Congenital Myasthenic Syndromes (CMS)

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Congenital myasthenic syndromes (CMS) are a family of rare, inherited neuromuscular disorders characterized by weakness and easy fatigability. While CMS is similar to myasthenia gravis (MG), CMS is not autoimmune.

News

CMS has been in the news lately because Catalyst Pharmaceuticals is seeking FDA approval for Firdapse, a medication that could treat CMS. FDA approval would force the existing low-cost treatment 3,4-DAP made by Jacobus Pharmaceutical out of the market under FDA “orphan drug” laws.

These articles cover the developing issue:

How drug companies are gaming an old law for greater profits.
PBS Newshour. December 25, 2015.

FDA Approval Could Turn A Free Drug For A Rare Disease Pricey
NPR. December 23, 2015.

Doctors target Catalyst Pharma's forthcoming pricing on old-turned-new med Firdapse
FiercePharma. December 23, 2015.

Patients Fear Spike in Price of Old Drugs
The New York Times. December 22, 2015.

Editorial by concerned physicians: Unintended effect of the orphan drug act on the potential cost of 3,4-diaminopyridine
Muscle & Nerve. December 21, 2015.

Catalyst Pharmaceuticals Announces FDA Orphan Drug Designation of Firdapse for Treatment of Congenital Myasthenic Syndromes
Catalyst Pharmaceuticals press release. March 5, 2015.


Baby RB will be allowed to die after father withdraws opposition
The Telegraph. November 10, 2009.

About CMS

There are several types of CMS and symptoms range widely. Symptoms include weakness, especially of the eye, mouth, and throat that may worsen with activity, droopy eyelids (ptosis), curvature of the spine (scoliosis), and feeding and respiratory problems, and symptoms begin most often after birth or before adolescence. It can improve after severe symptoms appear at birth but may worsen late in adulthood.

There is no cure, and treatments range in effectiveness on a case-by-case basis. The prevalence of CMS is estimated at 1 in 500,000 in Europe. CMS is similar to myasthenia gravis (MG) which is much more prevalent (around 1 in 10,000), but while MG is an autoimmune disease, CMS is not. Because CMS is inherited, there are often relatives with similar symptoms.

Communities for CMS patients and families

Supporting Organizations

There are no known organizations specifically for CMS patients and families. However CMS is often included in the breadth of work of organizations whose focus is myasthenia gravis, including:

Basic Reference Information

These articles provide a high-level overview of CMS:

Medical Journal Articles

These medical journal articles are relatively understable and are very informative for those of us with CMS. They are listed newest first:

What causes CMS?

A problem at the synapse

CMS is caused by a problem at the connection between neurons and muscles. For one of several reasons, the chemical signal from the nervous system to the muscle does not make it across the small gap between the neuron and muscle called the synapse, and as a result the muscle cannot carry out the commands coming from the brain. This can result from several underlying problems and have been linked to many independent genetic mutations.

The neurotransmitter acetylcholine

The chemical that is the signal is called acetylcholine, a neurotransmitter. This chemical can fail to be produced or released in large enough quantities, or the muscle can fail to detect it properly. Another form of CMS is caused not by insufficient acetylcholine but too much, owing to a deficiency in another chemical called acetylcholinesterase. Acetylcholinesterase is crucial to end a neuron's signal before the next signal can start.

Comparison to myasthenia gravis

The problem is due to a genetic defect. This differs from the autoimmune disorder myasthenia gravis (MG). The diagnosis of CMS relies on a negative test for antibodies involved in MG (though a single test may not be sufficient as the antibodies may appear sporadically), and the diagnosis of CMS can be informed by electrophysiology. Muscle biopsy can rule out myopathy and can provide evidence specifically for synaptic and postsynaptic forms of CMS. It is also possible to have both CMS and MG together.

Therapy

Treatment for CMS generally involves one of a few drugs.

Cholinesterase inhibitors, such as Mestinon, increase the effectiveness of the acetylcholine neurotransmitter by blocking acetylcholinesterase, a chemical that cleans up acetylcholine after it has been released into the synapse. 3,4-diaminopyridine (3,4-DAP) increases the amount of acetylcholine released during a nerve impulse by prolonging the presynaptic action potential. 3,4-DAP has not been approved by the US FDA for this purpose.

In the slow-channel postsynaptic form of CMS (see below), these treatments will exacerbate the symptoms. In these cases, quinidine and fluoxetine are used, which reduce the duration that the receptors of acetylcholine on the muscle side react to the neurotransmitter. Ephedrine has also been reported to have some benefit in some cases.

Types of CMS

There are at least ten very different types of CMS, which are divided into presynaptic, synaptic, and postsynaptic dysfunction, referring to the parts of the junction between the nervous system and the muscle where the problem occurs, and synaptopathy. Besides these, there are also types whose underlying cause is not understood. I'm summarizing from the journal articles listed above. But keep in mind that new types of CMS are being discovered on a regular basis, and as a result the descriptions of each type are sure to be incomplete.

The journal article “The Therapy of Congenital Myasthenic Syndromes” (2007) linked above reports the number of cases of each subtype of CMS investigated at the Mayo Clinic between 1988 and 2006, a total of 248 cases. I’ve included the break-down below. The numbers are sure to be only a rough approximation of the prevalence rates of the different subtypes.

