Congenital Myasthenic Syndromes

Relief at Last

Expanding the Treatment Arsenal Ricardo Maselli Andrew Engel Both 7Ricardo Maselli and Andrew Engel are investigating better treatments for CMS — from drugs to gene therapy. To identify new drugs, they're relying on the same approach that established quinidine as a useful CMS treatment. Before Engel discovered the basis of slow-channel syndrome, quinidine already had a long, colorful history in medicine. In humans, it had been used to treat malaria and cardiac problems. By chance, it was found that when people with myasthenia gravis took the drug, their weakness and fatigue got worse (and by the 1950s, doctors were using it in diagnostic tests for myasthenia gravis). Years later, in experiments on animals, Engel and colleagues found that quinidine has that effect because it plugs ACh receptors. When Engel discovered that slow-channel syndrome is caused by overactive ACh receptors, he quickly recognized quinidine as a potential treatment. To determine whether it would work, Engel first tested the effects of quinidine on muscle biopsies from people with slow-channel syndrome, and on isolated cells forced to express the defective ACh receptors that cause slow-channel syndrome. After those laboratory studies showed that quinidine could dampen the overactive ACh receptors, Engel began using it to treat people. This process — first putting together clues to recognize a candidate treatment, then testing that treatment in the laboratory — is still the major research strategy used by Engel and Maselli. "We just have to go to the drawing board and continue to think about it," Engel says. "We come to these insights slowly and gradually." On the gene therapy front, Engel and Maselli are making great strides in identifying the defective genes that cause different types of CMS. Many postsynaptic CMS disorders, Engel and Maselli have independently found, are caused by genetic defects in the ACh receptor itself. The ACh receptor is composed of five different "subunit" proteins, and so far, CMS-causing mutations have been identified in genes for four of the five. Engel has found that synaptic CMS is caused by mutations in the gene for AChE, and that some cases of presynaptic CMS are caused by mutations in the gene for CHAT, the enzyme that manufactures ACh. "We're working very much in molecular genetics because we hope that gene therapy will someday be beneficial in these patients," says Maselli. "The molecular changes [that cause CMS] are really minimal ... so theoretically they may be relatively easy to fix with gene therapy." Until gene therapy becomes available, Engel and Maselli say, drugs that act at the NMJ remain the best options for CMS treatment.

Soon after Engel had properly diagnosed Thour's disorder, he was able to help her with quinidine, a drug that suppresses the NMJ's activity.

Thour, now 35, has noticed significant improvement. Before she began receiving treatment from Engel, Thour didn't have enough strength to go up and down stairs or walk more than short distances, let alone work. Now, she's an educational assistant at an elementary school. "I work in the lunchroom, which involves a lot of walking," she says. "My job would have been totally impossible before."

After years of disappointment, Thour's still surprised at how well the new treatment works. "Sometimes when I think about it, I'm shocked," she says. "It's like day and night. I have my life back." Thour's 14-year-old son, Steven, also has slow-channel CMS, and is benefiting from treatment with quinidine.

Amy Brewer

Like Thour, Amy Brewer of Iowa Park, Texas, has taken control of her CMS, thanks to a visit with Engel this year. Now 32, she'd been treated for myasthenia gravis since childhood, only to find out that she has a type of CMS called ACh receptor deficiency. Engel now treats her with a combination of Mestinon and a drug called 3,4-DAP, which enhances signals from the nerve at the NMJ.

Brewer, a special education teacher, says the new treatment has "dramatically improved" her life. "By about 1 o'clock every afternoon, I would just collapse [at school]," she says. "I almost always had to be helped to my car. Now, I make it through the day ... and the kids see a big, big difference in me."

Engel and Maselli agree that quinidine is the best treatment for slow-channel syndrome, and that a combination of Mestinon and 3,4-DAP works well for ACh receptor deficiency and the "fast-channel" type of CMS. Maselli often prescribes ephedrine (the active ingredient in many nasal decongestants), which might help some types of CMS by enhancing NMJ activity. Engel usually only prescribes ephedrine as a last resort, noting that its mechanism of action isn't clear, and it may cause unwanted side effects like hyperexcitability.

When Treatment Falls Short

Unfortunately, the four CMS medications don't always produce the spectacular results experienced by Thour and Brewer.

Jason Paas, who has an unusual type of CMS somewhat like the fast-channel form, says that a combination of 3,4-DAP and ephedrine has significantly improved his strength, but that "it would be nice if [researchers] could find something better."

Jason Paas

Paas, who lives in Loveland, Ohio, was diagnosed with CMS at 16, after he began having trouble walking, climbing stairs, and getting in and out of cars. Now 21, he says his medication has made him feel stronger, but he still has physical limitations. Even taking just a few computer science classes each quarter at a junior college completely saps his energy, he says.

For people with severe forms of CMS, like 4-year-old Brendan Johnson, the need for improved treatment is especially clear. Brendan has severe ACh receptor deficiency, and was born completely floppy and unable to breathe without assistance from a ventilator.

Brendan Johnson

A combination of time, physical therapy, and medication with Mestinon and 3,4-DAP has improved his condition to the point that he no longer needs a ventilator all the time, and he can walk on his own, say his parents, Brett and Dianne. But because of prominent weakness in his upper body and face, he still needs a feeding tube to eat, can't speak above a whisper, and uses a ventilator to support his breathing while he sleeps.

The Johnsons, of Sacramento, Calif., say that Brendan has greatly benefited from treatment, administered by Maselli and his team at UC-Davis, and by Craig McDonald, MDA clinic co-director at the UC-Davis Medical Center in Sac-ramento. "He'd been given a death sentence" by doctors unfamiliar with CMS, Dianne says.

Still, she's hoping that research will yield better treatments in the near future. "I'm a very strong advocate for research and improvement of therapy," she says. "I spend most of my time fund raising for Dr. Maselli and others like him to try to help fund [their] research."  

Function at the Junction To understand the defects underlying CMS, it's important to understand how the neuromuscular junction (NMJ) normally works (see the first panel at left). The NMJ is a type of synapse, a site of cell-to-cell communication, where a nerve cell can stimulate a muscle cell to contract and produce movement. The nerve cell, or presynaptic side of the NMJ, stimulates the muscle cell by releasing a chemical signal called acetylcholine (ACh). The ACh travels across a synaptic space to reach the postsynaptic surface of the muscle cell, where it triggers contraction by opening pores (or "channels") called ACh receptors. To shut off the signaling process, an enzyme called acetylcholinesterase (AChE) breaks down ACh in the synaptic space. Myasthenia gravis is caused by antibodies that destroy postsynaptic ACh receptors or associated proteins, thus lowering the muscle's response to ACh (second panel). In contrast, congenital myasthenic syndromes (CMS) can be caused by genetic defects in either the presynaptic, synaptic or postsynaptic parts of the NMJ. Presynaptic CMS is caused by decreased production or release of ACh at the NMJ. In synaptic CMS, a deficiency of AChE leads to excessive muscle stimulation, which ultimately damages the muscle. And finally, postsynaptic CMS is caused by changes in the ACh receptors. Postsynaptic CMS accounts for about 75 percent of all CMS cases, perhaps because so much can go wrong with ACh receptors. Even a small mechanical change in the opening and closing of the receptors can have large consequences. Some mechanical changes cause extended opening of ACh receptors and overstimulation of muscles, resulting in slow-channel CMS, while others cause short-lived opening of ACh receptors and understimulation, producing fast-channel CMS. In ACh receptor deficiency, there simply aren't enough ACh receptors on the muscle cell surface.