patients presenting in childhood become disabled only in 2nd
decade while in some others with severe symptoms at birth
had improved during adolescence.
•11 yo, weak since infancy with ptosis, restricted EOM, sluggish
pupillary reflex, lordosis
•Worsening with Mestinon, some response to pseudo-ephedrine
 Fig 66-7
Congenital End plate Acetylcholinesterase
deficiency
 Electrophysiology
1. Decremental response at 2 Hz
2. Nerve stimulation evokes a repititive CMAP which is because of prolonged
lifetime of acetyl choline.
3. In vitro microelectrode- MEPP normal or reduced, decay time prolonged
(MEPP & MEPC), no response to prostigmine.
4. Quantal content(m) is decreased which is because of decrease in readily
releasable quanta (n).
5. Kinetic property of AchR are normal by patch clamp analysis.
Decrement after 3 HZ RNS
Repetitive CMAP after single
stimuli
Congenital End plate Acetylcholinesterase
deficiency
 Morphologic Features
1. AChE absent
2. Small and Decreased nerve terminal size and presynaptic
membrane length. Schwann cell extend in synaptic cleft
and presynaptic membrane reduce availability of Ach
release. This decrease the quantal content.
3. Sometimes Junctional fold are degenerated with
shedding of AchR.
4. Total no. of AChR/ endplate is normal to reduced.
Congenital End plate Acetylcholinesterase
deficiency
 Pathogenesis
Degeneration of presynaptic membrane reduction in
quantal release  AChe reduced Increased lifetime of
Ach Causes cationic overloading and destruction Of
junctional fold with shedding of AchR.
 Prolonged deporalization at end plate blocks Na channel
and inhibits generation of AP.
Catalytic
Subunits
Collagen Tail
Formed by triple-helical association
of three collagen strands (ColQ)
Congenital End plate Acetylcholinesterase
deficiency
 Molecular studies
 AchE is asymmetrical enzyme composed of catalytic
subunit attached to collagenic tail.
 Collagenic tail is formed by ColQ.
 ColQ contains PRAD (proline rich attachment
domain) associates AchE tetramer.
 AchE is anchoraged to synaptic space by two
cationic heparan sulfate binding domains.
 Tail subunit is anchored by heparan proteoglcan and
extracellar domain of Musk.
Congenital End plate Acetylcholinesterase
deficiency
AchE deficiency may occur
1. Defect in ColQ
2. Basal lamina binding partners
3. Defect in transport of assembled asymmetrical
enzyme
1. Four major ColQ mutations are:
 Mutation that Involve PRAD prevent attachment of AchE to
ColQ
 Mutation that truncate collagen domain that prevent triple
helical association.
 Carboxyl terminal mutant produces incompetent enzyme
 Other C terminal mutation that produces reduced amount of
enzyme.
Congenital End plate Acetylcholinesterase
deficiency
 Therapy
1. AChE medication should be avoided enhances
muscarinic side effects.
2. ? Ephedrine, ?prednisone
3. Atracurium is AchR blocker that prevents
overexposure of Ach.
Post-Synaptic Syndromes
Ligand- Gated Ion Channel
2α + β + ε + δ
Ach binding site is at α to ε and α to δ
Over view of AChR structure
α
 Each subunits has
1. N terminal domain that occupy about 50 % of
primary sequence
2. 4 transmembarne domain (TMD 1-4)
3. Large cytoplasmic domain between TMD3 and TMD
4
4. Small C extracellular domain.
 Ach binding sites are formed between interface
between subunits. This interface are called loops.
 Seven linearly designated loops between aplha and
non alpha are A to G.
 The recent X ray structure of Ach suggested that
residues in all seven loops are present at the binding
sites. For ex αY198 in loop A.
 These residues confer binding Ach or releasing Ach
from bound site at postsynaptic membrane.
 Besides at the level of membrane there 5 rods typical
of alpha helices that twist upons itself to permit flow
of ion. These rods are TMD2.
 TMD 2 of each alpha helices constrict upon itself to
dilate and allow flow of ions.
 CMS have been found in all AchR subunits and in
several domain of subunits.
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 Syndromes
 Recognized by Engel and co workers in 1982
 Dominant inheritance
 Repetitive CMAP that decremented abnormally on
RNS and prolonged synaptic response to Ach in
absence of AChE deficiency is characteristic.
 Selectively involves cervical, scapular, finger extensor,
mild opthalmoparesis and variable weakness of other
muscles.
Clinical features.
 Some present early in life and others later and progress
gradually in an intermittent manner.
 Weakness usually fluctuate not as rapid as
autoimmune MG and cranial muscles are usually
spared. Muscles become atrophiccc…
Family M.
Slow channel
Intra familial
variability
for severity
mild
severe
G153S
Slow Channel Syndromes
Slow Channel Syndromes
Slow Channel Syndromes
 Morphologic features
1. LM
Type 1 fiber predominance, atrophy, varying fiber size and splitting,
tubular aggregates and endomysial connective tissue deposition.
