Clinical Manifestations of Congenital
Myasthenic Syndromes
Duygu Selcen, MD
Mayo Clinic
No disclosures
Signs and Symptoms
Prenatal
Decreased fetal movements
Neonatal
Poor cry, suck, choking spells, stridor,
apnea, droopy eyelids; symptoms
worsened by crying or activity; joint
contractures
Later life
Delayed motor milestones; seldom learn
to run, cannot climb stairs well
Abnormal fatigability on exertion, cannot
keep up with peers in sports
Ptosis, limited eye movements
Spinal deformities, small muscles
Generic diagnosis of a CMS
• Fatigable weakness of ocular, bulbar and limb muscles
since infancy or early childhood
• Similarly affected relative
• Decremental EMG response at 2-3 Hz stimulation
• Negative tests for anti-AChR and anti-MuSK antibodies
Exceptions and caveats
• Late onset in some CMS
• Family history can be negative
• EMG abnormalities only in some muscles or after
stimulation
• Weakness can be restricted to selected muscles
CMS: Differential diagnosis
• Neonatal period, infancy
– Birth trauma, SMA1, congenital myopathies
(myotubular, nemaline, central core), congenital
dystrophies, congenital myotonic dystrophy,
mitochondrial myopathy, Möbius syndrome, congenital
fibrosis of EOM, infantile botulism
• Children and adults
– Mitochondrial myopathy, motor neuron disease,
muscular dystrophies (OPD, FSH, LGD, Distal),
botulism, autoimmune MG
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
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)
Case 1
• Boy, age 5. Hypomotility in utero.
Floppy at birth. Intermittent respiratory
insufficiency since birth, some with
apnea. Walked at 27 mos. Slurred
speech and strabismus when tired
• No FH of similar illness
• EMG: mild decrement at 2 Hz; on 10
Hz stimulation for 5 min: CMAP fell to
10% and recovered over 15 min and
decrement at 2 Hz increased to 50%
• Slow recovery of CMAP after
subtetanic stimulation suggested
delayed ACh resynthesis
Genetic studies
• Two recessive mutations identified in choline
acetyltransferase (ChAT)
• Pyridostigmine therapy abolished the acute episodes
and improved the abnormal fatigability
Case 2
• Age 4 mo
• Hypomotility in utero
• Floppy at birth. Poor suck, ptosis,
intermittent resp insufficiency since
birth, some with apnea
• Severe restriction of ocular ductions
• Slow pupillary light reflex
• No FH of similar illness
• EMG: Severe CMAP decrement at 2
Hz; unaffected by edrophonium
administration
Case 3
• 15 y-old pt
• Unusual gait at age 4
• Cheer leader at age 11
• Progressive limb girdle and axial
weakness after age 12
•No response to pyridostigmine
•31% EMG decrement in trapezius
muscle
Case 2 and 3
• Genetic studies: 2 recessive mutations in ColQ
• Treatment: Albuterol; increased endurance and
decreased
Case 4
• 10 y. Floppy at birth, poor suck, feeble cry. At 5 mo, ptosis,
easy fatigability, poor head control. Walked at 3 y, never
learned to run. Not able to walk >100 feet
• No FH of similar disease
• Lordotic, waddling, foot-drop gait. Cannot abduct arms to
horizontal, mod ptosis, oculoparesis, mod facial paresis,
diffuse weakness of all limb muscles
Case 4
Slow-Channel Myasthenia
• Genetic studies: Dominant mutation in
a-subunit of AChR
• Clinically unaffected father proved to be mosaic for
the same mutation
• Treatment: Quinidine, then fluoxetine
Case 5
• 8 y old girl
• 2 mo of age: droopy eyelids
• Normal early motor milestones
• After age 2 y, frequent falls, could not run well
• No FH of similar disease
• 3 y of age: Diagnosed with myasthenia, treated with
pyridostigmine, thymectomy, cyclosporine and prednisone
• Mild facial weakness, marked limitation of eye movements,
diffuse moderate limb weakness with waddling
hyperlordotic gait
Case 5
• Genetic studies: Homozygous N88K mutation in rapsyn
which is required to anchor AChR at the EP
• Treatment: Pyridostigmine and
3,4 diaminopyridine (3,4-DAP)
CMS caused by mutations in rapsyn
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•
•
•
•
•
Mutations occur in all rapsyn domains
Common N88K mutation in Indo-Europeans
E-box mutations with facial deformities in Near-East
Arthrogryposis at birth in ~25%
Respiratory crises with febrile illnesses
Presentation can be in adulthood mimicking autoimmune MG
Cases 6 and 7
• 2 siblings, 7&9 y old. Both
had a weak cry neonatally.
Ptosis before 1y, limitation
of ocular ductions by age 3.
Both fatigue easily, never
learned to run
• Severe ptosis, limitation of
ocular ductions, fatigable
weakness
• EMG: decrement repaired
with exercise & with
edrophonium
Case 6 & 7
• Genetic studies: Two heterozygous mutations in the
epsilon subunit of AChR
• Treatment: Pyridostigmine and 3,4-DAP
Case 8
• 29 y old
• Lifelong, nonprogressive weakness in his shoulder and hip
girdle muscles
• When walked long distance, became progressively fatigued
• Muscle biopsy at age 12 y “nonspecific congenital
myopathy”
• EMG: significant decrement on repetitive stimulation of the
musculocutaneous and spinal accessory nerves
• Therapy with Mestinon 60 mg qid – no benefit
Case 8
• Small endplates, decreased number of AChR
• Genetic studies: Two frameshifting mutations in Dok7
which is essential for maturation and maintenance of
the EP
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