Discussed about the case and about the Myastenic syndromes

1. A Case of Myasthenia
Dr.U.Meenakshisundaram Unit
Presenter: Dr.M.Ramesh Babu

4. History
• Mr. X 16yrs old young boy, From Andhra, studying +1,
Right handed came with ℅
• Difficulty in getting up and walking since from the age 1 yr
• Drooping of both Eyelids since from the age of 1 yr

5. HOPI
• Patient was born to non-consangious parents - observed
delay in mile stones from the age of 10 months, mile
motor stone in standing and walking.
• Before 10 months parents didn’t noticed/ or pay attention
in drooping of eyelids, fatiguability in activities.
• Parents started observing from the age of 1 - delay in mile
motor stones, difficulty in standing for a longer time,
fatiguability in walking more towards end of the day,
drooping of eyelids.

6. • No h/o change in voice, swallowing difficulty, breathing
difficulty.
• Later he admitted and evaluated and diagnosed as
Congenital Myasthenia - ? Post synaptic defect - started
on pyridostigmine - and showed response.
• Now he is unable to get up or walk on his own, needs 1
person support. With Pyridostigmine - he can do his daily
activities, affect lasting for 1 hour
• Came here for further management.

7. • Family history : No one suffers in the family with similar
complaints.
• Birth History : normal vaginal delivery, Cried immediately
after birth, sucking normal, no hypokinesia observed
• Personal history : Appetite, sleep - normal, takes mixed
diet. Bowel, bladder - normal
• Drug History : No h/o any ayurvedic or homeopathic or
heavy metal medication usage. Presently on
Pyridostigmine and on Salbutamol.

8. On Examination
• Patient was conscious, alert
• Moderately built & nourished
• No PICCLE
• No facial anomalies
• No Neurocutaneous markers
• Vitals - stable

9. CNS Examination
• Conscious, alert, well oriented, MMSE 30/30
• Pupils - 3mm b/l reactive
• Drooping of both eyelids +, complete closure on looking to ceiling for few
minutes
• No difficulty in eye closure, Minimal weakness on attempting to open on forced
eye closure
• EOM - full, convergence, pursuit, saccades - N, No nystagmus
• Facial sensation - N
• No facial asymmetry or weakness
• Tongue and palate - normal
• Normal gag & Jaw jerk
• Neck muscles - normal

10. • Motor system: No muscle, wasting, thinning or twitching
• Tone & bulk normal
• Power - proximally -4/5 in both UL & LL
• Distally 4/5 in both UL & LL
• DTR’s - present
• Plantar - b/l flexors
• Sensory system - Normal
• No in-coordination
• Gait - waddling+ type of gait
• Spine & Cranium - normal

12. Investigations

24. Final Diagnosis
• Onset of symptoms since infancy
• Ocular and weakness/ fatiguability of limbs
• No family history
• Negative for antibodies
• RNS studies +
• Response to CHEI’S
• Myasthenia gravis- Congenital ? post synaptic defect

25. What isCongenital Myasthenic
Syndrome??
• CMS - Inherited disorder of neuromuscular transmission
associatedwith abnormal weakness and fatiguability onexertion.
• The prevalence of CMSis 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.

26. Is CMS the same as
Myasthenia Gravis?
• No.
• An autoimmune condition
• 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).

27. CONGENITAL MYASTHENIC SYNDROMES

28. INTRODUCTION
❑ Heterogeneous genetic disorders characterized by compromised
neuromuscular transmission
❑ Rare (one in 500 000) but an important cause of seronegative
myasthenia
❑ Clinical manifestations vary by congenital myasthenic syndrome
subtype
▪ Present signs from birth or shortly after
▪ mild presentations, go undiagnosed until adolescence or
adulthood
Congenital myasthenic syndromes. Hantaı et al. Current Opinion in Neurology 2004, 17:539–551 Congenital
Myasthenic Syndrome: A Brief Review. Pediatric Neurology 46 (2012) 141- 148

29. ACETYLCHOLINE RECEPTOR
MASC = muscle-associated specificity component; MuSK =muscle-specific receptor tyrosine kinase
Continuum Lifelong Learning Neurol 2009;15(1)

30. EventsreleaseofAch

31. action potential  opening voltage-gatedCa2+ channels
↑Ca2+ permeability
Ca2+
Ca2+
channel Presynaptic
terminal
Action
potential

32. Ca2+
Ca2+
channel
↑Ca2+  calcium calmodulin protein kinasephosphorylates
synapsin releases Ach from synaptic vesicles by exocytosis
ACh
Presynaptic
terminal

