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