Myasthenia gravis
Encyclopedia
Myasthenia gravis is an autoimmune neuromuscular disease
leading to fluctuating muscle weakness and fatiguability
. It is an autoimmune disorder
, in which weakness is caused by circulating antibodies
that block acetylcholine receptor
s at the postsynaptic neuromuscular junction
, inhibiting the excitatory effects of the neurotransmitter
acetylcholine
on nicotinic receptors throughout neuromuscular junctions. Myasthenia is treated medically with cholinesterase inhibitors or immunosuppressants, and, in selected cases, thymectomy
. The disease incidence
is 3–30 cases per million per year and rising as a result of increased awareness. MG must be distinguished from congenital myasthenic syndrome
s that can present similar symptoms but offer no response to immunosuppressive treatments.
The hallmark of myasthenia gravis is fatigability. Muscles become progressively weaker during periods of activity and improve after periods of rest. Muscles that control eye and eyelid movement, facial expressions, chewing, talking
, and swallowing
are especially susceptible. The muscles that control breathing and neck and limb movements can also be affected. Often, the physical examination yields results within normal limits.
The onset of the disorder can be sudden. Often symptoms are intermittent. The diagnosis of myasthenia gravis may be delayed if the symptoms are subtle or variable.
In most cases, the first noticeable symptom is weakness of the eye muscles. In others, difficulty in swallowing and slurred speech may be the first signs. The degree of muscle weakness involved in MG varies greatly among patients, ranging from a localized form that is limited to eye muscles (ocular myasthenia
), to a severe and generalized form in which many muscles - sometimes including those that control breathing - are affected. Symptoms, which vary in type and severity, may include asymmetrical ptosis
(a drooping of one or both eyelid
s), diplopia
(double vision) due to weakness of the muscles that control eye movements, an unstable or waddling gait, weakness in arms, hands, fingers, legs, and neck, a change in facial expression, dysphagia
(difficulty in swallowing), shortness of breath and dysarthria
(impaired speech, often nasal due to weakness of the velar muscles).
In myasthenic crisis a paralysis
of the respiratory muscles occurs, necessitating assisted ventilation to sustain life. In patients whose respiratory muscles are already weak, crises may be triggered by infection, fever, an adverse reaction to medication, or emotional stress. Since the heart muscle
is only regulated by the autonomic nervous system, it is generally unaffected by MG.
Myasthenia gravis is an autoimmune channelopathy
: it features antibodies directed against the body's own proteins. While various similar diseases have been linked to immunologic cross-reaction with an infective agent, there is no known causative pathogen
that could account for myasthenia. There is a slight genetic predisposition: particular HLA
types seem to predispose for MG (B8 and DR3 with DR1 more specific for ocular myasthenia). Up to 75% of patients have an abnormality of the thymus
; 10% have a thymoma
, a tumor (either benign or malignant) of the thymus, and other abnormalities are frequently found. The disease process generally remains stationary after thymectomy (removal of the thymus).
In MG, the autoantibodies most commonly act against the nicotinic acetylcholine receptor
(nAChR), the receptor
in the motor end plate for the neurotransmitter
acetylcholine
that stimulates muscular contractions. Some forms of the antibody impair the ability of acetylcholine to bind to receptors. Others lead to the destruction of receptors, either by complement
fixation or by inducing the muscle cell to eliminate the receptors through endocytosis
.
The antibodies are produced by plasma cells, derived from B-cells. B-cells convert into plasma cells by T-helper cell stimulation. To carry out this activation, T-helpers must first be activated themselves, which is done by binding of the T-cell receptor (TCR) to the acetylcholine receptor antigenic peptide fragment (epitope
) resting within the major histocompatibility complex
of antigen presenting cells. Since the thymus plays an important role in the development of T-cells and the selection of TCR, myasthenia gravis is closely associated with thymoma
. The exact mechanisms are, however, not convincingly clarified, although resection of the thymus (thymectomy) in MG patients without a thymus neoplasm often have positive results.