33. Na+
Synapticcleft
Na+
ACh
Receptor
molecule
 ACh binding to Ach receptors  opening ligand-gated Na+
channels.

34. ↑Na+ permeability depolarization action potential
generation in the postsynaptic membrane
Na+
Action
potential
Action
potential
Na+

35. ACh
receptor
site
Acetylcholinesterase
Acetic
acid
CholineACh
Ach →acetic acid +choline
▲
Ach-Esterase

36. Presynaptic
terminal
Synaptic
vesicle
ACh
Acetic
acid
Choline
CholineACh
in thepresynaptic terminal
Choline + acetic acid → Ach → Synaptic vesicles
CHAT
VACht

37. CLASSIFICATION
❑ Depending on the location of the primary defect within the
neuromuscular junction
▪ Presynaptic (generally caused by an anomaly of
choline acetyltransferase ChAT),
▪ Synaptic (corresponding to an anomaly of the
acetylcholinesterase collagen tail)
▪ Postsynaptic (secondary to an anomaly of
acetylcholine receptor or rapsyn).
P.J. Lorenzoni et al. / Pediatric Neurology 46 (2012) 141-148

39. PRESYNAPTIC DEFECTS
❑ rarest, affecting an estimated 7-8% of patients
❑ 4 subtypes
▪ Episodic apnea
▪ paucity of synaptic vesicles
▪ “Lambert-Eaton-like”
▪ other presynaptic defects
SYNAPTIC DEFECTS
❑ account for approximately 14-15% of patients
▪ Endplate acetylcholinesterase deficiency
▪ Abnormal laminin β2 chain
P.J. Lorenzoni et al. / Pediatric Neurology 46 (2012) 141-148

40. POSTSYNAPTICDEFECTS
❑ 75-80% of patients
▪ Acetylcholine receptor deficiency without kinetic abnormality
▪ Primary kinetic abnormality of the acetylcholine receptor
➢ Slow-channel syndrome
➢ Fast-channel syndrome
▪ Defects of acetylcholine receptor complex
➢ Rapsyn deficiency
➢ Dok-7 deficiency
➢ MuSK deficiency
▪ Voltage-gated sodium channel
▪ Agrin deficiency
▪ With tubular aggregates
▪ Other defects
P.J. Lorenzoni et al. / Pediatric Neurology 46 (2012) 141- 148

41. Patients with congenital myasthenic syndrome,according to site of defect in
neuromuscular junction and molecular analysis

42. IDENTIFIEDGENESOFCONGENITALMYASTHENIC
SYNDROME

43. Proteinproductsofknowncandidategenesforcongenitalmyasthenic syndromesat
theneuromuscularjunction

44. CLINICALFEATURES
A.G. Engel / Neuromuscular Disorders 22 (2012)99–111
❑ Generic features
▪ Fatigable weakness involving ocular, bulbar, and limb muscles
since infancy or early childhood
▪ Similarly affected relative
▪ Decremental EMG response at 2- to 3-Hz stimulation, or abnormal
jitter and blocking on single fiber EMG
▪ Negative tests for anti-AChR antibodies, MuSK, and P/Q type
calcium channels

45. ❑ Exceptions
▪ In some CMS the onset is delayed
▪ There may be no similarly affected relatives
▪ EMG abnormalities may not be present in all muscles, or are
present only intermittently
A.G. Engel / Neuromuscular Disorders 22 (2012)99–111

46. CLINICAL CLUES – SPECIFIC CMS
Weakness/fatigability of limbs and oculobulbarmuscles
—Early onset (since neonatal period)
—Positive family history
—EDX findings (RNS, SFEMG)
—Response to anti-cholinesterases
—Absence of anti-AChR, MuSK , VGCCantibodies
❑ Endplate acetylcholinesterase deficiency
▪ Delayed pupillary light reflex in some cases
▪ Repetitive CMAPs
▪ Refractoriness to cholinesterase inhibitors; negative
edrophonium test
▪ Absence of cholinesterase reactivity from EPs in muscle
specimensA.G. Engel / Neuromuscular Disorders 22 (2012)99–111

47. ❑ Slow-channel myasthenic syndrome
▪ Cranial muscles only mildly affected; slowly progressive
course
▪ Selectively severe involvement of neck and wrist and finger
extensor muscles in most cases
▪ Dominant inheritance in nearly all cases
▪ Repetitive CMAPs
▪ Worsened by long-term pyridostigmine therapy; little or no
response to edrophonium
A.G. Engel / Neuromuscular Disorders 22 (2012)99–111

