Congenital myaesthenic syndromes

1. CONGENITAL MYASTHENIC
SYNDROMES
Zubair Sarkar
24th Jan’2020

2. Contents
• NMJ
Structure and function
• CMS
Introduction & epidemiology
Classification
Brief review of common CMS
Differential diagnosis
Treatment considerations

3. NMJ : structure and function
• A nerve impulse triggers release
of Ach into the synaptic cleft.
• Ach diffuses and binds to AChRs
• Central ion channel pore of the
AChR opens  depolarizing the
muscle membrane.
• If the degree of depolarisation
exceeds a critical threshold,
VGNa+C open, generating an
action potential.

4. NMJ : structure and function

5. NMJ : structure and function

6. NMJ : structure and function
Agrin: Nerve-derived organizer of post-
synaptic differentiation
Stimulates AchR cluster formation
LRP4: LDL-receptor protein 4 :
mediates agrin action on MuSK
MuSK: Receptor tyrosine kinase :
essential for agrin-induced clustering
and NMJ formation
Rapsyn: Receptor associated protein of
synapse
Concentrates AchR in post-synaptic
membrane and links it to subsynaptic
cytoskeleton through dystroglycan
DOK7: Downstream of kinase: essential
for activation of MuSK

7. Acetylcholinesterase (AchE) structure
• AChE is an asymmetric enzyme expressed in many tissues and in a variety
of molecular forms :
 The H form is a dimer of catalytic subunits anchored to the membrane by
glycophosphatidylinositol.
 The R form is a secreted monomer, and
 T form can associate with two different structural proteins called PRiMA
(proline-rich membrane anchor) and ColQ (collagen Q).
• In the nervous system, PRiMA is mostly expressed in the brain, whereas
ColQ is produced and secreted by muscle cells at the NMJ.

8. Acetylcholinesterase (AchE) structure
• ColQ is a nonfibrillar collagen
• N-terminus contain proline-rich domains
(PRADs) : association with the AChE
catalytic subunits.
• Following the PRAD domain, there is a
collagen domain that is responsible for
the formation of the triple helix and
contains two heparin-binding sites
(HBS).
• Each of the three collagen strands can
bind a tetramer of catalytic subunit 
up to 12 AChE subunits can fill this
collagen : assymetric forms

9. Acetylcholinesterase (AchE) structure
• Perlecan, a heparan sulfate proteoglycan binds the two HBS to dystroglycan.
• The C-terminus of ColQ binds MuSK.
• Both the C-terminus and HBS are necessary to anchor ColQ in the synaptic
basal lamina.
• Mutations in the collagen domain can prevent the interaction of ColQ with
MuSK and perlecan.

10. Acetylcholine Receptor (AchR)
• Central to neuromuscular
transmission.
• Hetero-pentamer comprising
four different subunits (α, β, δ,
ɛ in a ratio of 2:1:1:1)
• Combine to form a
transmembrane ligand-gated
ion channel.
• Each subunit encoded by a
separate gene.

11. Acetylcholine Receptor (AchR)
• Genes encoding the α (CHRNA1), δ (CHRND), and γ (CHRNG) subunits :
different loci on chromosome 2q
• Those encoding the β (CHRNB) and ɛ (CHRNE) subunits : different loci on
chromosome 17p.
• Each AChR has two ACh- binding sites located at the α/ɛ (or α/γ) and α/δ
subunit interfaces.
• Mutations in receptor subunit genes can cause
either a reduced number of available receptors (receptor deficiency),
abnormal kinetic properties of the channel (fast or slow channel
syndromes) or
reduced channel conductance.

12. Introduction to CMS
• A group of inherited disorders in which neuromuscular transmission is
impaired at the motor endplate by one or more specific mechanisms.
• Result from gene mutations affecting the neuromuscular junction structure
and function.
• Unlike autoimmune myasthenia gravis
immune system is not involved
there is no association with antibodies to AChR or MuSK
• All CMS share the feature of fatiguable muscle weakness  discrete
syndromes with distinct phenotypes.