Endplate configuration is abnormal with focal deposits of calcium.
2. EM –
Junctional fold degeneration with widening of synaptic space,
degenerating and apoptotic nuclei etc. There is absence nerve
terminal in some of the postsynaptic membrane. There is also
degeneration of sarcoplasm. AchR is also lost from due destruction
of junctional fold.
Slow Channel Syndromes
 Electrophysiology
Patch clamp analysis
 Strongest proof of kinetic abnormality came from patch
clamp analysis.
 There was slowing of conduction across Achr.
 Molecular Genetics
Total 20 slow channel mutations have been uncovered since
1995(TMD2, αG153S etc)
Majority of slow channel results from mutation of TMD2.
Slow Channel Syndromes
 Pathogenetic Mechanisms
 Prolonged opening of AchR Increased Ca at the
junctional fold and surrounding region  causes
activation of proteases and free radical productions
promotes apoptosis degeneration of junctional fold,
loss of AchR, nuclear apoptosis and features of
myopathy decreased MEPP amplitude.
Slow Channel Syndromes
 Diagnosis
1. Clinical, dominant inheritance, normal AChE, decremental
and repetitive CMAP.
2. Invitro demonstration of slowly decaying MEPC and
abnormally prolonged opening events at AChR channels.
3. Previous DD’s were –
 Mobius syndrome
 peripheral neuropathy
 MND
 Syrings
 Limb girdle dystrophy etc.
Slow Channel Syndromes
 Treatment
1. Quinidine (200 mg 3-4 times daily) blocker of AChR
and shortens the activity of Ach.
1. Fluoxetine (up to 80 mg/ day)
Fast Channel Syndromes
 First recognized in 1993
 Derives name due to abnormal brief channel
opening events with fast decay of synaptic response.
 Responds to anticholinesterase medications.
 Patch clamp analysis revealed receptor opening
impaired and closing enhanced.
 Proline to leucine mutation in ε subunits and
phenotype determined was εP121L.
 Types of mutation:
 Subunits impair kinetics
 Extracellular domain decreases affinity
 TMD impair gatting
 Cytoplasmic loop  destabalizes the membrane.
Clinical Features
1. Mild gating efficacy impaired
2. Moderate channel kinetics impaired
3. Severe affinity and gating eficacy imapired.
 At birth pt with severe may require ventilator support.
 Pt cannot hold head erect, stand or walk
 May have eyelid ptosis, facial diplegia, unable to close
mouth and dysphagia.
 Sometimes arthrogroposis may develop.
Fast Channel Syndromes
Fast Channel Syndromes
 Morphologic studies
1. Endplate morphology and AChR expression are
normal in εP121L and αV132L mutations.
2. In mutations of αV285I and ε1254ins18 mutation
AChR expression is decreased
Fast channel Syndromes
 Electrophysiology
Fast channel Syndromes
 Diagnosis
1. In Vitro microelectrode studies showing rapidly
decaying MEPC’s
2. Genetic studies
 Therapy
Combination therapy with anticholinesterases and
3,4-DAP which increases number of quanta per
release.
Low-Expressor AChR mutations
 Reduced AChR expression to < 15%
 Mild to severe phenotype
 Most cases mutation in ε-subunit of AchR fetal
AchR harboring γ-subunit is substituted
 Mutations in both alleles of a non-ε subunit
incompatible with life
 Most respond well to AChE Inh ± DAP
 The described mutations are numerous (60 or more),
either homozygous or heterozygous
 They are of all types: missense mutations,
chromosomal deletions, insertions, deletions.
•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)
Low expressor AChR mutations with no or
minor kinetic abnormality
 Morphologic Studies
1. Increased no. of endplate regions distributed over an
increased span of muscle fiber.
2. No. of secondary synaptic clefts/unit length of
primary is lower and distribution of AChR on the
junctional fold is patchy.
3. Immunocytochemical reaction for rapsyn molecule
that cross links AChR is decreased.
Low expressor AChR mutations with no or
minor kinetic abnormality
 Electrophysiological Studies
1. Amplitude of MEPP & MEPC are less but quantal
release by nerve impulse is higher.
 Molecular studies
1. This results from homozygous or more frequently
heterozygous recessive mutations of AChR subunit
genes( eg. 1369delG mutation )
Low expressor AChR mutations with no or
minor kinetic abnormality
 Treatment
1. Most patients respond well to anticholinesterase
drugs with additional benefit from 3,4-DAP
Rapsyn
Tyrosine kinase function :
AChR concentration and linkage to cytoskeleton
Rapsyn deficiency
 Rapsyn under the influence of neurally supplied
agrin has a crucial role in concentrating AChR in the
postsynaptic membrane and linking it to
subsynaptic cytoskeleton through dystroglycan
 Effector of agrin induced clustering of AChR.
