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Clinical Manifestations of Congenital Myasthenic Syndromes. Duygu Selcen, MD Mayo Clinic No disclosures. Signs and Symptoms. Prenatal Decreased fetal movements Neonatal

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Clinical Manifestations of Congenital Myasthenic Syndromes

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clinical manifestations of congenital myasthenic syndromes

Clinical Manifestations of Congenital Myasthenic Syndromes

Duygu Selcen, MD

Mayo Clinic

No disclosures

signs and symptoms
Signs and Symptoms


Decreasedfetal movements


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
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
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
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


  • 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)

Frequencies of identified mutations
case 1
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
Genetic studies
  • Two recessive mutations identified in choline acetyltransferase (ChAT)
  • Pyridostigmine therapy abolished the acute episodes and improved the abnormal fatigability
case 2
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
Case 2 and 3
  • Genetic studies: 2 recessive mutations in ColQ
  • Treatment: Albuterol; increased endurance and decreased
case 4
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
Case 4Slow-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
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 51
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
CMS caused by mutations in rapsyn
  • 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
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
Case 6 & 7
  • Genetic studies: Two heterozygous mutations in the epsilon subunit of AChR
  • Treatment: Pyridostigmine and 3,4-DAP
case 8
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 81
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

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 acetazolamideDok-7 myasthenia

Avoid AChE inhibitor; use ephedrine or albuterol