13. Epidemiology
• Rare disease:
Estimated prevalence 1–9 per million
The prevalence of CMS was initially estimated at 2 per million in Europe.
Presently, in the French national CMS network, more than 200 cases have
been diagnosed ….Eymard et al. 2013
The prevalence of genetically confirmed cases in the UK is at least 3.8 per
million ....Finlaysen et al. 2013
Study of 680 suspected CMS patients in Germany found positive genetic
study in 299 patients ….Abicht et al. 2014
• Prevalence is higher near large neuromuscular centers  under-diagnosis is
a possibility.

14. Classification

15. Classification cont.

16. Location of various proteins

17. When to suspect CMS?
In Neonatal Period and Infancy:
• Floppy infant
• Arthrogryposis multiplex/ congenital
deformities
• Bulbar symptoms
• Weak cry
• Respiratory distress/insufficiency
• Family history
At Every Age:
• Ptosis (even unilateral)
• External ophthalmoplegia
• Facial weakness with hypomimia
• Bulbar symptoms
• Exercise intolerance
• Fluctuation of symptoms over days/ weeks
• Crises with/without respiratory insufficiency
caused by infection, fever, and exercise
• Recurrent apnoea
• Progressive muscle atrophy
• Progressive contractures and scoliosis
• Family history

18. Presynaptic CMS

19. Endplate choline acetyl-transferase (ChAT) deficiency
• Pathogenic mutations alter the expression, catalytic efficiency or structural
stability of the enzyme.
When neuronal impulse flow is increased (such as during exercise)
Reduced rate of ACh synthesis progressively decreases the Ach content of the
synaptic vesicles and at synaptic space
Decrease in the amplitude of the EPP and CMAP  safety factor of NMT is
compromised  failure of contraction

20. Endplate choline acetyl-transferase (ChAT) deficiency
• C/f:
Usually presents from birth or early infancy with episodic events.
Sudden apnoea episodes and bulbar weakness : often precipitated by
infection.
May be relatively strong in between such crises.
Ptosis is common but extra-ocular muscles are spared.
Other myasthenic symptoms may also be present

21. Endplate choline acetyl-transferase (ChAT) deficiency
• NCS show a decrement of the CMAP
that repairs with brief exercise but
decreases further with prolonged
exercise or continuous repetitive
stimulation at 10 Hz for 3 to 5 minute.
• This progressive pattern of decrement
can be seen in autoimmune
myasthenia gravis and in congenital
AChR deficiency but is
much more severe and
recovers more slowly over 10 to 15
minutes

22. Endplate choline acetyl-transferase (ChAT) deficiency
• When c/f are mild (ie, older patients / between crises)  routine RNS is
normal, but prolonged exercise or repetitive stimulation will induce a
decrement with slow recovery over 10 to 15 minutes.
• Standard needle EMG may be normal or show small varying MUPs.
• Single fiber EMG is generally abnormal even in mild cases with increased jitter
and blocking

23. Endplate choline acetyltransferase (ChAT) deficiency
• Therapy consists of
AChE inhibitors that must be continued even in asymptomatic patients
3, 4-diaminopyridine (3, 4-DAP) may also give symptomatic relief.
• The parents must be instructed in use of a portable respirator, an apnea
monitor at home, and intramuscular injection of neostigmine.

24. Synaptic CMS

25. AChE deficiency/ColQ
ColQ mutations cause loss of AChE
Prolonged lifetime of acetylcholine in the synapse
Desensitization of the AChR
Prolonged end-plate potentials (EPP)
Secondary excitotoxic myopathy because of
excessive cationic flow onto the muscle

26. AChE deficiency/COLQ
• C/f:
Classically, severe, generalized and progressive weakness from birth or early
infancy  persists through life
In some cases : later onset and milder phenotypes.
Respiratory involvement is common  respiratory crises and/or chronic
hypoventilation.
Ophthalmoplegia and ptosis are common.
Pupillary light reflex is delayed in some patients : differentiating feature

27. AChE deficiency/COLQ

28. AChE deficiency/COLQ
• NCS reveal one or more repetitive CMAPs
(R-CMAPs) with single stimulus
• Administration of cholinesterase inhibitors
has no effect because there is little or no
cholinesterase to inhibit.
• A decrement of the CMAP is present at low
rates of repetitive stimulation  worsens at
higher rates and fails to repair with
cholinesterase inhibitor.
• Needle EMG/SF-EMG : nonspecific and
consistent with a disorder of neuromuscular
transmission and an associated endplate
myopathy.