Clinical Features
1. Symptoms at birth or in neonatal period and rarely in second
decade.
2. Some are born with arthrogryposis
3. Motor milestones are delayed and respiratory compromise
resulting in anoxic encephalopathy are reported
4. Facial deformities with prognathisnm is usually pronounced
in jewish population.
5. Pts have weakness of masticatory muscles, eyelid ptosis, facial
weakness and hypernasal speech.
Rapsyn deficiency
 Morphologic features
1. Reduced expression of Rapsyn and a proportionately
reduced AChR
2. Ultrastructural studies show shallow postsynaptic
folds and clefts and smaller than normal nerve
terminals.
Rapsyn deficiency
 Electrophysiological features
1. Decremental response maybe seen
2. Invitro reveal reduced MEPP and MEPC
 Molecular studies
1. N88K E-box Rapsyn mutation is found to be
frequent cause
 Treatment
1. Anticholinesterase ± 3,4-DAP
Sodium Channel Myasthenia
1. 20 year old normokalemic woman with abrupt attacks of respiratory and
bulbar paralysis since birth lasting 3-30 mins and recurring 1-3 times per
month.
2. She was on apnea monitor since infancy and had delayed motor milestones
3. At age 20 she had ptosis, eye movement restriction had facial,truncal and
limb weakness.
4. Had High arched palate, knock knees and lumbar lordosis
5. She was mental retarded secondary to episodic cerebral anoxia (MRI
confirmed)
6. AChR antibodies negative
Sodium Channel Myasthenia Nerve Conduction
Sodium Channel Myasthenia
 Morphology studies
1. Type1 fiber was smaller
2. EM- No significant changes
3. Immunolocalization of sodium channels was
comparable with control
Sodium Channel Myasthenia
 In vitro Electrophysiology
EPP- Normal
MEPP and Quantal EPP – Normal
Patch Clamp- Normal conductance
 Molecular genetic study revealed SCN4A ( which
encodes Na) mutations
Sodium Channel Myasthenia
Sodium Channel Myasthenia
 Treatment-
Pyridostigmine ( 60-120mg,TID) + Acetazolamide
improved patient.
PLECTIN deficiency
 Plectin is significantly expressed intermediate
filament linking protein which is concentrated at the
sites of mechanical stress,as post synaptic membrane ,
sarcolemma, skeletal muscle, skin.
 Plectin mutations are associated with epidermolysis
bullosa, myopathy and myesthenic syndrome
PLECTIN deficiency
 These patients with skin disease were found to have
abnormal fatigability involving ocular, facial, and limb
muscles.
 Had decremental response with No antibodies
 Morphology revealed necrotic and regenerative fibers with
junctional changes
 AChR-Normal and Low MEPP
 3,4- DAP was useful
Dok-7 interacts with MuSK and is essential for post-
synaptic specialization of the neuromuscular junction
DOK7 Synaptopathy
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
Partially Characterized Syndromes
 END PLATE AChR DEFIECIENCY WITH NO MUTATIONS
IN AChR OR RAPSYN
Cause of CMS obscure
? End plate specific protein defect
 Familial Limb-Girdle Myasthenia
1. Autosomal recessive
2. Limb girdle weakness in childhood or teens
3. Response to anticholinesterase, No steroids
4. EMG- Decrement, MEPP- low, No AChR deficiency
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 and presence of features
of myopathy
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
Pharmacotherapy
ChAT deficiency
AChE inhibitor
AChE deficiency
Avoid AChE inhibitors; ephedrine or albuterol*
Simple AChR deficiency
AChE inhibitor; 3,4-DAP also helps in 30-50%
Slow-channel CMS
Quinidine or Fluoxetine (long-lived open channel blockers)
Fast-channel CMS
AChE inhibitor and 3,4-DAP
Rapsyn deficiency
AChE inhibitor; 3,4-DAP; ephedrine or albuterol*
Na-channel myasthenia
AChE inhibitor and acetazolamide
Dok-7 myasthenia
Avoid AChE inhibitor; use ephedrine or albuterol
References
 Chapter 66 Congenital myasthenia syndrome
Andrew G. Engel

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Congenital myasthenic syndromes

  • 2. What is congenital myasthenic syndrome??  Inherited disorder of neuromuscular transmission associated with abnormal weakness and fatiguability on exertion.  The prevalence of CMS is estimated at one in 500 000 in Europe, and CMSs are much more uncommon than autoimmune myasthenia  Acetylcholinesterase deficiency was the first CMS identified, based on the lack of the enzyme at neuromuscular junctions  In the experience of Engel’s group, postsynaptic CMSs are three times more frequent than acetylcholinesterase deficiency and 10 times more frequent than presynaptic
  • 3. Is CMS the same as myasthenia gravis?  No.  An autoimmune condition like rheumatoid arthritis, which can affect both children and adults.  Myasthenia gravis causes the body to produce proteins that block and destroy some of their receptors, making messaging from nerves to muscles less effective.  Myasthenia gravis can be treated with steroids, immunosuppressive drugs and thymectomy (surgical removal of the thymus gland).
