Terra Messmer is a practicing attorney in Tucson, Ariz. She’d had symptoms of muscle weakness since childhood and got a correct diagnosis of congenital myasthenic syndrome in 2000. Her symptoms are stabilized with medication. Introduction Questions and Answers Part I - MG Part II - LEMS,CMS MDA's Search for Treatments and Cures MDA Is Here to Help You

QUESTIONS AND ANSWERS
Part II

LAMBERT-EATON MYASTHENIC SYNDROME (LEMS)

What Is LEMS?

LEMS symptoms usually begin with leg weakness, often followed by weakness in the muscles of the eyes, face and throat. Sometimes the weakness temporarily improves after exertion.

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disease whose symptoms and origins are somewhat similar to those of MG. While MG targets the ACh receptors on muscle cells, LEMS interferes with ACh release from nerve cells.

Some 85 percent to 90 percent of people with LEMS test positive for antibodies against the P/Q type voltage-gated calcium channel (VGCC). This protein is a pore that allows calcium entry into nerve cells, which is required for ACh release.

In about 60 percent of cases, LEMS is associated with small-cell lung cancer (and more rarely with other types of cancer), which might be diagnosed at the same time as LEMS or years later. There’s evidence that the cancerous cells inappropriately make VGCC, triggering the immune system to make anti-VGCC antibodies. The trigger for LEMS without cancer is unknown.

What Are the Symptoms of LEMS?

The first symptoms are usually leg weakness and difficulty walking. Oculobulbar weakness (affecting the muscles of the eyes, face and throat) may occur later, causing ptosis, speech impairment and swallowing problems. Unlike weakness in MG, weakness in LEMS temporarily improves after exertion. (It’s thought that, with repeated activity, calcium gradually builds up in the nerve cells, increasing the amount of ACh released.)

Because ACh regulates many bodily functions, LEMS sometimes causes autonomic (involuntary) symptoms such as dry mouth, constipation, impotence and bladder urgency.

LEMS with cancer has its onset in adulthood, but LEMS without cancer may affect children.

How Is LEMS Treated?

	Julie Long is an artist who has LEMS.

Long-term treatment and prognosis of LEMS depend on whether it occurs with or without cancer. Although cancer is life-threatening, it can be treated with radiation, surgery or chemotherapy. When these treatments are successful and the cancer goes into remission, LEMS usually goes into complete or partial remission as well.

Prior to cancer treatment, or in LEMS patients without cancer, immunosuppressant drugs, IVIg and/or plasmapheresis are often helpful.

Symptomatic relief can be achieved with Mestinon and/or 3,4-diaminopyridine (3,4-DAP), a drug that prolongs the opening of VGCC in nerve endings and thus enhances ACh release. This drug may be hard to obtain as it’s only formulated by a few pharmacies in the United States.

How Is LEMS Diagnosed?

The autonomic symptoms and predominant leg weakness of LEMS help to distinguish it from MG. Electrodiagnostic testing that shows an increased muscle response to repeated stimulation also favors LEMS rather than MG (in which the response decreases). In most cases, LEMS can be confirmed by detection of anti-VGCC antibodies in the blood.

CONGENITAL MYASTHENIC SYNDROME (CMS)

What Is CMS?

Like MG, CMS produces weakness and fatigue caused by problems at the neuromuscular junction. But while MG is autoimmune, CMS is an inherited disease caused by defective genes. Genes are recipes for making proteins, and the genes defective in CMS are required for making the ACh receptor or other components of the neuromuscular junction.

CMS results from genetic flaws at the neuromuscular junction — where the nerve cell meets the muscle cell. The type of CMS depends on where the defective gene lies: (A) in the nerve cell — presynaptic CMS; (B) the muscle cell — postsynaptic CMS; or (C) the space in between — synaptic CMS.

There are many types of CMS, grouped into three main categories named for the part of the neuromuscular junction that’s affected: presynaptic (the nerve cell), postsynaptic (the muscle cell) or synaptic (the space in between).

Symptoms and treatment options vary depending on the type of CMS. The cholinesterase inhibitors used to treat MG are helpful in some types of CMS, but may be harmful in others. It’s important to realize that since CMS isn’t an autoimmune disease, it doesn’t respond to immunosuppressant drugs or other treatments aimed at the immune system.

As its name implies, CMS usually has a congenital (at or near birth) onset, but it can manifest in children and even in adults. Later-onset cases tend to be less severe.

What Are the Types of CMS and How Are They Treated?

Presynaptic CMS

Cause: Insufficient release of ACh

Symptoms: Commonly manifests as CMS with episodic apnea (CMS-EA), which has its onset in infancy and causes oculobulbar weakness and episodes of apnea — a temporary cessation of breathing.

Drug treatment: cholinesterase inhibitors

Postsynaptic CMS (ACh receptor deficiency, Fast-channel CMS)

Cause: ACh receptors are missing or don’t stay open long enough.

Symptoms: Vary from mild to severe. In infants, may cause severe weakness, feeding and respiratory problems, and delayed motor milestones (sitting, crawling and walking). Childhood and adult-onset cases often cause ptosis and fatigue, but usually don’t interfere with daily living.

Drug treatment: cholinesterase inhibitors and 3,4-DAP

Postsynaptic CMS (Slow-Channel CMS)

Cause: ACh receptors stay open too long.

Symptoms: Infant-onset cases cause severe weakness, often leading to loss of mobility and respiratory problems in adolescence. Adult-onset cases may not be disabling.

Drug treatment: quinidine or fluoxetine (both plug the ACh receptor)

Synaptic CMS

Cause: acetylcholinesterase deficiency

Symptoms: Severe weakness with feeding and respiratory difficulties from birth or early childhood. Weakness also causes delayed motor milestones, and often leads to reduced mobility and scoliosis (curvature of the spine).

Drug treatment: none

Unlike MG, CMS isn’t an autoimmune disease. The earlier the symptoms appear, the more severe the disease is likely to be.

How Is CMS Inherited?

With the exception of slow-channel CMS, the inheritance pattern for the types of CMS described here is autosomal recessive. This means that it takes two copies of the defective gene — one from each parent — to cause the disease. Slow-channel CMS is inherited in an autosomal dominant manner. This means that one copy of a defective ACh receptor gene is enough to cause the disease, so an affected parent has a 50 percent chance of passing the disease on to a child.

How Is CMS Diagnosed?

A negative test for ACh receptor antibodies in the serum (blood) can help distinguish CMS from MG, but doesn’t rule out seronegative MG. A family history of myasthenic symptoms supports the CMS diagnosis, but isn’t necessary. Genetic testing and physiological tests on biopsied muscle tissue, done on a research basis, may be needed to define some types of CMS.

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