In normal muscle contraction
, cumulative activation of the nAChR leads to influx of sodium
ions, which in turn causes the depolarization of muscle cell and subsequent opening of voltage-gated sodium channels. This ion influx then travels down the cell membranes via T-tubules and, via calcium channel complexes, leads to the release of calcium from the sarcoplasmic reticulum. Only when the levels of calcium inside the muscle cell are high enough will it contract. Decreased numbers of functioning nAChRs therefore impairs muscular contraction by limiting depolarization. In fact, MG causes the motor neuron action potential to muscular twitch ratio to vary from the nonpathological one to one ratio.
A second category of gravis is due to autoantibodies against the MuSK protein
(muscle specific kinase), a tyrosine kinase
receptor which is required for the formation of the neuromuscular junction
. Antibodies against MuSK inhibit the signaling of MuSK normally induced by its nerve-derived ligand, agrin
. The result is a decrease in patency of the neuromuscular junction, and the consequent symptoms of MG.
People treated with penicillamine can develop MG symptoms. Their antibody titer is usually similar to that of MG, but both the symptoms and the titer disappear when drug administration is discontinued.
MG is more common in families with other autoimmune diseases. A familial predisposition found in 5% of the cases is associated with certain genetic variations, such as an increased frequency of HLA-B8 and DR3. People with MG suffer from coexisting autoimmune diseases at a higher frequency than members of the general population. Of particular mention is coexisting thyroid disease
, where episodes of hypothyroidism
may precipitate a severe exacerbation.
The acetylcholine receptor is clustered and anchored by the Rapsyn protein, research into which might eventually lead to new treatment options.
Seropositive and "double-seronegative" patients often have thymoma
or thymic hyperplasia. However, anti-MuSK positive patients do not have evidence of thymus pathology.
does not affect myasthenia gravis. The mothers themselves suffer from exacerbated myasthenia in a third of cases, and in those for whom it does worsen, it usually occurs in the first trimester of pregnancy. Signs and symptoms in pregnant mothers tend to improve during the second and third trimesters. Complete remission can occur in some mothers. Immunosuppressive therapy should be maintained throughout pregnancy, as this reduces the chance of neonatal muscle weakness, as well as controls the mother's myasthenia.
Up to 10% of infants with parents affected by the condition are born with transient (periodic) neonatal myasthenia (TNM), which generally produces feeding and respiratory
difficulties. TNM usually presents as poor suckling and generalized hypotonia
(low muscle tone). Other reported symptoms include a weak cry, facial diplegia
(paralysis of one part of the body) or paresis
(impaired or lack of movement) and mild respiratory distress. A child with TNM typically responds very well to acetylcholinesterase inhibitor
s. Very rarely, an infant can be born with arthrogryposis multiplex congenita, secondary to profound intrauterine weakness. This is due to maternal antibodies
that target an infant's acetylcholine
receptors. In some cases, the mother remains asymptomatic
.
can reveal easy fatiguability, with the weakness improving after rest and worsening again on repeat of the exertion testing. Applying ice
to weak muscle groups characteristically leads to improvement in strength of those muscles. Additional tests are often performed, as mentioned below. Furthermore, a good response to medication can also be considered a sign of autoimmune pathology.
can be performed in a blood test
to identify certain antibodies
:
(SFEMG), which is considered to be the most sensitive (although not the most specific) test for MG, a thin needle electrode is inserted into different areas of a particular muscle to record the action potentials from several samplings of different individual muscle fibers. Two muscle fibers belonging to the same motor unit are identified and the temporal variability in their firing patterns are measured. Frequency and proportion of particular abnormal action potential patterns, "jitter" and "blocking," are diagnostic. Jitter refers to the abnormal variation in the time interval between action potentials of adjacent muscle fibers in the same motor unit. Blocking refers to the failure of nerve impulses to elicit action potentials in adjacent muscle fibers of the same motor unit.
