Clinical Manifestations of Congenital Myasthenic Syndromes

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Clinical Manifestations of Congenital Myasthenic
Syndromes

• Duygu Selcen, MD
• Mayo Clinic
• No disclosures

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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

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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

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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

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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

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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 lt1

• 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)

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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

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Genetic studies

• Two recessive mutations identified in choline
  acetyltransferase (ChAT)
• Pyridostigmine therapy abolished the acute
  episodes and improved the abnormal fatigability

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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

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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

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Case 2 and 3

• Genetic studies 2 recessive mutations in ColQ
• Treatment Albuterol increased endurance and
  decreased

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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 gt100 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

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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

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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

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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)

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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

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Cases 6 and 7

• 2 siblings, 79 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

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Case 6 7

• Genetic studies Two heterozygous mutations in
  the epsilon subunit of AChR
• Treatment Pyridostigmine and 3,4-DAP

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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

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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

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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 acetazolamideDok-7 myasthenia
• Avoid AChE inhibitor use ephedrine or albuterol