29. AChE deficiency/COLQ
• Treatment is with oral salbutamol or ephedrine.
• Typically symptoms worsen with pyridostigmine.
• 3, 4-DAP should also be avoided.

30. Post-synaptic CMS

31. AChR deficiency
• Results from homozygous or heterozygous
recessive mutations in subunit genes.
• Mutations in the ε subunit : MC cause of CMS
• ɛ subunit in adults replaces the γ subunit in fetal
AChRs during late gestation.
• Fetal receptor type maintains low level expression
into adulthood  partially compensate for
absence of the ε subunit from the adult receptor.
• Patients with ɛ subunit null mutations survive
• Non-ɛ subunits mutations are rare and usually
severe.

32. AChR deficiency
• C/f:
Most present with feeding problems and ptosis at birth or infancy.
Ophthalmoplegia
invariably present and severe
usually not noticed at birth
likely develops within 1st year.
Weakness worsens during infection, but acute crises do not occur
Patients with mutations in the alpha subunit also have severe weakness of
limb, facial and masticatory muscles

33. AChR deficiency

34. AChR deficiency
• The findings on Edx studies are variable and depend primarily on the severity
and distribution of weakness .
• RNS at slow rates (2 Hz to 3 Hz) demonstrates a decrement of CMAP in most
patients  may be absent or restricted to facial muscles in mild cases.
• The decrement is partially repaired with either AchE inhibitors or 3,4-DAP.
• In moderate to severe cases, the decrement frequently worsens with higher
rates of repetitive stimulation (10 Hz to 50 Hz).

35. AChR deficiency
• The findings on standard needle EMG
and single fiber EMG are nonspecific.
• Small MUPs with rapid recruitment and
amplitude variation without fibrillation
potentials are observed on standard
needle EMG.
• SFEMG demonstrates increased jitter
and blocking.

36. AChR deficiency
• The CMS associated with AChR deficiency tends to be relatively non-
progressive and may even improve slightly as the patient ages.
• Patients generally respond well to pyridostigmine with or without the addition
of 3, 4-DAP.
• Ephedrine/salbutamol produces benefit in some cases.

37. Rapsyn deficiency
• Rapsyn concentrates and anchors AChR to dystroglycan in the postsynaptic
membrane and is required for development of the junctional folds.
• AchR deficiency : milder than primary form and phenotype is different.
• C/f:
Onset at birth with respiratory weakness, feeding difficulties and
generalised hypotonia.
Mild arthrogryposis (due to in-utero hypomobility)
Characteristic facial dysmorphism : high-arched palate
Weakness is usually generalized
Ptosis and strabismus common; ophthalmoplegia is very rare.

38. Rapsyn deficiency
• Acute life-threatening crises with respiratory failure are frequent.
particularly during infancy and early childhood
precipitated by infection.
• Frequency and severity of life-threatening crises diminish later.
• Weakness responds well to pyridostigmine with or without 3, 4-DAP.
• The long-term prognosis is good
Resolves around the age of 7 years.
Many adults can reduce or stop treatment.

39. Rapsyn deficiency

40. DOK-7 myasthenia
• Dok-7 is a muscle-intrinsic activator of MuSK
• Mutation leads to synaptopathy and instability of NMJ (loss of agrin-lrp4-
musk-dok7 pathway signaling)
• C/f:
Usual presentation : deterioration in walking in a normal child with normal
motor milestones.
Some patients present earlier with respiratory weakness, feeding difficulties
and stridor in infancy.
Typical limb girdle distribution of weakness
Usually ptosis but no ophthalmoplegia (similar to rapsyn CMS)
Bulbar and respiratory weakness may develop later in life : About 25% of
patients require regular non-invasive ventilation at some point.

