MGA News Winter 2001

The Slow and Fast Channel Syndromes

A “nerve’s eye view” of the AChR, looking down from outside the muscle, showing the five subunits arranged around the central pore, and the sites where the transmitter (Ach) binds. Each subunit is a chain of ~ 450 building bricks (which come in 20 different types). Most of them have to be exactly right; a single change can be disastrous.

In the myasthenias, the defect is in the ‘ignition system’ of muscles. As you will remember, nerves trigger muscles by releasing showers of a chemical transmitter called acetylcholine (ACh) – the ignition keys. When the ACh latches onto the special ignition locks on the muscle surface – the ACh receptors (AChRs) – their central channels open, allowing salt to enter and then trigger a muscle contraction. The spare ACh is rapidly destroyed by “ACh esterase”; it is blocked by mestinon, which prolongs the ACh lifetime, giving the muscle a better chance to get triggered in cases of difficulty.

The AChRs are the major target for the ‘autoimmune’ attack in ~ 80% of typical MG patients. In another ~ 5% of myasthenics, there are inherited faults in one of the subunits of the AChR (see diagram). Although rare, these ‘mutations’ are the main focus of my team’s research. They teach us valuable lessons about how the AChR should normally work. Their correct diagnosis is also important, because one patient’s best treatment can sometimes be another one’s poison.

The faults we see fall into two broad categories. In one, there just are not enough AChRs, and triggering is inefficient. The other mutations that alter the actual functioning of the AChRs are the focus of this article. [We suspect that a third group are so severe that they cause death before the babies are even born].

The five AChR subunits come together to form a cylinder in the muscle surface membrane with a channel running through the middle. The opening of a special “gate” in this channel is the key event in the ‘ignition’, and is very precisely controlled. However, some inherited faults actively cause harm by making this gate open for too long a time – the “slow channel syndrome”. By contrast, in the “fast channel syndrome”, it loses activity by shutting too soon and failing to trigger altogether.

The Slow Channel Syndrome

On the left, the faulty channels in the slow channel syndrome allow damaging amounts of charged salts to enter the muscle (Na+ = sodium; Ca2+ = calcium). In the fast channel syndrome, too little salt gets in to trigger a contraction.

This “dominant “disorder is caused by inheriting an actively harmful AChR gene from just one parent; there is also a 1 in 2 chance that any child of a patient will be affected. The myasthenia may be obvious in early childhood or may not appear until well into adulthood, sometimes even during pregnancy. The weakness often particularly affects finger straightening and/or the shoulder and neck muscles; unlike many inherited myasthenic syndromes, it tends gradually to get worse with age.

This syndrome can be caused by mutations in any of the AChR subunits, and in different regions thereof. They may cause the key (ACh) to get jammed in the lock (AChR), so that the gate keeps re-opening and cannot click shut. Or they may cause the gate to get stuck when open. In either case, too much calcium is thought to get into the muscle cells; this, in turn, causes damage, which gradually builds up over the years, explaining the variable but delayed start of weakness. There used to be no satisfactory treatments; indeed, mestinon can even make this syndrome worse. Recently, however, quinidine sulphate has helped some patients by blocking the channel when it opens for too long. As with any drug, there may be side-effects, and it should only be taken under careful medical supervision. Because the patients have only one damaging gene, my team are now trying to develop tricks for turning it off selectively, so that the alternative unaffected gene can restore normality.

The Fast Channel Syndrome

Because it causes a loss of ignition activity, this syndrome shows “recessive” inheritance (affected children inherit mutations from each parent). The fatiguable weakness is usually present at birth or shortly afterwards; it particularly affects the eye and facial movements and causes difficulty in feeding. Patients may get bad chest infections, which may, in turn, make their weakness worse. That can cause a sudden failure to breathe; parents should be trained in resuscitation, and urgent hospital treatment may be needed. Mercifully, the symptoms are not progressive and may improve with age.

Mutations in the AChR a, d and e subunits have been found, again located in several different regions. Most of them change the AChR shape, so that it binds the ACh too weakly and releases it too quickly. Hence the channel gate either fails to open or else closes too quickly, so that the muscle entirely fails to contract. Because of this contrast with the slow channel syndrome, different treatments are used – aiming to boost the signal to the muscle. They include our old friend mestinon (see first paragraph) and another drug called 3,4, diaminopyridine which increases ACh release from the nerve endings. Both improve muscle strength, but also have side-effects; 3,4-diaminopyridine is only available after application to the Oxford MGA/MDC Centre, and should only be taken under very careful medical supervision.

The severity of both fast and slow channel syndromes varies greatly, even in patients with the same mutations; in general, the fast is more severe. If we understood what modifies their severity, that might help us devise better treatments.

What David was too modest to say (Nick Willcox adds). Thanks to very loyal MGA/MDC support since 1985, David was the first to “clone” nearly all of the human AChR genes. His team is still one of the two leading groups in the world researching their inherited faults (the other is in the Mayo clinic in the USA). He has just set up a nation-wide routine diagnostic service to identify these faults in new cases. As in typical MG, a hard-and-fast diagnosis can already be a great relief in itself, while we are waiting for new ‘gene therapies’.

MGA NEWS Winter 2001

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