Clinical Manifestations of Congenital Myasthenic Syndromes Duygu Selcen, md



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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

  • 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--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  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 2 <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

  • 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 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

  • -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

  • 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




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