41. DOK-7 myasthenia
Facial muscles often affected - ‘myasthenic snarl’
About half cases have tongue wasting: differentiating feature

42. DOK-7 myasthenia
• Slowly progressive : ?secondary myopathy.
• Muscle biopsy may show mild non-specific changes including increased fiber
size variability, type II fibre atrophy, central nuclei, fiber necrosis and
regeneration.
• Pyridostigmine typically worsens the symptoms.
• 3, 4-DAP can help but should be used with caution : some patients may show
a significant deterioration.
• Responds well to oral salbutamol or ephedrine over months

43. Defects of Glycosylation
• Glycosylation increases solubility, folding, stability, assembly, and intracellular
transport of nascent peptides.
• Four enzymes subserving glycosylation are known to be associated with a
CMS:
Glutamine fructose-6- phosphate transaminase (GFPT1)
Dolichylphosphate N-acetyl-glucosamine-phosphotransferase 1 (DPAGT1)
Alpha-1,3-mannosyl transferase (ALG2)
UDP-N-acetyl-glucosaminyl-transferase subunit (ALG14)

44. Defects of Glycosylation
• Share several features.
• Typically insidious onset of limb girdle weakness in early childhood.
• Minimal craniofacial and bulbar muscles involvement
• No ptosis and ophthalmoplegia.
• Stable course, no acute crises.
• Maybe misdiagnosed as myopathy
Clinical appear as LGMD
Muscle biopsy — non specific myopathic features with tubular aggregates :
differentiating feature.

45. Defects of Glycosylation
• AChE inhibitors and 3,4-DAP beneficial.
• Salbutamol and ephedrine may also help.

46. Kinetic mutations ofAchR : Slow-channel syndrome
• The only dominantly inherited CMS.
Gain-of-function mutations in extracellular ligand-
binding domains of AChR
Prolonged decay of the synaptic currents and
potentials  desensitization blockade of the receptor
Cationic overloading of the postsynaptic region
Excitotoxic EP myopathy and loss of structural
integrity
• Single motor neuron firing causes multiple
contractions – repeated jerky movements  leads
to atrophy of muscle cells and weakness.

47. Kinetic mutations ofAchR : Slow-channel syndrome
• Age of onset : birth to 4-5th decade
• Most present in childhood with neck flexion
weakness and difficulty running.
• After childhood : upper limb weakness
• Selective and asymmetrical involvement of
cervical and distal upper limb muscles
wrist and finger extensors and thumb
abductors.
• Ptosis and ophthalmoplegia may be present
• Feeding difficulty/apnoea/crises : uncommon
• Examining asymptomatic family members may
pick subtle signs

48. Kinetic mutations ofAchR : Slow-channel syndrome
• NCS reveal repetitive CMAPs (R-
CMAPs) when single supra-maximal
stimulus is applied.
• Also observed in congenital AChE
deficiency or pharmacologic inhibition of
AChE.
• Result from prolonged endplate
currents.
• Administration of a AChE inhibitor :
increases the number and size of
repetitive potentials in SCCMS but not in
congenital AChE deficiency.

49. Kinetic mutations ofAchR : Slow-channel syndrome
• RNS reveals a decrement of the main
motor response that worsens with
increasing rates of stimulation.
• Needle EMG findings (standard or single
fiber EMG) are identical to those
observed in other disorders of NMT.

50. Kinetic mutations ofAchR : Slow-channel syndrome
• Pyridostigmine and 3,4-DAP cause deterioration.
• Treatment is with fluoxetine or quinidine : act as open channel blockers.

