Myasthenia gravis (childhood) Flashcards
What part of NS does MG affect?
NMJ
What is the primary mechanism leading to muscle weakness in Myasthenia Gravis?
Myasthenia Gravis is an autoimmune disorder in which antibodies target the acetylcholine receptors (AChRs) or associated proteins at the neuromuscular junction (NMJ), preventing acetylcholine from binding. This reduces muscle activation and leads to fatigue and weakness.
Which two types of antibodies are associated with MG, and what clinical features are they linked to?
- AChR antibodies → Ocular and generalized MG.
- Anti-MuSK (Muscle-Specific Kinase) antibodies → More associated with bulbar and respiratory symptoms.
What is the most common initial symptom of Myasthenia Gravis?
Ptosis (drooping eyelid) and ocular muscle weakness are the first symptoms in almost 100% of patients
Differentiate between a myasthenic crisis and a cholinergic crisis.
*Myasthenic crisis → Severe muscle weakness leading to respiratory failure, due to worsening MG. Treated with plasmapheresis or IVIG.
*Cholinergic crisis → Overdose of cholinesterase inhibitors (e.g., pyridostigmine), causing excess acetylcholine, leading to muscle weakness, fasciculations, sweating, and bradycardia. Treated by stopping cholinesterase inhibitors.
Which treatment is considered first-line for symptomatic relief in MG?
Pyridostigmine, a cholinesterase inhibitor, is the first-line symptomatic treatment.
Why is thymectomy performed in MG patients?
Many MG patients have thymoma or thymic hyperplasia. Thymectomy can improve symptoms or induce remission, especially in AChR antibody-positive cases
What is the hallmark finding on repetitive nerve stimulation in MG?
Decremental response (reduced compound muscle action potential [CMAP] amplitude with repeated stimulation)
How does Myasthenia Gravis affect reflexes?
Reflexes remain normal unless severe weakness is present.
Definition of infantile botulism
Infant botulism is an intestinal toxemia that results after spores of the bacterium Clostridium botulinum or related species are swallowed.
What bacterial species causes infantile botulism, and how does it affect the neuromuscular junction?
*These spores temporarily colonize an infant’s large intestine and produce botulinum neurotoxin.
*The neurotoxin binds to cholinergic nerve terminals and cleaves intracellular proteins necessary for acetylcholine release.
List clinical signs of infantile botulism: Cows Play Pretty Softly For Grandma’s Weak, Resting Cry
Cows = Constipation
Play = Poor feeding
Pretty = Ptosis (drooping eyelid)
Softly = Sluggish pupils
For = Flattened facial expression
Grandma’s = Diminished gag and suck reflexes
Weak = Weak and altered cry
Resting = Respiratory difficulty
Cry = Respiratory arrest (if severe)
Why does infantile botulism result in constipation as a presenting symptom?
The autonomic nervous system is affected, leading to reduced gut motility and intestinal paralysis
Which specific neurotransmitter is blocked by botulinum toxin?
Acetylcholine (ACh) at both neuromuscular and autonomic synapses
What is the treatment for infantile botulism?
Botulism immune globulin (BIG-IV) and supportive care (e.g., respiratory support, feeding assistance
How do congenital myasthenic syndromes differ from Myasthenia Gravis in terms of pathophysiology?
CMS is genetic (not autoimmune) and results from mutations affecting NMJ proteins. MG is caused by autoantibodies
Prevalence of CMS
1 in 500,000 in Europe.
Typical onset of CMS
Early onset, birth or infancy. Adolescence or adulthood more rare.
Which inheritance pattern is most common in CMS?
Autosomal recessive (AR)
Which type of CMS is most common and what mutation is responsible?
Postsynaptic CMS is most common, with mutations in the ε-subunit of the ACh receptor (AChR-ε)
Causes of CMS
*Currently 20 genes responsible for CMS
*85% are postsynaptic: ε-subunit of AChR, Rapsyn, Dok-7
*10% synaptic (basal lamina-associated): COLQ (collagen tail of AChE)
*5% presynaptic: CHAT (choline acetly-transferase)
Clinical features of CMS: Happy Old People Don’t Feel Much Excitement, And Sometimes Struggle
Happy = Hypotonia
Old = Ophthalmoplegia
People = Ptosis
Don’t = Dysphagia
Feel = Facial paresis
Much = Muscle fatigability
Excitement = Exacerbations
And = Amyotrophy
Sometimes = Scoliosis
Struggle = Acute respiratory failure
Which subtype of CMS worsens with cholinesterase inhibitors?
Slow-channel CMS (due to prolonged AChR activation).
What is the key electrophysiological feature of presynaptic CMS (ChAT deficiency)?
10 Hz repetitive nerve stimulation (RNS) causes prolonged slow recovery (5-10 minutes)
Which CMS subtype is associated with prolonged acetylcholine receptor (AChR) opening?
Slow-channel CMS
Course and progression of CMS
*Family history argues for CMS: most are AR, slow channel is AD
*Progression patterns variable
*Transient worsening with or without return to previous state
*Regularly progressive deterioration or improvement
*Course may change at various life stages
*Triggers: infections, pregnancy, menstrual periods
*Worsening in adulthood
*Favorable progression in childhood after severe neonatal course
Which genetic mutation affects the anchoring of acetylcholinesterase (AChE) and what is the resulting effect on the neuromuscular junction?
ColQ mutation → AChE cannot anchor properly, leading to prolonged ACh presence and receptor desensitization
What is the typical response of CMS patients to cholinesterase inhibitors?
Most CMS patients improve, but some subtypes worsen (e.g., slow-channel CMS).
Which CMS subtype mimics limb-girdle muscular dystrophy (LGMD)?
Dok-7 myasthenia.
What clinical features can suggest CMS in an infant presenting with hypotonia?
Ptosis, ophthalmoplegia, bulbar weakness, muscle fatigability, and respiratory issues.
Why do infections, pregnancy, and menstrual periods trigger worsening in CMS patients?
They increase metabolic stress on the NMJ, worsening synaptic transmission failure.
Which treatment is specifically useful for slow-channel CMS and why?
Quinidine and Fluoxetine (block excessive AChR opening).
Why do some forms of CMS respond better to ephedrine and albuterol rather than pyridostigmine?
Pyridostigmine is ineffective in CMS subtypes where ACh release is already excessive, while ephedrine/albuterol enhance neuromuscular transmission via β2-adrenergic receptor pathways.
Explain why neonatal apnea is a common feature in synaptic CMS.
Mutations in ColQ (AChE deficiency) cause prolonged depolarization, leading to NMJ failure and recurrent apnea episodes.
What is the main reason for variability in progression patterns of CMS?
Different genetic mutations affect NMJ function in different ways (some worsen, some stabilize, some improve with age).
Which molecular pathway is disrupted in MuSK-Dok7-Rapsyn-related CMS?
The Agrin-LRP4-MuSK signaling pathway, which is crucial for AChR clustering at the NMJ.
What is the role of agrin and LRP4 in neuromuscular junction function, and how does its disruption lead to CMS?
Agrin binds LRP4, activating MuSK, which organizes AChR clustering. Disruption leads to impaired synapse formation and muscle weakness.
List of txs for MG
- Pyridostigmine
- Prednisone
- Immunosuppression
- Plasma exchange
- Thymectomy