  • 4. Basic anatomy and physiology NMJ
  • 5.
  • 7. Transmitter quantum  Amount of Ach released from single synaptic vesicles.  Electrophysiologically measurable parameters of quantal release – mnp mnumber of quantum realeased n number of readily releasable quanta p probablity of release
  • 9. action potential  opening voltage-gated Ca2+ channels ↑Ca2+ permeability Ca2+ Ca2+ channel Presynaptic terminal Action potential
  • 10. Ca2+ Ca2+ channel ↑Ca2+  calcium calmodulin protein kinase phosphorylates synapsin releases Ach from synaptic vesicles by exocytosis ACh Presynaptic terminal
  • 11. Na+ Synaptic cleft Na+ ACh Receptor molecule  ACh binding to Ach receptors  opening ligand-gated Na+ channels.
  • 12. ↑Na+ permeability depolarization action potential generation in the postsynaptic membrane Na+ Action potential Action potential Na+
  • 14. Presynaptic terminal Synaptic vesicle ACh Acetic acid Choline CholineACh in the presynaptic terminal Choline + acetic acid → Ach → Synaptic vesicles CHAT VACht
  • 15. Structure of AchE  Acetylcholinesterase (AchE) is an enzyme, which hydrolyses the neurotransmitter acetylcholine.  The active site of AChE is made up of two subsites, both of which are critical to the breakdown of ACh.  The anionic site serves to bind a molecule of ACh to the enzyme. Once the ACh is bound, the hydrolytic reaction occurs at a second region of the active site called the esteratic subsite.  Here, the ester bond of ACh is broken, releasing acetate and choline. Choline is then immediately taken up again by the high affinity choline uptake system on the presynaptic membrane. 15
  • 16. MEPP , MEPC & EPP  Single quantum Deporalization and current flow  MEPP and MEPC  MEPP Number and conductance per channel opened, resistance of muscle fibre and functional state of AchE  MEPC number of channel opening and the current per channel flowing  EPP nonlinear summation of individual quanta produces a large deporalization which is EPP.
  • 17. SAFETY MARGIN OF NM TRANSMISSION  Difference between the depolarization caused by EPP and depolarization required to activate the Na Channel.  All congenital or acquired cause of neuromuscular transmission have been shown to sub threshold EPP for activating Na or Na channel unresponsiveness to EPP
  • 18. Saturating disc model of NM transmission  MEPPs are believed to be the depolarization of the muscle membrane caused by the action of the acetylcholine released by a single synaptic vesicle which spontaneously fused with the presynaptic membrane – this is the vesicle hypothesis  Quantal nature of the small EPPs Fusion of no vesicles = no EPP Fusion of one vesicle = MEPP (0.5mV) Fusion of three vesicles = EPP with an amplitude 3x the MEPP (1.5mV)  10-20% of 10,000 molecules of ACh released by a single vesicle bind to AChE in the cleft  the remaining NT binds to AChR in a patch of about 0.3m m2 in area = the disk of AChR saturated with agonist NT  Saturated disk model: vesicle releases enough ACh to bind all AChE and AChR in 0.1 ms
  • 19. Congenital Myasthenic Syndromes  Congenital Myasthenic Syndromes are inherited disorders of neuromuscular transmission.  CMS was recognized 1st time in late 1970’s and early 1980’s after recognization of auto immune origin of myasthenia gravis  During the past decade various divergent types of CMS were identified  Various classifications were done but Mayo clinic and European neuromuscular centre classification was mostly accepted
  • 20.
  • 21. Frequencies of identified mutations  Mutations in AChR subunits, 55%  Low-expressor in e subunit, 34%  Low expressor in other AChR subunits, 3%  Slow channel mutations, 12%  Fast channel mutations, 6%  Rapsyn, 15%  ColQ, 15%  Dok-7, 9%  ChAT, 6%  Nav1.4, Plectin, Agrin, MuSK, Laminin b2 <1%  If clinical data provides no clues for targeted mutation analysis, search for mutations in descending order as listed  Screen for common mutations in RAPSN and DOK7  Search for common mutations in ethnic groups (e.g, e1267delG)
  • 22. 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
  • 23. 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
  • 24. Investigations of Endplate Diseases  Clinical - History, examination, response to Tensilon or 3,4-DAP - EMG: repetitive nerve stimulation, SFEMG - Serologic tests: AChR and MuSK antibodies, tests for botulism  Muscle biopsy studies: morphology - Cytochemical localization of AChR, AChE, immune deposits - AChR per endplate (125I-a-bungarotoxin) - Quantitative EM, immuno-EM  Muscle biopsy studies: electrophysiology - Microelectrode studies: MEPP, MEPC, EPP, m, n, p - Single-channel patch-clamp recordings  Mutation analysis and expression studies
  • 26. Presynaptic Syndromes  Choline Acetyltransferase Deficiency  Paucity of synaptic vesicles and reduced quantal release  Lambert-Eaton-Like syndrome  Other syndromes associated with reduced quantal release
  • 27. Choline Acetyltransferase Deficiency  Recognized 3 decades ago  Previously it was called as Familial Infantile Myasthenia  Distinguishing features are sudden and expected dyspnea and bulbar weakness CMS with episodic apnea (CMS-EA)  Impaired vesicular packaging and resynthesis of Ach.
