Congenital Myasthenic Syndromes (CMS)

Note: The user likely means Congenital Myasthenic Syndromes (CMS), not autoimmune myasthenia gravis. These are distinct entities. CMS is a genetic, non-autoimmune disorder of the neuromuscular junction (NMJ).

Definition

Distinguishing CMS from Other Forms of Childhood Myasthenia

• Barash, Cullen & Stoelting's Clinical Anesthesia, 9e, p. 1839

Clinical Features (Common to All CMS Types)

• Positive family history (autosomal recessive in most forms)
• Weakness with easy fatigability present since infancy
• Ptosis (drooping of eyelids)
• Decremental response to repetitive nerve stimulation on EMG
• Negative anti-nicotinic ACh receptor antibodies and anti-MuSK antibodies (required for diagnosis)
• Delayed motor milestones
• Subnormal skeletal muscle development/bulk
• Fluctuating ocular palsies brought out by sustained activity
• Eric Kandel, Principles of Neural Science, p. 1483; Adams & Victor's Principles of Neurology, 12th Ed.

Classification by Site of Defect

1. Presynaptic Forms

2. Synaptic Cleft Forms

3. Postsynaptic Forms (Most Common)

• Adams & Victor's Principles of Neurology, 12th Ed.

Pathophysiology Key Points

• Slow channel syndrome: Mutations increase AChR affinity for ACh and slow channel closing. Prolonged opening leads to cation overload and end-plate myopathy. Same danger as AChE deficiency - AChE inhibitors are potentially harmful.
• Fast channel syndrome: Mutations accelerate channel closing, reducing depolarization time. 3,4-DAP helps by blocking presynaptic K+ channels, prolonging the action potential, and increasing quantal ACh release.
• Neonatal myasthenia (passive) resolves spontaneously within weeks as maternal antibodies are cleared. CMS persists lifelong.

Diagnosis

1. Clinical suspicion - fatigable weakness since birth/infancy, family history
2. Serological testing - absence of anti-AChR, anti-MuSK, anti-LRP4 antibodies (required)
3. EMG - decremental response to repetitive stimulation; repetitive CMAP in AChE deficiency
4. Edrophonium (Tensilon) test - inconsistently positive; positive in some forms (fast channel, rapsyn deficiency), negative or harmful in others (AChE deficiency, slow channel)
5. Genetic testing - definitive; whole exome sequencing is the modern gold standard
6. Muscle biopsy / electron microscopy - can show end-plate morphology, synaptic vesicle paucity

• Bradley & Daroff's Neurology in Clinical Practice; Adams & Victor's

Treatment Summary

Recent Literature

• Beeson D (2024). Congenital myasthenic syndromes. Handbook of Clinical Neurology - comprehensive current review [PMID: 39174255]
• Spendiff S et al (2025). Congenital myasthenic syndromes. Int Rev Neurobiol - covers emerging genetic subtypes [PMID: 40675739]
• Wiendl H et al (2023). Guidelines for the management of myasthenic syndromes. Therapeutic Advances in Neurological Disorders - includes CMS management [PMID: 38152089]

Key Takeaways

• CMS = genetic, not autoimmune; antibody-negative
• Must distinguish from neonatal (transient, maternal antibodies) and juvenile (autoimmune) forms
• Three anatomical subtypes: pre- / synaptic / postsynaptic - each with distinct mutations and treatment implications
• Critical pearl: AChE inhibitors are contraindicated in AChE deficiency and slow channel syndrome (worsen end-plate myopathy)
• Genetic confirmation is now feasible with next-generation sequencing and is the standard of care

Monoclonal Antibodies in T-Cell ALL (T-ALL)

Important Context First

As Harrison's states directly: "Immunotherapy for T-ALL is still not available, and intensive chemotherapy is still the mainstay in combination with the T cell-specific drug nelarabine." - Harrison's 22E

Agents Currently Used or Under Investigation in T-ALL

1. Blinatumomab (Anti-CD19 x Anti-CD3 BiTE)

• Type: Bispecific T-cell engager (BiTE) - not a classic monoclonal antibody
• Mechanism: Links CD3 on T cells to CD19 on leukemic blasts - recruits the patient's own T cells to kill CD19+ cells
• T-ALL use: CD19 is variably expressed in T-ALL (unlike B-ALL where it is nearly universal). Its use in T-ALL is therefore limited and investigational
• Primarily established in B-ALL (MRD+ and relapsed/refractory settings)
• Goldman-Cecil Medicine, p. 1925

2. Nelarabine (not a monoclonal antibody - important distinction)

• A nucleoside analogue prodrug converted to ara-GTP, toxic to T cells
• The only T-ALL-specific agent approved by FDA (for relapsed/refractory T-ALL)
• Achieves ~30% CR rate as a single agent in recurrent T-ALL
• Often combined with standard regimens (e.g., COG AALL0434 pediatric protocol)
• Goldman-Cecil Medicine, p. 1925

Investigational Monoclonal Antibodies Targeting T-ALL Antigens

Surface Antigens of T-ALL (Diagnostic Markers, Not All Therapeutic Targets)

Why T-ALL Immunotherapy Lags Behind B-ALL

Summary

Can Rituximab Be Used in T-Cell ALL?

The Short Answer: No

Why Rituximab Does Not Work in T-ALL

• Complement-dependent cytotoxicity (CDC)
• Antibody-dependent cellular cytotoxicity (ADCC)
• Direct apoptosis induction

T-Cell Surface Markers (What T-ALL Actually Expresses)

• B-cell ALL: CD19+, TdT+, CD20+, CD5+, CD10+, CD22+, CD79a+, PAX-5+
• T-cell ALL: TdT+, CD1a+, CD2+, CD3c+, CD4+, CD5+, CD7+, CD8+ ← No CD20

Where Rituximab IS Used in ALL

What IS Used in T-ALL Instead

Memory Hook

Rituximab = anti-CD20 = B-cells only T-ALL expresses CD2, 3, 5, 7, 38 - never CD20 Therefore rituximab has no target in T-ALL and is not used.