48. ❑ Endplate choline acetyltransferase deficiency
▪ Recurrent apneic episodes, spontaneous or with fever,
vomiting, or excitement
▪ No or variable myasthenic symptoms between acute episodes
❑ Rapsyn deficiency
▪ Ophthalmoparesis in 25%; strabismus relatively common
▪ Multiple congenital joint contractures or dysmorphic features
in 30%
▪ Increased weakness and respiratory insufficiency precipitated by
intercurrent infections
A.G. Engel / Neuromuscular Disorders 22 (2012)99–111

49. ❑ Dok-7 myasthenia
▪ Predominantly limb-girdle and axial distribution of weakness,
mild facial weakness, and ptosis are common, and normal ocular
ductions in most patients
▪ Significant bulbar muscles involvement in some patients
▪ Can present with stridor and vocal cord paralysis in neonates and
infants
❑ GFPT1 (GFAT) myasthenia
▪ Tubular aggregates in muscle in most patients
▪ Predominantly limb-girdle and axial distribution of weakness
▪ Responds to pyridostigmine
A.G. Engel / Neuromuscular Disorders 22 (2012)99–111

50. ❑ Laminin-b2 myasthenia
▪ Nephrotic syndrome, ocular abnormalities (Pierson syndrome)
▪ Refractoriness to cholinesterase inhibitors
❑ Plectin deficiency myasthenia
▪ Epidermolysis bullosa simplex
❑ Myasthenic syndrome associated with centronuclear myopathy
▪ Muscle histology
A.G. Engel / Neuromuscular Disorders 22 (2012)99–111

51. • 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 , VGCCantibodies
Diagnostic clues in CMS

52. • Diagnostic problems
—Late onset (inadult)
—No response toanticholinesterases
—No family history
—Episodic symptoms
—No ophthalmoplegia or cranial involvement
—Decrement may not be present in all muscles, or present on
—Misdiagnosed as
—congenital myopathy
—Seronegative MG (late onset)
—Metabolic myopathies
Diagnostic Difficulties

53. DIFFERENTIAL DIAGNOSIS
❑ Vs Neonatal transient Myasthenia
 +ve h/o MG in mother (affects 10-20% of newborns whose mothers
have autoimmune MG)
▪ Transient symptoms (usually last < 2wks but may occur upto 12
wks)
❑ Vs Infantile Botulism
▪ Suggestive history ( 4mths of age, infants fed with honey)
▪ Rapidity of symptom progression
▪ Prominent involvement of ocular & bulbar musculature (pupillary
invovement seen in ~ 50% )
Bradley’s Neurology in Clinical Practice. 6th edition

54. ❑ Vs Juvenile MG (<18 yrs)
▪ Almost never occurs <1 year of age ( CMS- birth)
▪ Association with other autoimmune disorders (diabetes, thyroid dx
and JRA, Thymoma rare)
▪ Seropositivity for AChR Ab (~20% of JMG & ~ 50% thosewith
prepubertal onset are seronegative )
 +ve response to immunomodulatory therapy
▪ Spontaneous remission
▪ Skeletal deformities(scoliosis, lordosis)- favours CMS
Bradley’s Neurology in Clinical Practice. 6th edition

55. ❑ Vs SMA (neonatal & infantile onset)
▪ neonatal form – diffuse weakness of limb & trunk muscles, facial
sparing or mild involvement , arthrogryposis
▪ Infantile form- weakness in first 6 mths of life, proximal> distal,
lower> distal
▪ Relative preservation of diaphragmatic muscle as compared to
abdominal & chest musculature
▪ Needle EMG- denervation
▪ Genetic testing- SMN (survival motor neuron gene)
Bradley’s Neurology in Clinical Practice. 6th edition

56. ❑ Vs Congenital myopathies
▪ Autosomal recessive or X-linked pattern of inheritance
▪ Diffuse weakness & hypotonia , weakness may be severe but is
typically static or slowly progressive
▪ Midly elevated CK
▪ EMG- myopaathic
▪ Histopathology- type I predominance
Bradley’s Neurology in Clinical Practice. 6th edition

57. ❑ Vs Congenital Muscular dystrophies
▪ diffuse weakness and hypotonia
▪ significant elevations in serum CK
▪ subcortical white matter abnormalities may be seen on
brain MRI , cognition is usually normal
▪ Epilepsy may occur
▪ Supportive EMG, Histopatholgy, genetic analysis is confirmatory
Bradley’s Neurology in Clinical Practice. 6th edition

58. ❑ Vs Congenital Myotonic dystophy
▪ type 1 myotonic dystrophy (~25% of infants born to mothers with
myotonic dystrophy)
▪ hypotonia and weakness of the face and limbs in infancy
▪ global developmental delay- intellectual impairment and motor
disability
▪ Later develop myotonia and other characteristic symptoms
▪ Electrphysiology & Genetic analysis
Bradley’s Neurology in Clinical Practice. 6th edition