  • 28. Choline Acetyltransferase Deficiency  Clinical Features  Most cases in infancy  Sudden unexpected episodes of dyspnea and bulbar weakness culminating in apnea (CMS-EA)  Some patients had hypotonia, bulbar and respiratory weakness at birth requiring ventilator
  • 29.  Others develop symptoms during childhood precipitated by cold or infection.  After age of 10 symptoms less severe and there is no loss of muscle bulk nor permanent myopathy  Phenotypic heterogenity may be seen in kinships.  With increase in age exacerbation are less severe.
  • 31. Choline Acetyltransferase Deficiency  Electrophysiology 1. Decremental response seen in weak muscles. 2. SFEMG similar to MG 3. Weakness induced by exercise and RNS at 10 Hz. 4. Decrement can be corrected by edrophinium.  End plate studies 1. Number of AChRs/end plate and postsynaptic structure normal 2. Synaptic vesicles smaller in rested muscle 3. MEPP and EPP normal at rest but decreases with 10 Hz stimulation with slow recovery over 10 to 15 mins.
  • 32. Molecular study….  Impaired vesicular packaging and Ach resynthesis  4 genes impicated: 1. Presynaptic high affinity choline transporter 2. CHAT 3. VAchT 4. Vesicular proton pump 5. Patients had no ANS and CNS involvement suggested that selectively vulnerable to CHAT.
  • 33. Choline Acetyltransferase Deficiency  Treatment 1. Anticholinesterase medications prophylactically and during crisis found to be usefull 2. Long term apnea monitoring required in whom CMS-EA suspected.
  • 34. Paucity of synaptic vesicles and reduced quantal release  Only 1 patient reported till date  Clinical and EMG finding similar to auto immune MG  But onset was at birth, Anti- AChR antibodies absent, no endplate AChR deficiency  EM Revealed No Post synaptic abnormality
  • 35. Paucity of synaptic vesicles and reduced quantal release  Decreased (20%) ACh Quanta (m) release by nerve impulse due to decreased number of readily releasable qaunta (n).  Decreased density of synaptic vesicles by about 20% of normal in unstimulated nerve terminals  Patients symptom improved by pyrodistigmine.
  • 36. Paucity of synaptic vesicles and reduced quantal release  Disorder stems from paucity of synaptic vesicles.  Synaptic vessel protein in perikaryon of Ant horn cell carried distally by kinesin assembled in nerve terminal Packed to form Ach.  Basic defects maybe due to- 1. Defect in formation of synaptic vesicles precursors in anterior horn cells 2. Defect in axonal transport 3. Impaired assembly of mature vesicles 4. Impaired recycling
  • 37. Paucity of synaptic vesicles and reduced quantal release
  • 38. Lambert-Eaton-Like syndrome  At Mayo clinic, a 6 months old girl presented with severe bulbar and limb weakness, hypotonia, areflexia and respirator dependency since birth.  EMG showed low amplitude CMAP which facilitated 500% on high frequency stimulation and 40% decrement on low frequency.  Amplitude of CMAP was abnormally small but facilated several fold on tetanic stimulation.
  • 39. Lambert-Eaton-Like syndrome  EM revealed no defect in pre or post synaptic regions.  AChR and synaptic vesicles were normal.  MEPP amplitude was normal for muscle fiber size  Quantal content of EPP at 1 Hz stimulation was less than 10% and at 40Hz increased by 300%
  • 40. Lambert-Eaton-Like syndrome  EMG abnormality improved by 3,4-DAP but patient remained weak.  Molecular basis- ? presynaptic voltage gated calcium channel or ? Vesicular release complex defect.  Mutation analysis of CACNA1A gene revealed no abnormality.
  • 41. Other syndromes associated with reduced quantal release  Maselli et al reported 3 sporadic patients, 1 more than 5 years and 2 in early infancy.  They had truncal or limb ataxia and 1 had horizontal nystagmus with sparing of external occular muscles.  EMG- decremental response at 2 Hz which did not improve with high frequency  No AChR deficiency
  • 42. Other syndromes associated with reduced quantal release  EM-normal nerve terminal, normal no. of synaptic vesicles with small double membrane  In vitro microelectrode- decrease in no. of quanta released at 1 Hz  No mutation detected  One patient responded to pyridostigmine and 3,4-DAP and another mild response to pyridostigmine and ephedrine.
