Myasthenia gravis: an animated, cited guide

This page needs JavaScript for its animations. The outline and key answers are below, and every claim in the full version carries a numbered citation.

Not medical advice. Myasthenia Gravis Companion is an educational synthesis of published literature. It does not replace a clinician.

What is in it

What myasthenia gravis is Who gets it, the numbers, the muscles it reaches.
The neuromuscular junction One nerve impulse in slow motion, and the safety factor.
Antibodies at the junction AChR, complement, MuSK and LRP4, animated.
Weakness over a day Why muscles tire with use and recover with rest.
Diagnosis Antibodies, nerve tests, single-fibre EMG, a calculator.
MGFA class & scores MGFA classes I to V, MG-ADL and QMG, scored live.
The differential Lambert-Eaton, botulism, ALS, eye and muscle disease.
Pyridostigmine, animated Buying time at the receptor, dose by dose.
The treatment ladder From symptom relief to immunotherapy and biologics.
Thymectomy over the years The thymus, thymoma and the MGTX trial.
Complement & FcRn inhibitors The newer biologics, trial week by trial week.
Myasthenic crisis Triggers, the breathing numbers, ICU care.
Drugs that can worsen MG A cited checker: antibiotics, magnesium and more.
Nursing care Assessment, timing the doses, teaching, documentation.
Living with MG Pregnancy, surgery, exercise, vaccines, work.
Toward a cure CAR-T, B-cell targets and the evidence for each route.
History & people From Willis in 1672 to the biologics.
Flashcards, quiz and glossary Revision for students.
Sources Every reference behind the guide.

Part 1 · The disease

The neuromuscular junction

One nerve impulse crossing to a muscle fibre, in slow motion: calcium, acetylcholine release, receptors opening, the endplate potential and the safety factor. Press play, step through, then switch to MG.

Junction Impulse

Timeline

Schematic, not to scale. The animation runs in uneven slow motion; the trace's time axis is real milliseconds.

Zoom: from muscle to fold

Schematic. Each level magnifies the boxed area of the one before.

The junction in numbers

Quantity	Value	Note
Bouton size	usually 1–5 µm across	Swellings of the fine (about 0.1 µm) terminal branches. ⁴⁹⁷
Synaptic vesicle	about 50 nm	Clustered at active zones. ⁴⁹⁷
ACh per quantum	about 10,000 molecules	An iontophoretic estimate gives fewer than 10,000; 6,000 molecules depolarise the membrane by 1 mV. ^303,497
Quantal content (human)	about 20–30 quanta per impulse	Mouse: 50–100. Humans release the fewest quanta of the vertebrates studied. ⁴⁹⁷
Spontaneous release	about 1 per second	Each gives an mEPP of about 1 mV. ⁴⁹⁷
Synaptic cleft	about 50–100 nm	Filled with extracellular matrix (basal lamina). ⁴⁹⁷
AChR density on crests	about 10,000 per µm²	Near-crystalline array. ^190,497
Fold depth (human)	up to about 1 µm	Folding raises membrane area about 8-fold, the deepest folds known. ⁴⁹⁷
Channel open time	about 1 ms	Each quantum depolarises the fibre about 1 mV from about −75 mV. ⁴⁹⁷
ACh lifetime in the cleft	under 1 ms	Hydrolysis plus diffusion; the depolarisation lasts several ms more. ⁴⁹⁴
Safety factor	2.98 (controls) vs 1.09 (MG)	Human intercostal muscle. Threshold depolarisation 13.5 vs 21.6 mV. ⁴⁶⁷
AChRs per junction	2.1 × 10⁷ (controls) vs 0.7 × 10⁷ (MG)	Deltoid, 49 controls and 76 patients. ⁴²¹

The receptor: five subunits, two keys

The muscle receptor is a ring of five subunits: α2βδε in adults, α2βγδ before birth. The γ-to-ε switch changes how the channel conducts and gates. ^364,494

The two ACh sites sit at the α–δ interface and at the α–ε (adult) or α–γ (fetal) interface. They are not equal: ACh leaves one about 100 times faster than the other. ⁴⁹⁴ The main immunogenic region, the target of half or more of MG antibodies, sits at the top of α1. ^328,494 Antibodies at the junction picks up from there.

Established

Crests and troughs

The folds split the membrane into two domains. Crests carry AChR with rapsyn (the 43 kDa protein); troughs carry Na⁺ channels with ankyrin. ^180,497

Rapsyn is needed for clustering itself: rapsyn-deficient mice form no AChR clusters. ¹⁹⁰ Human junctions are small, fragmented into coin-shaped patches, and stable from age 34 to 92. ²⁷⁴

Established

The safety factor

SF = EPP ÷ E_AP, where E_AP is the step from resting potential to threshold. Trough Na⁺ channels raise the safety factor by lowering that threshold. ⁴⁶⁷

Frogs get their margin by releasing a lot of transmitter. Humans release little and rely on elaborate postsynaptic folds that amplify each quantum. ^497,555

How big is it normally? 2–4 times what is needed (Slater), 3–5 in adult mammals (Wood & Slater), 4–5 times (Kouyoumdjian). ^301,497,555

Measured in people 2.98 in control intercostal muscle, 1.09 in MG. ⁴⁶⁷

The clean-up crew

Acetylcholinesterase (AChE) is held in the basal lamina by a collagen tail, ColQ. Mice without ColQ have no asymmetric AChE at the junction at all. ¹⁷⁶

With AChE working, each quantum acts on its own patch of membrane. When the enzyme is inhibited, quanta overlap and add up, and the synaptic current lasts longer. ²²⁶ That is the idea behind pyridostigmine, a cholinesterase inhibitor. ¹⁵⁰ Too much ACh action has a cost: ColQ mutations prolong it and damage the postsynaptic membrane. ⁴⁹⁷

The nerve turns up the volume

In MG muscle and in rats with experimental MG, quantal content was raised over control. The smaller an endplate's mEPPs, the larger its increase: a muscle-to-nerve compensation. ⁴²⁷ The signals behind it are not fully known. ⁴²⁸

In mice given MuSK antibodies this compensation did not happen. ²⁹⁴

Established

Rundown during a train

At 10–100 Hz, quantal content and EPP fall as the ready-to-release vesicle store is used up; healthy EPPs stay above threshold. ^301,497 After 1–2 seconds a second store refills the first, giving the "U" shape of the decrement. ³⁰¹

When the margin is thin, rundown pushes fibres below threshold one by one. That is the decrement on repetitive nerve stimulation and the weakness that grows with use in Weakness over a day.

Exam hookIn MG the endplate potential still forms but sits close to threshold: the safety factor fell from 2.98 to 1.09 in human muscle. ⁴⁶⁷ Two things shrink it: fewer AChRs make a smaller EPP, and loss of trough Na⁺ channels raises the threshold. ⁴⁶⁷ With rundown during repeated firing, some fibres fail, which is the decrement and the fatigable weakness. MG is in the end the failure of the EPP to reach threshold. ⁴⁹⁴

In plain wordsThe nerve throws handfuls of a chemical messenger across a tiny gap. Catchers on the muscle side pick it up, and when enough are caught the muscle fires. A healthy junction catches about three times more than it needs. In MG there are fewer catchers, so the muscle only just fires, and after a few rapid signals it may not fire at all.