Because the most common form is a postsynaptic type, I'll begin there:

Postsynaptic congenital myasthenic syndromes

Three types of postsynaptic dysfunctions have been identified: having too few acetylcholine receptors, and two types of poorly functioning acetylcholine receptors on the muscle called "slow channel" and "fast channel". The postsynaptic types of CMS are the most common form, accounting for nearly three-quarters of all cases.

Endplate acetylcholine receptor (AChR) deficiency

The most prevalent subtype of CMS (37%) is an insufficient number of acetylcholine receptors on the muscle side of the synapse. As with most forms of CMS, the severity ranges widely from mild or severe. It may be that the younger the symptoms arise the more severe they are likely to be. Cholinesterase inhibitors like Mestion can be used for treatment, along with 3,4-diaminopyridine. In some cases the effectiveness of medication reduces with use. Its inheritance is autosomal recessive, meaning someone can carry the mutation without having CMS. Parents both with CMS will have children with CMS. If just one parent has CMS, the children will be carriers but the likelihood of having CMS is far less.

Kinetic defects

"Slow-channel" syndromes have a wide range of severity, from a sever disability by age 10 to little disability through age 60 (or beyond). The cervical, wrist, and finger muscles are most severely affected. This type cannot be treated with cholinesterase inhibitors like Mestinon, and instead it may be treated with quinidine and fluoxetine. This type is generally (but not always) autosomal dominant, which is unusual for CMS, meaning there are no carriers of the mutation that don't actually have this type of CMS. If both parents have this type of CMS, there is a 75 percent chance that each of their children will have CMS. If just one parent has CMS, it is 50 percent. A recessive form has also been reported.

"Fast-channel" syndromes, whose severity ranges from mild to severe as with most types of CMS, may be treated with a combination of cholinesterase inhibitors like Mestinon and 3,4-diaminopyridine. This type of CMS is generally autosomal recessive (see the explanation earlier) but an autosomal dominant case has been reported. The "fast-channel" CMS is the mirror-image of the "slow-channel" CMS.

The "slow-" and "fast-channel" syndromes account for around 20% of CMS cases.

Other post-synaptic forms of CMS

Mutations in the genes that affect the rapsyn and plectin proteins also cause forms of CMS. The rapsyn dysfunction accounts for around 15% of CMS cases, it is recessive, and it is treated with cholinesterase inhibitors like Mestinon, 3,4-DAP, and ephedrine. The plectin cases are much rarer, particularly affect the ocular, facial, and limb muscles, and are likely to worsen over time. It has been treated with 3,4-DAP. One case has been investigated (at Mayo) of a sodium channel dysfuntion and was treated with a cholinesterase inhibitor like Mestinon and acetazolamide.

Synaptic congenital myasthenic syndromes

Endplate acetylcholinesterase (AChE) deficiency

This type of CMS, covering 14% of CMS cases, is improved less often with treatment. The medications used for most other forms of CMS will exacerbate the symptoms of this form of CMS. Some patients improved with ephedrine sulfate and atracurium. When symptoms arise at birth, as they usually do, they may be severe or lethal, but they are less severe when they arise during infancy. The symptoms are often disabling by around age 10-20. The genetic condition is autosomal recessive (see the explanation earlier).

This type of CMS is caused by a deficiency of acetylcholinesterase, the chemical that breaks down the neurotransmitter acetylcholine once it has done its job of transmitting the nervous signal from the neuron to the muscle. Twenty-four independent mutations have been linked to this type of CMS.

Presynaptic congenital myasthenic syndromes

The presynaptic types of CMS are the rarest. Each type is found in only one to three percent of CMS cases. In all they account for 8% of cases.

Choline acetyltransferase (ChAT) deficiency

The most well understood type is ChAT deficiency, formerly known as CMS with episodic apnea. This form is CMS is different from the rest in that symptoms are generally restricted to spontaneous episodes of severe shortness of breath and bulbar (speech, chewing, and swallowing) weakness. Symptoms can sometimes last in some form for weeks after an episode. Episodes can also be triggered by fevers, for example. This form appears to be severest at birth when the newborns may need the help of a ventilator. Cholinesterase inhibitors, like Mestinon, are effective for this type of CMS as a prophylactic to prevent or mitigate the episodes. Parents of CMS children are also instructed to take precautions to be able to handle incidents of apnea. This type of CMS is caused by a genetic mutation affecting the choline acetyltransferase (ChAT) gene, which catalyzes acetylcholine production and affects the formation and maturation of synapses. Fourteen separate mutations have been shown to affect ChAT.

Other presynaptic forms of CMS

Another type of presynaptic CMS is CMS with paucity of vessicles and reduced quantal release. Vessicles are the small pouches that carry the acetylcholine across the synapse. Only one patient has ever been reported with this form of CMS, who responded partially to a cholinesterase inhibitor like Mestion.

Other forms of CMS

Synaptopathy: Dok-7 myasthenia

This form of CMS is caused by a mutation in the Dok-7 gene, which is a protein important for maturation and maintenance of the synapse. Symptoms are similar to what has been called familial limb girdle myasthenia, which lacks or has much less severe ocular and bulbar (speech, chewing, and swallowing) symptoms, primarily affecting limb-girdle and axial muscles. They are treated with cholinesterase inhibitors, 3,4-DAP, and ephedrine and are of recessive inheritance (see the description for synaptic CMS).

CMS resembling Lambert-Eaton syndrome

CMS resembling Lambert-Eaton syndrome, another form, is treated with 3,4-DAP and guanidine.

Archival Links

These mail lists are either now mostly defunct or are not very focused on CMS: