Congenital Myasthenic Syndromes

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.

Phillip Martin

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.

It's Not Myasthenia Gravis

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

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.

The CMS Medicine Chest 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.