59. TREATMENT
P.J. Lorenzoni et al. / Pediatric Neurology 46 (2012) 141- 148
❑ Presynaptic
▪ Pyridostigmine- 1 mg/kg every 4 hours (maximal, 7 mg/kg/day,
divided into 5-6 doses
▪ 3,4-DAP- 1 mg/kg/day, divided into 3-4 doses
❑ Synaptic
▪ Ephedrine-1 mg/kg/day and slowly increased to a maximum of 3
mg/kg/day, divided into three doses per day
▪ Albuterol- 0.1 mg/kg/day (maximum, 2 mg/dose) divided into
three doses for children at 2-6 years of age, and 2 mg/dose 2-3
times daily for children between 6-12 years of age

60. ❑ Postsynaptic
▪ Acetylcholine receptor deficiency without kinetic abnormality-
Pyridostigmine, 3,4-DAP
▪ Primary kinetic abnormality of the acetylcholine receptor
➢ Slow-channel syndrome- Quinidine(15-60 mg/kg/day, divided
into 4-6 doses), Fluoxetine(No standard dose)
➢ Fast-channel syndrome- Pyridostigmine, 3,4-DAP
▪ Defects of acetylcholine receptor complex- Pyridostigmine , 3,4-
DAP
▪ Voltage-gated sodium channel- Pyridostigmine, Acetazolamide
P.J. Lorenzoni et al. / Pediatric Neurology 46 (2012) 141- 148

61. ▪ Agrin deficiency- Ephedrine, 3,4-DAP
▪ With tubular aggregates- Pyridostigmine
▪ Other defects(Plectin, With centronuclear myopathy)- 3,4-DAP,
Pyridostigmine
P.J. Lorenzoni et al. / Pediatric Neurology 46 (2012) 141- 148

62. TREATMENT

63. CONCLUSION
❑ CMS should be suspected in any patient with fatigable ocular,
bulbar, or limb weakness presenting in infancy or early childhood
❑ In older patients who are anti-AChR and anti–MuSK-antibody
negative and fail to respond to immunosuppressant medications
❑ Certain clinical features, such as a delayed pupillary light reflex,
prominent weakness of finger/wrist extensors, scoliosis, or a
repetitive CMAP, may aid in making a diagnosis in certain cases
❑ Definitive diagnosis in many cases requires detailed morphologic,
microphysiologic, and genetic studies

64. Presynaptic CMS
Congenital myasthenic syndromes caused by ChAT
mutations
Manifest at birth or in the neonatal period with
bulbar disorders and respiratory insufficiency with
apnoea or even sudden death.
Triggered by fever, fatigue and overexertion
Apart from these bouts, the myasthenic signs are
often modest or not present.

65. CHAT gene encoding ChAT, located on 10q11.2.
ChAT is a presynaptic protein localized in the
nerve terminals, where it catalyses acetylcholine
production.
Mutations lead to a reduction or even abolition of
the catalytic capacity of the enzyme
14 mutations reported

66. • Microelectrophysiology-after prolonged10 Hz
repetitive stimulation, a reduction in amplitude
of the miniature endplate potentials.
• Ultrastructural examination-when muscle is at
rest, the synaptic vesicles are of reduced size
• Cholinesterase inhibitors are effective.

67. Lambert–Eaton-like CMS
Diminished action potentials markedly potentiated
by tetanic stimulation
Good response to guanidine
No mutation found in calcium channel
Sporadic myasthenic syndrome with associated signs
of cerebellar ataxia
Marked reduction in the spontaneous or nerve
stimulation-induced release of acetylcholine quanta.

68. Synapatic congenital
Myasthenia
Acetylcholinesterase deficiency
Autosomal recessive
Symptoms usually arise in the neonatal period
Slowed but inconstant pupil responses to light.
Repetitive compound muscle action potential (CMAP)
after single stimulation
Absence of response to cholinesterase inhibitors
Genetics- Mutations in the COLQ gene coding for
the collagenic tail of acetylcholinesterase
Twenty-four recessive mutations
No effective treatment

69. Post synaptic CMS
• Broadly categorised in 2 category
1. CMS in connection with a kinetic anomaly
of the acetylcholine receptor
2. CMS with a decreased number of
acetylcholine receptors at the
neuromuscular junction

70. CMS caused by Ach receptor anomalies
• Slow channel syndrome
Autosomal dominant
Characterized by a prolonged opening time of
the acetylcholine receptor.
Fifteen missense point mutations causing a
gain of function of the acetylcholine receptor
M1 for mutations of the a and b subunits
M2 more frequent, affecting the a, b, d and e
subunits.