51. Kinetic mutations ofAchR : Fast-channel syndrome
• Autosomal recessive, loss-of-function
mutation in AchR α, δ and ɛ - subunit
• Mutation effect:
• Reduce gating efficiency (mild)
• Destabilize channel kinetics (moderate )
• Decreases affinity for Ach (severe)
• Or combination of above mechanism
(severe)
• Result in abnormally brief channel opening
leading to abnormal fast decay of synaptic
response.

52. Kinetic mutations ofAchR : Fast-channel syndrome
• Most severe form of congenital myasthenia.
• Patients are affected from birth with respiratory failure, feeding difficulties and
generalized hypotonia.
• Ptosis and ophthalmoplegia : invariable and severe
• Respiratory symptoms : episodic apnoea and chronic hypoventilation 
require regular respiratory assessment and often NIV at home
• Feeding difficulties persist into childhood  often necessitate nasogastric or
percutaneous endoscopic gastrostomy feeding.
• Life-threatening acute crises are common even when treated.

53. Kinetic mutations ofAchR : Fast-channel syndrome

54. Kinetic mutations ofAchR : Fast-channel syndrome
• EDx studies reveal a decrement with slow rates of repetitive stimulation and
repair of the decrement with exercise, high-frequency stimulation,
cholinesterase inhibitors and 3,4- DAP.
• No repetitive CMAPs are observed.
• EMG findings are non specific.

55. Kinetic mutations ofAchR : Fast-channel syndrome
• Pyridostigmine and 3, 4-DAP effective
• Effect of pyridostigmine may diminish after an initial striking response.

56. Slow vs fast channel syndrome

57. Diagnostic clues to CMS types
• Dominant inheritance :
SCCMS
• Worsening with AChE inhibitors :
ColQ, Dok-7, SCCMS
• R-CMAPs :
SCCMS, ColQ
• Delayed pupillary response :
ColQ
• Congenital contractures :
Rapsyn, ChAT
• Delayed recovery after prolonged
RNS :
ChAT
• Sudden apnoeic episodes :
ChAT, Rapsyn
• Limb-girdle distribution :
Dok-7, glycosylation defects
• Tubular aggregates :
Glycosylation defects
• Stridor and vocal cord paralysis in
infants :
Dok-7

58. Differential diagnosis
Neonatal, infancy and childhood
• Congenital myopathies
• Congenital muscular dystrophy
• Mitochondrial myopathy
• Spinal muscular atrophy
• Congenital fibrosis of extraocular
muscles
• Transient neonatal myasthenia
• Autoimmune myasthenia gravis
• Mobius syndrome
Adults
• Autoimmune myasthenia gravis
• Motor neuron disease
• LGMD/FSHD
• Mitochondrial myopathy
• Chronic fatigue syndrome

59. CMS vs autoimmune MG
• When the c/f or EDx results
suggest a myasthenic
condition but antibodies are
negative, it is critical to
distinguish the congenital
from autoimmune
myasthenia gravis.
• Can avoid unnecessary
thymectomy and immuno-
suppressive therapy.
• Some patients with
myasthenia gravis may
remain seronegative .

60. CMS vs Myopathy
• Many patients with CMS, particularly those with DOK7 and glycosylation
defects, are initially diagnosed with muscular dystrophies and congenital
myopathy.
• Myopathy can have a similar pattern of weakness and occasionally show mild
improvement with AChE inhibitors (particularly those with centronuclear core
myopathies).
• They can show jitter on single-fiber EMG (particularly mitochondrial
myopathies).
• Often muscle biopsy helps to distinguish the two.
• In congenital myasthenia phenotypes with myopathic features the muscle
biopsy often shows variable fiber size and other mild non-specific myopathic
features.
• Tubular aggregates are seen in CMS with glycosylation defects

61. Treatment considerations
DOK 7: LGMD, facial, tongue
SC: Neck, wrist weakness with
wasting
COLQ: weakness at birth
Resp distress

62. Cholinesterase inhibitors and 3, 4-DAP
• Both reduce myasthenic weakness by increasing EPP amplitude and
therefore, safety factor.
• But different mechanisms:
Cholinesterase inhibitors prolong the lifetime of acetylcholine at the end-
plate giving more opportunity for each molecule to bind to a receptor.
3, 4-DAP is a potassium channel blocker whose action on the presynaptic
nerve terminal results in increased release of acetylcholine into the
synaptic cleft.
• The two drugs are often used together to provide symptom relief.

