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%
• 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, 1267delG)
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
• 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 3
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 4Slow-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 inhibitorAChE 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
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