The "edrophonium test" is infrequently performed to identify MG; its application is limited to the situation when other investigations do not yield a conclusive diagnosis. This test requires the intravenous administration of edrophonium chloride
(Tensilon, Reversol) or neostigmine (Prostigmin), drugs that block the breakdown of acetylcholine by cholinesterase
(cholinesterase inhibitors) and temporarily increases the levels of acetylcholine at the neuromuscular junction
. In people with myasthenia gravis involving the eye muscles, edrophonium chloride will briefly relieve weakness.
A chest X-ray
is frequently performed; it may point towards alternative diagnoses (e.g. Lambert-Eaton syndrome due to a lung tumor) and comorbidity. It may also identify widening of the mediastinum
suggestive of thymoma
, but computed tomography
(CT) or magnetic resonance imaging
(MRI) are more sensitive ways to identify thymomas, and are generally done for this reason.
(lung function testing) may be performed for the assessing of respiratory function if there are concerns about a patient's ability to breathe adequately. The forced vital capacity
may be monitored at intervals so as not to miss a gradual worsening of muscular weakness. Acutely, negative inspiratory force may be used to determine adequacy of ventilation. Severe myasthenia may cause respiratory failure
due to exhaustion of the respiratory muscles.
shows IgG antibodies on the neuromuscular junction. (The antibody which causes myasthenia gravis does not fluoresce, but rather a secondary antibody directed against it.) Muscle electron microscopy shows receptor infolding and loss of the tips of the folds, together with widening of the synaptic
clefts. Both these techniques are currently used for research rather than diagnostically.
is a surgical method to treat MG. For emergency treatment, plasmapheresis
or IVIG can be used as a temporary measure to remove antibodies from the blood circulation.
can be used to remove the putative antibodies from the circulation. Also, intravenous immunoglobulin
s (IVIGs) can be used to bind the circulating antibodies. Both of these treatments have relatively short-lived benefits, typically measured in weeks.
, is essential in cases of thymoma
in view of the potential neoplastic effects of the tumor. However, the procedure is more controversial in patients who do not show thymic abnormalities. Although some of these patients improve following thymectomy, some patients experience severe exacerbations and the highly controversial concept of "therapeutic thymectomy" for patients with thymus hyperplasia is disputed by many experts, and efforts are underway to unequivocally answer this important question.
There are a number of surgical approaches to the removal of the thymus gland: transsternal (through the sternum, or breast bone), transcervical (through a small neck incision), and transthoracic (through one or both sides of the chest). The transsternal approach is most common and uses the same length-wise incision through the sternum (breast bone)used for most open-heart surgery. The transcervical approach, a less invasive procedure, allows for removal of the entire thymus gland through a small neck incision. There has been no difference in success in symptom improvement between the transsternal approach and the minimally invasive transcervical approach. For patients with a thymoma, though, complete tissue removal is important, as thymic tissue can regrow. Thymomas can be malignant and are thought to be the onset of other diseases, as well, so many surgeons will only recommend the full sternotomy approach to a thymectomy.
Thymoma is relatively rare in younger (<40) patients, but especially younger patients with generalized MG without thymoma benefit, paradoxically, from thymectomy. Resection is also indicated for those with a thymoma, but it is less likely to improve the MG symptoms.
(whose lesser life expectancy is on account of the thymoma itself and is otherwise unrelated to the myasthenia). Quality of life can vary depending on the severity and the cause. The drugs used to control MG either diminish in effectiveness over time (cholinesterase inhibitors) or cause severe side effects of their own (immunosuppressants). About 10% of MG patients are found to have tumors in their thymus glands, in which case a thymectomy is a very effective treatment with long-term remission. However, most patients need treatment for the remainder of their lives, and their abilities vary greatly. MG is not usually a progressive disease; the symptoms may come and go, but do not always get worse as the patient ages. For some, the symptoms decrease after a span of three to five years.
is estimated at 20 cases per 100,000. Risk factors are the female gender with ages 20 – 40, familial myasthenia gravis, D-penicillamine ingestion (drug-induced myasthenia), and having other autoimmune diseases.
