1. Clinical Manifestations of Congenital Myasthenic Syndromes Duygu Selcen, MD Mayo Clinic No disclosures

2. 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

3. 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

4. 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

5. 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 ( 125 I-  -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

7. 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)

8. 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

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

11. 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

12. 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

13. Case 2 and 3 Genetic studies: 2 recessive mutations in ColQ Treatment: Albuterol; increased endurance and decreased

14. 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

15. 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

16. 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

17. 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)

18. 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

19. 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

20. Case 6 & 7 Genetic studies: Two heterozygous mutations in the epsilon subunit of AChR Treatment: Pyridostigmine and 3,4-DAP

21. 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

22. 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

23. 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