Congenital Myasthenic Syndromes

National Organization for Rare Disorders, Inc.

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It is possible that the main title of the report Congenital Myasthenic Syndromes is not the name you expected.

Disorder Subdivisions

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General Discussion

The congenital myasthenic syndromes (CMS) are a diverse group of disorders that have an underlying defect in the transmission of signals from nerve cells to muscles. These disorders are characterized by muscle weakness, which is worsened upon exertion. The age of onset, severity of presenting symptoms, and distribution of muscle weakness can vary from one patient to another. A variety of additional symptoms affecting other organ systems can be present in specific subtypes. Severity can range from minor symptoms such as mild exercise intolerance to severe, disabling ones. Most CMS are transmitted by autosomal recessive inheritance; a few specific subtypes are transmitted by autosomal dominant inheritance. Genetic diagnosis these disorders is important because therapy that benefits one type CMS can worsen another type.

The CMS involve the neuromuscular junction which is a synapse where signals from motor nerves are passed to muscle fibers and tell the muscles fibers when to contract.

The normal neuromuscular junction consists of a presynaptic region, a synaptic space, and a postsynaptic region. The presynaptic region contains the end of a motor nerve cell called the motor nerve terminal. The motor nerve terminal overlies a specialized region of the muscle fiber called the postsynaptic region. The space between the motor nerve terminal and the postsynaptic region is called the synaptic space or synaptic cleft. The postsynaptic region displays multiple folds, known as junctional folds. The motor nerve terminal contains small vesicles that are filled by the neurotransmitter, acetylcholine, or ACh for short that acts as a chemical ‘messenger' with instructions for the muscles to contract.

The membrane covering the motor nerve terminal and facing the synaptic space is known as the presynaptic membrane. The membrane covering the postsynaptic region is known as the postsynaptic membrane.. The segment of the postsynaptic membrane that covers the tips of junctional folds is lined by molecules of the acetylcholine receptor, or AChR for short. The synaptic space is lined by a membrane known as the synaptic basement membrane. This membrane anchors molecules of acetylcholinesterase, or AChE for short, an enzyme that converts ACh to acetate and choline.

The process of how the motor nerve endings communicate with the muscle fibers is a highly specialized process and a genetic defect that impairs that communication can result in a congenital myasthenic syndrome. Understanding this process helps to understand myasthenic disorders.

When muscles are in the resting state, there is a randomly occurring release of acetylcholine from single synaptic vesicles in the motor nerve terminal. This release is known as exocytosis. The amount of ACh released from a single synaptic vesicle is referred to as quantum of ACh.

ACh released from a synaptic vesicle travels through the synaptic space and binds to the AChRs that are concentrated on the tips of the junctional folds. When this binding occurs, it causes a channel in the center of AChR to and allows positively charged sodium and lesser amounts of calcium ions to enter the muscle fiber. This process briefly changes the electric charge across the postsynaptic membrane from negative to positive (small postsynaptic depolarization) which is referred to as a miniature endplate potential (MEPP).

When a person wants to perform a voluntary action, (e.g. raising one's hand, dancing, kicking a ball, etc.), a series of successive nerve impulses are sent to the motor nerve terminal where they depolarize the presynaptic membrane, causing structures called voltage-gated calcium channels to open which allows calcium to enter the motor nerve terminal. This calcium influx results in a nearly synchronous release of the contents of several synaptic vesicles which results in a larger depolarization of the postsynaptic membrane, known as the endplate potential (EPP). When the EP reaches a certain threshold, it opens voltage-gated sodium channels found along the entire muscle fiber outside of the motor endplate area and this triggers a propagated muscle fiber action potential which causes the muscle fiber to contract.

The difference between the endplate potential and the depolarization required to activate the voltage-gated sodium channels is known as the safety margin of neuromuscular transmission. In healthy individuals, the amplitude of the EPP is quite large. With continued activity the EPP begins to decrease but still remains large enough to trigger a muscle fiber action potential.

After the muscle contracts, ACh is released from the AChRs into the synaptic space) where it is broken down (hydrolyzed) AChE into two molecules, acetate and choline. Choline is transported back into the nerve terminal where it recombines with acetate under the influence of an enzyme known as choline acetyltransferase to be stored once again within the synaptic vesicles.

The factors governing the safety margin of neuromuscular transmission fall into four major categories: (1) factors that affect the number of ACh molecules in the synaptic vesicle; (2) factors that affect quantal release mechanisms; (3) the density of AChE in the synaptic space; and (4) factors that affect the efficacy of individual quanta. The efficacy of individual quanta depends on the endplate geometry, the packing density of AChRs on the tips of the junctional folds, the affinity of these AChRs for ACh, and the kinetic properties of the AChR ion channel.

Congenital myasthenic syndromes are caused when there is an alteration (mutation) in a specific gene. This results in an abnormal protein or even loss of a protein that impairs some part of the process described above. The abnormal protein (disease protein) can reside in the motor nerve terminal, or the synaptic space, or in the postsynaptic region that underlies the nerve terminal, but in some patients the disease protein is also present in others tissues or organs causing not only CMS but also a variety of other symptoms.

Supporting Organizations

European Alliance of Neuromuscular Disorders Associations

Linhartova 1
SI-1000 Ljubljana
Slovenia, GAR 04
Tel: 386 (0)1 47 20 500

Muscular Dystrophy Association

3300 East Sunrise Drive
Tucson, AZ 85718-3208
Tel: (520)529-2000
Fax: (520)529-5300
Tel: (800)572-1717

Muscular Dystrophy Campaign

61 Southwark Street
London, SE1 0HL
United Kingdom
Tel: 2078034800

Myasthenia Gravis Foundation of America, Inc.

355 Lexington Ave 15th Floor
New York, NY 10017-6603
Tel: (212)297-2156
Fax: (212)370-9047
Tel: (800)541-5454

NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases

Information Clearinghouse
One AMS Circle
Bethesda, MD 20892-3675
Tel: (301)495-4484
Fax: (301)718-6366
Tel: (877)226-4267

NIH/National Institute of Neurological Disorders and Stroke

P.O. Box 5801
Bethesda, MD 20824
Tel: (301)496-5751
Fax: (301)402-2186
Tel: (800)352-9424

For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders (NORD). For a full-text version of this report, go to and click on Rare Disease Database under "Rare Disease Information".

The information provided in this report is not intended for diagnostic purposes. It is provided for informational purposes only.

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This disease entry is based upon medical information available through the date at the end of the topic. Since NORD's resources are limited, it is not possible to keep every entry in the Rare Disease Database completely current and accurate. Please check with the agencies listed in the Resources section for the most current information about this disorder.

Last Updated:  3/21/2016
Copyright  2016 National Organization for Rare Disorders, Inc.

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Congenital Myasthenic Syndromes