Once incorrectly diagnosed and improperly treated, they're now among the most treatable neuromuscular disorders
When Phillip Martin was a baby, most people — even doctors — didn't notice anything unusual about him, except perhaps that he was a little quiet compared to other babies. But as they watched him grow, Richard and Daina Martin of Kelseyville, Calif., began to sense their son might have a physical disability.
Phillip couldn't hold his head up by himself until he was nearly 6 months old, Daina recalls. As he grew older, he seemed slow to reach motor milestones like sitting, crawling and walking.
He was always "on the later side of average," says Daina.
After Phillip started walking, Daina and Richard noticed that he was experiencing longer delays, frequent trips and falls, and a tendency to become unusually tired.
"We mentioned these things to doctors, but nobody suggested there was a problem," says Daina. "Some doctors said he was just a lazy kid."
By the time Phillip was 5, his accidental trips and bumps had escalated, and he was referred to a neurologist, who diagnosed a "nonspecific myopathy." In other words, Phillip had muscle weakness and fatigue, but it still wasn't clear why. "We were told to just accept it and deal with it," says his mother.
For some people affected by neuromuscular disease, this story might sound all too ordinary: years of struggling to get a correct diagnosis, wondering when treatment will come. But for Phillip, the story has taken an extraordinarily positive twist. It turns out that he has a form of congenital myasthenic syndrome (CMS) — one of a group of genetic disorders that are largely unrecognized but often treatable.
At 11, Phillip is still in the early stages of treatment and is currently unable to climb stairs or walk long distances. But thanks in part to MDA, his prospects are good. For many people with CMS, MDA-funded research over the last decade or so has led to highly effective drug treatments.
Although Phillip Martin's road to treatment took several years, many adults with CMS have faced even greater hardship. When they were children, many were mistakenly given a diagnosis of the autoimmune disorder myasthenia gravis (MG), and subjected to decades of pointless immunosuppressive therapy before finally getting an accurate diagnosis.
Doctors can easily mistake CMS and MG for one another because the two disorders can cause similar symptoms, and they even share a similar underlying disease process. Both diseases cause muscle weakness (myasthenia) and unusual fatigue that can progress with age.
Typically in MG and CMS, muscles of the eyes, face and/or limbs are prominently affected, but sometimes the respiratory muscles are also compromised. Extra strain on the body, such as infection or emotional stress, can cause a severe aggravation of general and respiratory weakness called myasthenic crisis. In both CMS and MG, those symptoms are caused by defects in the connection between nerve and muscle, the neuromuscular junction (NMJ).
Still, there are important distinctions. First, as the name implies, CMS is usually congenital (having onset at birth). In contrast, myasthenia gravis usually begins in adulthood. Also, MG almost always involves the muscles of the eyes and face, causing droopy eyelids (ptosis) and a partial paralysis of eye movements (ophthalmoparesis), but those symptoms are conspicuously absent in some cases of CMS. Finally, MG is caused by an immune system attack on the NMJ and usually has no family history, while CMS is caused by inheritable genetic defects at the NMJ.
Brenda Thour of Brookland Center, Minn., whose CMS was thought to be MG during childhood, remembers several confusing visits to doctors. "I didn't have droopy eyes like the regular myasthenia [gravis] patients did, and that didn't quite add up," recalls Thour. Thour's mother also had CMS symptoms, but doctors told Thour that MG "isn't genetic," and that the two women had different conditions. Her mother later received a CMS diagnosis.
When Thour was 9, her doctor prescribed a drug called Mestinon, one of the most effective drug treatments for MG (and even for some types of CMS). "I remember him coming in and saying 'We've found something that will help.' But it didn't," says Thour.
Later, attempts to treat Thour with immunosuppressant drugs (which stop the immune system from mistakenly attacking the body), a thymectomy (removal of the immune system gland called the thymus) and plasmapheresis (a procedure that filters immune factors from the blood) also proved unsuccessful.
Still without treatment at 26, Thour experienced a life-threatening myasthenic crisis after giving birth to her daughter, and a year later, it happened again during a sinus infection. The second time, she had the good fortune to be sent to the Mayo Clinic in Rochester, Minn., to see neurologist Andrew Engel, a longtime MDA collaborator and a pioneer in CMS research.
In the late 1970s, Engel's studies suggested that, in different families, CMS arises from very different functional defects at the NMJ. (See "Function at the Junction") Over time, he and others identified new drug treatments that could be used to compensate for those defects.
The power (and problems) of diagnosis
A year after Thour's first visit to Engel, he found she had slow-channel CMS, at long last explaining why immunosuppressant therapy had failed to help her.
CMS expert and MDA grantee Ricardo Maselli, who diagnosed Phillip Martin's CMS, says he's seen many people like Thour at his lab at the University of California at Davis. One CMS patient who had undergone intensive immunosuppressant therapy was rapidly deteriorating when he came to Maselli, but stabilized when appropriate therapy was started, Maselli says.
"Many times, when the disease is misdiagnosed and treated improperly, that can result in very bad reactions and even death," says Maselli. "The first way to fight the disease is to be able to recognize it."
And recognizing CMS, Engel and Maselli say, is difficult. Not only can it mimic myasthenia gravis; it can also resemble diseases like spinal muscular atrophy, nemaline myopathy or myotubular myopathy.
"CMS exists on a large spectrum," says Maselli. "Some people have no symptoms until they've gone into surgery, and they get some kind of muscle relaxant. At the other end of the spectrum are people who are born extremely weak, and have to be put on a respirator immediately."
Once CMS is recognized, the exact type must be determined before treatment can begin. Some types of CMS (and nearly all cases of MG) are caused by decreased activity at the NMJ, while other types — like Thour's slow-channel CMS — are actually caused by increased activity. Therefore, Engel warns, "Medications that work in one syndrome might be harmful in another."
For example, Mestinon is an effective treatment for MG and for some types of CMS because it acts by boosting the activity of the NMJ. For that same reason, it wasn't an effective treatment for Thour.
Relief at last
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.
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.
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."
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.
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 Sacramento. "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 fundraising for Dr. Maselli and others like him to try to help fund [their] research."
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.
The drug treatments for CMS have different modes of action that make them useful for different types of CMS, mostly the postsynaptic types. The drug 3,4-DAP (and possibly ephedrine) increase the amount of ACh released from nerve cell endings. By blocking the action of AChE, the anti-cholinesterase drug Mestinon also increases the amount of ACh available at the NMJ.
Both 3,4-DAP and Mestinon can be used to overcome a poor response by the ACh receptors, making them an effective duo for most cases of fast-channel CMS and AChE deficiency. In contrast, quinidine is an "open-channel blocker" of ACh receptors that can plug up the overactive receptors underlying slow-channel CMS.
Presynaptic CMS (the kind Phillip Martin has) is relatively difficult to treat with current medications, but does respond favorably to some, say Andrew Engel and Ricardo Maselli. Synaptic CMS (AChE deficiency), they say, is even more challenging to treat. Even people with postsynaptic CMS — in general, the most treatable version of the disease — don't always respond optimally to available treatment.
Both Ricardo 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.