Three types of myasthenic symptoms in children can be distinguished:
The congenital myasthenias cause muscle weakness and fatigability similar to those of MG. The symptoms of CMS usually begin within the first two years of life, although in a few forms, patients can develop their first symptoms as late as the seventh decade of life. A diagnosis of CMS is suggested by the following:
The symptoms of CMS can vary from mild to severe. It is also common for patients with the same form, even members of the same family, to be affected to differing degrees. In most forms of CMS, weakness does not progress, and in some forms, the symptoms may diminish as the patient gets older. Only rarely do symptoms of CMS become worse with time.
Neuromuscular disease
Neuromuscular disease is a very broad term that encompasses many diseases and ailments that either directly, via intrinsic muscle pathology, or indirectly, via nerve pathology, impair the functioning of the muscles....
leading to fluctuating muscle weakness and fatiguability
Fatigue (physical)
Fatigue is a state of awareness describing a range of afflictions, usually associated with physical and/or mental weakness, though varying from a general state of lethargy to a specific work-induced burning sensation within one's muscles...
. It is an autoimmune disorder
Autoimmunity
Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...
, in which weakness is caused by circulating antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
that block acetylcholine receptor
Acetylcholine receptor
An acetylcholine receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.-Classification:...
s at the postsynaptic neuromuscular junction
Neuromuscular junction
A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...
, inhibiting the excitatory effects of the neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
on nicotinic receptors throughout neuromuscular junctions. Myasthenia is treated medically with cholinesterase inhibitors or immunosuppressants, and, in selected cases, thymectomy
Thymectomy
A thymectomy is an operation to remove the thymus. It usually results in remission of myasthenia gravis with the help of medication including steroids...
. The disease incidence
Incidence
Incidence may refer to:* Incidence , a measure of the risk of developing some new condition within a specified period of time* Incidence , the binary relations describing how subsets meet...
is 3–30 cases per million per year and rising as a result of increased awareness. MG must be distinguished from congenital myasthenic syndrome
Congenital myasthenic syndrome
Congenital myasthenic syndrome is an inherited neuromuscular disorder caused by defects of several types at the neuromuscular junction...
s that can present similar symptoms but offer no response to immunosuppressive treatments.
Classification
The most widely accepted classification of myasthenia gravis is the Myasthenia Gravis Foundation of America Clinical Classification:- Class I: Any eye muscle weakness, possible ptosis, no other evidence of muscle weakness elsewhere
- Class II: Eye muscle weakness of any severity, mild weakness of other muscles
- Class IIa: Predominantly limb or axial muscles
- Class IIb: Predominantly bulbar and/or respiratory muscles
- Class III: Eye muscle weakness of any severity, moderate weakness of other muscles
- Class IIIa: Predominantly limb or axial muscles
- Class IIIb: Predominantly bulbar and/or respiratory muscles
- Class IV: Eye muscle weakness of any severity, severe weakness of other muscles
- Class IVa: Predominantly limb or axial muscles
- Class IVb: Predominantly bulbar and/or respiratory muscles (Can also include feeding tube without intubation)
- Class V: Intubation needed to maintain airway
Signs and symptoms
Manner of articulation
In linguistics, manner of articulation describes how the tongue, lips, jaw, and other speech organs are involved in making a sound. Often the concept is only used for the production of consonants, even though the movement of the articulars will also greatly alter the resonant properties of the...
, and swallowing
Swallowing
Swallowing, known scientifically as deglutition, is the process in the human or animal body that makes something pass from the mouth, to the pharynx, and into the esophagus, while shutting the epiglottis. If this fails and the object goes through the trachea, then choking or pulmonary aspiration...
are especially susceptible. The muscles that control breathing and neck and limb movements can also be affected. Often, the physical examination yields results within normal limits.