  • 45. Congenital End plate Acetylcholinesterase deficiency  Myasthenia refractory to AChE inhibitors.  AChe was absent from endplate detected by cytochemical and immunocytochemcal criteria.
  • 46. Clinical Features  Symptoms since birth (poor suck, cry, dyspnea)  Delayed motor milestones  Weakness of facial, cervical, axial and limb muscles  Ophthalmoparesis in some pts with abnormally slow pupillary reactions.  Fixed scoliosis, severe weakness & atrophy of dorsal forearm & intrinsic muscles of hand.  Patients presenting in childhood become disabled only in 2nd decade while in some others with severe symptoms at birth had improved during adolescence.
  • 47. •11 yo, weak since infancy with ptosis, restricted EOM, sluggish pupillary reflex, lordosis •Worsening with Mestinon, some response to pseudo-ephedrine
  • 49. Congenital End plate Acetylcholinesterase deficiency  Electrophysiology 1. Decremental response at 2 Hz 2. Nerve stimulation evokes a repititive CMAP which is because of prolonged lifetime of acetyl choline. 3. In vitro microelectrode- MEPP normal or reduced, decay time prolonged (MEPP & MEPC), no response to prostigmine. 4. Quantal content(m) is decreased which is because of decrease in readily releasable quanta (n). 5. Kinetic property of AchR are normal by patch clamp analysis.
  • 50. Decrement after 3 HZ RNS Repetitive CMAP after single stimuli
  • 51. Congenital End plate Acetylcholinesterase deficiency  Morphologic Features 1. AChE absent 2. Small and Decreased nerve terminal size and presynaptic membrane length. Schwann cell extend in synaptic cleft and presynaptic membrane reduce availability of Ach release. This decrease the quantal content. 3. Sometimes Junctional fold are degenerated with shedding of AchR. 4. Total no. of AChR/ endplate is normal to reduced.
  • 52. Congenital End plate Acetylcholinesterase deficiency  Pathogenesis Degeneration of presynaptic membrane reduction in quantal release  AChe reduced Increased lifetime of Ach Causes cationic overloading and destruction Of junctional fold with shedding of AchR.  Prolonged deporalization at end plate blocks Na channel and inhibits generation of AP.
  • 53. Catalytic Subunits Collagen Tail Formed by triple-helical association of three collagen strands (ColQ)
  • 54. Congenital End plate Acetylcholinesterase deficiency  Molecular studies  AchE is asymmetrical enzyme composed of catalytic subunit attached to collagenic tail.  Collagenic tail is formed by ColQ.  ColQ contains PRAD (proline rich attachment domain) associates AchE tetramer.  AchE is anchoraged to synaptic space by two cationic heparan sulfate binding domains.  Tail subunit is anchored by heparan proteoglcan and extracellar domain of Musk.
  • 55. Congenital End plate Acetylcholinesterase deficiency AchE deficiency may occur 1. Defect in ColQ 2. Basal lamina binding partners 3. Defect in transport of assembled asymmetrical enzyme
  • 56. 1. Four major ColQ mutations are:  Mutation that Involve PRAD prevent attachment of AchE to ColQ  Mutation that truncate collagen domain that prevent triple helical association.  Carboxyl terminal mutant produces incompetent enzyme  Other C terminal mutation that produces reduced amount of enzyme.
  • 57. Congenital End plate Acetylcholinesterase deficiency  Therapy 1. AChE medication should be avoided enhances muscarinic side effects. 2. ? Ephedrine, ?prednisone 3. Atracurium is AchR blocker that prevents overexposure of Ach.
  • 59. Ligand- Gated Ion Channel 2α + β + ε + δ Ach binding site is at α to ε and α to δ Over view of AChR structure α
  • 60.  Each subunits has 1. N terminal domain that occupy about 50 % of primary sequence 2. 4 transmembarne domain (TMD 1-4) 3. Large cytoplasmic domain between TMD3 and TMD 4 4. Small C extracellular domain.  Ach binding sites are formed between interface between subunits. This interface are called loops.
  • 61.  Seven linearly designated loops between aplha and non alpha are A to G.  The recent X ray structure of Ach suggested that residues in all seven loops are present at the binding sites. For ex αY198 in loop A.  These residues confer binding Ach or releasing Ach from bound site at postsynaptic membrane.
  • 62.  Besides at the level of membrane there 5 rods typical of alpha helices that twist upons itself to permit flow of ion. These rods are TMD2.  TMD 2 of each alpha helices constrict upon itself to dilate and allow flow of ions.  CMS have been found in all AchR subunits and in several domain of subunits.