63. Pyridostigmine
• Most commonly used AChE inhibitor; the dose is similar to that used in
myasthenia gravis.
• The dose is titrated according to response and in children is calculated by
weight : a typical high dose is 7 mg/kg/day.
• Higher doses (e.g., 10 mg/kg/day) are sometimes needed during episodes of
acute deterioration, particularly in children, though this increases the risk of
muscarinic side effects and cholinergic crises.
• Propantheline or glycopyrronium may help to reduce muscarinic side effects.

64. 3, 4-Diaminopyridine
• Short duration of action  dosage three or four times per day.
• At peak dose, patients often report short-lived tingling sensations in the
extremities and peri-orally.
• The dose required varies by severity and size : typical starting dose for an
adult is 10 mg three times daily.
• The total daily dose should not exceed 80 mg per day : risk of seizures.
• Actual risk of seizures is not known but uncommon at 80 mg/day or less.
• In children :
Should be used more cautiously and started under observation in hospital
and at a low dose (eg, 0.25 mg/kg/day).

65. Ephedrine and oral salbutamol
• Both agents stimulate muscle β2-
adrenergic receptors  improve signal
transmission by stabilizing the post-
synaptic architecture when :
Agrin-LRP4-MuSK-Dok7 pathway is
impaired
Excessive cholinergic stimulation in
ColQ mutation
• Mainstay of treatment of Dok-7 and ColQ
CMS.
• The response can be dramatic, even
when therapy is started in adulthood.
• Other subtypes : including AChR
deficiency, SCCMS, GFPT1 and
DPAGT1—have also found some benefit.

66. Ephedrine and oral salbutamol
• Salbutamol
A typical adult starting dose is 4 mg twice or three times daily.
Can increase gradually to a maximum total daily dose of 16 mg.
• Ephedrine
In adults, usually started at 15–30 mg twice daily
Increased as necessary to a maximum of 30 mg three times daily.

67. Ephedrine and oral salbutamol
• Improvement usually begins within a month of starting treatment and
continues for 6–9 months before plateauing.
• It is not clear if either ephedrine or salbutamol is superior; some patients
respond better to one or other.
• The main adverse events are insomnia and cardiac effects such as
tachycardia, palpitations and hypertension.
• Muscle cramps commonly develop when salbutamol is used in DOK7.

68. Fluoxetine and quinidine in slow channel syndrome
• Both fluoxetine and quinidine are open channel blockers  bind the channel
in its open state  reduce channel opening time.
• Comparative efficacy not known.
• Fluoxetine is the usual drug of choice : has a better safety profile
• Quinidine can cause QT interval prolongation and requires an ECG and
serum level monitoring.
• Flouxetine increases potential risk of suicide in children and adolescents.
• The effective dose of fluoxetine varies with some patients responding to low
doses (20 mg) and others requiring large doses of 120 mg per day.

69. Take home message
• Congenital myasthenic syndromes are rare but underdiagnosed.
• Although typically presenting in infancy, they can present later in adulthood.
• Patients with congenital myasthenia often carry a long-standing incorrect
diagnosis, such as an undefined (on muscle biopsy) congenital myopathy.
• It is worth pursuing a definite genetic diagnosis since this guides prognosis,
genetic counseling and, most importantly, treatment choice.
• The presence or absence of ophthalmoplegia is an important differentiating
feature guiding genetic screening.

70. Take home message
• There is no immune abnormality and so they do not respond to
immunotherapies.
• Some subtypes (slow channel syndrome, ColQ and Dok-7) can worsen with
pyridostigmine or 3,4-diaminopyridine.
• All treatments used for congenital myasthenia are out of license.