The onset of the disorder can be sudden. Often symptoms are intermittent. The diagnosis of myasthenia gravis may be delayed if the symptoms are subtle or variable.
In most cases, the first noticeable symptom is weakness of the eye muscles. In others, difficulty in swallowing and slurred speech may be the first signs. The degree of muscle weakness involved in MG varies greatly among patients, ranging from a localized form that is limited to eye muscles (ocular myasthenia
Ocular myasthenia
Ocular myasthenia gravis is a disease of the neuromuscular junction resulting in hallmark variability in muscle weakness and fatigability. MG is an autoimmune disease where anomalous antibodies are produced against the naturally occurring acetylcholine receptors in voluntary muscles...
), to a severe and generalized form in which many muscles - sometimes including those that control breathing - are affected. Symptoms, which vary in type and severity, may include asymmetrical ptosis
Ptosis (eyelid)
Ptosis is a drooping of the upper or lower eyelid. The drooping may be worse after being awake longer, when the individual's muscles are tired. This condition is sometimes called "lazy eye", but that term normally refers to amblyopia...
(a drooping of one or both eyelid
Eyelid
An eyelid is a thin fold of skin that covers and protects an eye. With the exception of the prepuce and the labia minora, it has the thinnest skin of the whole body. The levator palpebrae superioris muscle retracts the eyelid to "open" the eye. This can be either voluntarily or involuntarily...
s), diplopia
Diplopia
Diplopia, commonly known as double vision, is the simultaneous perception of two images of a single object that may be displaced horizontally, vertically, or diagonally in relation to each other...
(double vision) due to weakness of the muscles that control eye movements, an unstable or waddling gait, weakness in arms, hands, fingers, legs, and neck, a change in facial expression, dysphagia
Dysphagia
Dysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....
(difficulty in swallowing), shortness of breath and dysarthria
Dysarthria
Dysarthria is a motor speech disorder resulting from neurological injury of the motor component of the motor-speech system and is characterized by poor articulation of phonemes...
(impaired speech, often nasal due to weakness of the velar muscles).
In myasthenic crisis a paralysis
Paralysis
Paralysis is loss of muscle function for one or more muscles. Paralysis can be accompanied by a loss of feeling in the affected area if there is sensory damage as well as motor. A study conducted by the Christopher & Dana Reeve Foundation, suggests that about 1 in 50 people have been diagnosed...
of the respiratory muscles occurs, necessitating assisted ventilation to sustain life. In patients whose respiratory muscles are already weak, crises may be triggered by infection, fever, an adverse reaction to medication, or emotional stress. Since the heart muscle
Cardiac muscle
Cardiac muscle is a type of involuntary striated muscle found in the walls and histologic foundation of the heart, specifically the myocardium. Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth muscle...
is only regulated by the autonomic nervous system, it is generally unaffected by MG.
Pathophysiology
Channelopathy
Channelopathies are diseases caused by disturbed function of ion channel subunits or the proteins that regulate them. These diseases may be either congenital or acquired .There are a large number of distinct dysfunctions known to be caused by ion channel...
: it features antibodies directed against the body's own proteins. While various similar diseases have been linked to immunologic cross-reaction with an infective agent, there is no known causative pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
that could account for myasthenia. There is a slight genetic predisposition: particular HLA
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
types seem to predispose for MG (B8 and DR3 with DR1 more specific for ocular myasthenia). Up to 75% of patients have an abnormality of the thymus
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
; 10% have a thymoma
Thymoma
Thymoma is a tumor originating from the epithelial cells of the thymus. Thymoma is an uncommon tumor, best known for its association with the neuromuscular disorder myasthenia gravis. Thymoma is found in 15% of patients with myasthenia gravis. Once diagnosed, thymomas may be removed surgically...
, a tumor (either benign or malignant) of the thymus, and other abnormalities are frequently found. The disease process generally remains stationary after thymectomy (removal of the thymus).