  • 63. 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
  • 64. Slow Channel Syndromes  Recognized by Engel and co workers in 1982  Dominant inheritance  Repetitive CMAP that decremented abnormally on RNS and prolonged synaptic response to Ach in absence of AChE deficiency is characteristic.  Selectively involves cervical, scapular, finger extensor, mild opthalmoparesis and variable weakness of other muscles.
  • 65. Clinical features.  Some present early in life and others later and progress gradually in an intermittent manner.  Weakness usually fluctuate not as rapid as autoimmune MG and cranial muscles are usually spared. Muscles become atrophiccc…
  • 66. Family M. Slow channel Intra familial variability for severity mild severe G153S
  • 69. Slow Channel Syndromes  Morphologic features 1. LM Type 1 fiber predominance, atrophy, varying fiber size and splitting, tubular aggregates and endomysial connective tissue deposition. Endplate configuration is abnormal with focal deposits of calcium. 2. EM – Junctional fold degeneration with widening of synaptic space, degenerating and apoptotic nuclei etc. There is absence nerve terminal in some of the postsynaptic membrane. There is also degeneration of sarcoplasm. AchR is also lost from due destruction of junctional fold.
  • 70.
  • 71. Slow Channel Syndromes  Electrophysiology
  • 72. Patch clamp analysis  Strongest proof of kinetic abnormality came from patch clamp analysis.  There was slowing of conduction across Achr.  Molecular Genetics Total 20 slow channel mutations have been uncovered since 1995(TMD2, αG153S etc) Majority of slow channel results from mutation of TMD2.
  • 73. Slow Channel Syndromes  Pathogenetic Mechanisms  Prolonged opening of AchR Increased Ca at the junctional fold and surrounding region  causes activation of proteases and free radical productions promotes apoptosis degeneration of junctional fold, loss of AchR, nuclear apoptosis and features of myopathy decreased MEPP amplitude.
  • 74. Slow Channel Syndromes  Diagnosis 1. Clinical, dominant inheritance, normal AChE, decremental and repetitive CMAP. 2. Invitro demonstration of slowly decaying MEPC and abnormally prolonged opening events at AChR channels. 3. Previous DD’s were –  Mobius syndrome  peripheral neuropathy  MND  Syrings  Limb girdle dystrophy etc.
  • 75. Slow Channel Syndromes  Treatment 1. Quinidine (200 mg 3-4 times daily) blocker of AChR and shortens the activity of Ach. 1. Fluoxetine (up to 80 mg/ day)
  • 76. Fast Channel Syndromes  First recognized in 1993  Derives name due to abnormal brief channel opening events with fast decay of synaptic response.  Responds to anticholinesterase medications.  Patch clamp analysis revealed receptor opening impaired and closing enhanced.  Proline to leucine mutation in ε subunits and phenotype determined was εP121L.
  • 77.  Types of mutation:  Subunits impair kinetics  Extracellular domain decreases affinity  TMD impair gatting  Cytoplasmic loop  destabalizes the membrane.
  • 78. Clinical Features 1. Mild gating efficacy impaired 2. Moderate channel kinetics impaired 3. Severe affinity and gating eficacy imapired.  At birth pt with severe may require ventilator support.  Pt cannot hold head erect, stand or walk  May have eyelid ptosis, facial diplegia, unable to close mouth and dysphagia.  Sometimes arthrogroposis may develop.
  • 80. Fast Channel Syndromes  Morphologic studies 1. Endplate morphology and AChR expression are normal in εP121L and αV132L mutations. 2. In mutations of αV285I and ε1254ins18 mutation AChR expression is decreased
  • 81. Fast channel Syndromes  Electrophysiology
  • 82. Fast channel Syndromes  Diagnosis 1. In Vitro microelectrode studies showing rapidly decaying MEPC’s 2. Genetic studies  Therapy Combination therapy with anticholinesterases and 3,4-DAP which increases number of quanta per release.
  • 83.
  • 84. Low-Expressor AChR mutations  Reduced AChR expression to < 15%  Mild to severe phenotype  Most cases mutation in ε-subunit of AchR fetal AchR harboring γ-subunit is substituted  Mutations in both alleles of a non-ε subunit incompatible with life  Most respond well to AChE Inh ± DAP  The described mutations are numerous (60 or more), either homozygous or heterozygous  They are of all types: missense mutations, chromosomal deletions, insertions, deletions.
  • 85. •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
  • 86.
  • 87.  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)
  • 88.
  • 89. Low expressor AChR mutations with no or minor kinetic abnormality  Morphologic Studies 1. Increased no. of endplate regions distributed over an increased span of muscle fiber. 2. No. of secondary synaptic clefts/unit length of primary is lower and distribution of AChR on the junctional fold is patchy. 3. Immunocytochemical reaction for rapsyn molecule that cross links AChR is decreased.
  • 90. Low expressor AChR mutations with no or minor kinetic abnormality  Electrophysiological Studies 1. Amplitude of MEPP & MEPC are less but quantal release by nerve impulse is higher.  Molecular studies 1. This results from homozygous or more frequently heterozygous recessive mutations of AChR subunit genes( eg. 1369delG mutation )
  • 91. Low expressor AChR mutations with no or minor kinetic abnormality  Treatment 1. Most patients respond well to anticholinesterase drugs with additional benefit from 3,4-DAP
  • 92. Rapsyn Tyrosine kinase function : AChR concentration and linkage to cytoskeleton
  • 93. Rapsyn deficiency  Rapsyn under the influence of neurally supplied agrin has a crucial role in concentrating AChR in the postsynaptic membrane and linking it to subsynaptic cytoskeleton through dystroglycan  Effector of agrin induced clustering of AChR.
  • 94. Clinical Features 1. Symptoms at birth or in neonatal period and rarely in second decade. 2. Some are born with arthrogryposis 3. Motor milestones are delayed and respiratory compromise resulting in anoxic encephalopathy are reported 4. Facial deformities with prognathisnm is usually pronounced in jewish population. 5. Pts have weakness of masticatory muscles, eyelid ptosis, facial weakness and hypernasal speech.
  • 95. Rapsyn deficiency  Morphologic features 1. Reduced expression of Rapsyn and a proportionately reduced AChR 2. Ultrastructural studies show shallow postsynaptic folds and clefts and smaller than normal nerve terminals.
  • 96. Rapsyn deficiency  Electrophysiological features 1. Decremental response maybe seen 2. Invitro reveal reduced MEPP and MEPC  Molecular studies 1. N88K E-box Rapsyn mutation is found to be frequent cause  Treatment 1. Anticholinesterase ± 3,4-DAP
  • 97. Sodium Channel Myasthenia 1. 20 year old normokalemic woman with abrupt attacks of respiratory and bulbar paralysis since birth lasting 3-30 mins and recurring 1-3 times per month. 2. She was on apnea monitor since infancy and had delayed motor milestones 3. At age 20 she had ptosis, eye movement restriction had facial,truncal and limb weakness. 4. Had High arched palate, knock knees and lumbar lordosis 5. She was mental retarded secondary to episodic cerebral anoxia (MRI confirmed) 6. AChR antibodies negative
  • 98.
  • 99. Sodium Channel Myasthenia Nerve Conduction
  • 100. Sodium Channel Myasthenia  Morphology studies 1. Type1 fiber was smaller 2. EM- No significant changes 3. Immunolocalization of sodium channels was comparable with control
  • 101. Sodium Channel Myasthenia  In vitro Electrophysiology EPP- Normal MEPP and Quantal EPP – Normal Patch Clamp- Normal conductance  Molecular genetic study revealed SCN4A ( which encodes Na) mutations
  • 103. Sodium Channel Myasthenia  Treatment- Pyridostigmine ( 60-120mg,TID) + Acetazolamide improved patient.
  • 104. PLECTIN deficiency  Plectin is significantly expressed intermediate filament linking protein which is concentrated at the sites of mechanical stress,as post synaptic membrane , sarcolemma, skeletal muscle, skin.  Plectin mutations are associated with epidermolysis bullosa, myopathy and myesthenic syndrome
  • 105. PLECTIN deficiency  These patients with skin disease were found to have abnormal fatigability involving ocular, facial, and limb muscles.  Had decremental response with No antibodies  Morphology revealed necrotic and regenerative fibers with junctional changes  AChR-Normal and Low MEPP  3,4- DAP was useful
  • 106. Dok-7 interacts with MuSK and is essential for post- synaptic specialization of the neuromuscular junction DOK7 Synaptopathy
  • 107. 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
  • 108. Partially Characterized Syndromes  END PLATE AChR DEFIECIENCY WITH NO MUTATIONS IN AChR OR RAPSYN Cause of CMS obscure ? End plate specific protein defect  Familial Limb-Girdle Myasthenia 1. Autosomal recessive 2. Limb girdle weakness in childhood or teens 3. Response to anticholinesterase, No steroids 4. EMG- Decrement, MEPP- low, No AChR deficiency
  • 109. 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 and presence of features of myopathy
  • 110. 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
  • 111. Pharmacotherapy ChAT deficiency AChE inhibitor AChE deficiency Avoid AChE inhibitors; ephedrine or albuterol* Simple AChR deficiency AChE inhibitor; 3,4-DAP also helps in 30-50% Slow-channel CMS Quinidine or Fluoxetine (long-lived open channel blockers) Fast-channel CMS AChE inhibitor and 3,4-DAP Rapsyn deficiency AChE inhibitor; 3,4-DAP; ephedrine or albuterol* Na-channel myasthenia AChE inhibitor and acetazolamide Dok-7 myasthenia Avoid AChE inhibitor; use ephedrine or albuterol
  • 112. References  Chapter 66 Congenital myasthenia syndrome Andrew G. Engel