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
(nAChR), the receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
in the motor end plate for the neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
that stimulates muscular contractions. Some forms of the antibody impair the ability of acetylcholine to bind to receptors. Others lead to the destruction of receptors, either by complement
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
fixation or by inducing the muscle cell to eliminate the receptors through endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
.
The antibodies are produced by plasma cells, derived from B-cells. B-cells convert into plasma cells by T-helper cell stimulation. To carry out this activation, T-helpers must first be activated themselves, which is done by binding of the T-cell receptor (TCR) to the acetylcholine receptor antigenic peptide fragment (epitope
Epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...
) resting within the major histocompatibility complex
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
of antigen presenting cells. Since the thymus plays an important role in the development of T-cells and the selection of TCR, myasthenia gravis is closely associated with thymoma
Thymoma
Thymoma is a tumor originating from the epithelial cells of the thymus. Thymoma is an uncommon tumor, best known for its association with the neuromuscular disorder myasthenia gravis. Thymoma is found in 15% of patients with myasthenia gravis. Once diagnosed, thymomas may be removed surgically...
. The exact mechanisms are, however, not convincingly clarified, although resection of the thymus (thymectomy) in MG patients without a thymus neoplasm often have positive results.
In normal muscle contraction
Muscle contraction
Muscle fiber generates tension through the action of actin and myosin cross-bridge cycling. While under tension, the muscle may lengthen, shorten, or remain the same...
, cumulative activation of the nAChR leads to influx of sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
ions, which in turn causes the depolarization of muscle cell and subsequent opening of voltage-gated sodium channels. This ion influx then travels down the cell membranes via T-tubules and, via calcium channel complexes, leads to the release of calcium from the sarcoplasmic reticulum. Only when the levels of calcium inside the muscle cell are high enough will it contract. Decreased numbers of functioning nAChRs therefore impairs muscular contraction by limiting depolarization. In fact, MG causes the motor neuron action potential to muscular twitch ratio to vary from the nonpathological one to one ratio.
A second category of gravis is due to autoantibodies against the MuSK protein
MuSK protein
MuSK is a receptor tyrosine kinase required for the formation of the neuromuscular junction. It is activated by a nerve-derived proteoglycan called agrin.-MuSK is required for formation of the Neuromuscular Junction:...
(muscle specific kinase), a tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
receptor which is required for the formation of the neuromuscular junction
Neuromuscular junction
A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...
. Antibodies against MuSK inhibit the signaling of MuSK normally induced by its nerve-derived ligand, agrin
Agrin
Agrin is a large proteoglycan whose best characterised role is in the development of the neuromuscular junction during embryogenesis. Agrin is named based on its involvement in the aggregation of acetylcholine receptors during synaptogenesis. In humans, this protein is encoded by the AGRN...
. The result is a decrease in patency of the neuromuscular junction, and the consequent symptoms of MG.
People treated with penicillamine can develop MG symptoms. Their antibody titer is usually similar to that of MG, but both the symptoms and the titer disappear when drug administration is discontinued.
MG is more common in families with other autoimmune diseases. A familial predisposition found in 5% of the cases is associated with certain genetic variations, such as an increased frequency of HLA-B8 and DR3. People with MG suffer from coexisting autoimmune diseases at a higher frequency than members of the general population. Of particular mention is coexisting thyroid disease
Thyroid disease
-Hyper- and hypofunction:Imbalance in production of thyroid hormones arises from dysfunction of the thyroid gland itself, the pituitary gland, which produces thyroid-stimulating hormone , or the hypothalamus, which regulates the pituitary gland via thyrotropin-releasing hormone . Concentrations of...
, where episodes of hypothyroidism
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
may precipitate a severe exacerbation.
The acetylcholine receptor is clustered and anchored by the Rapsyn protein, research into which might eventually lead to new treatment options.
Associated condition
Myasthenia gravis is associated with various autoimmune diseases, including:- ThyroidThyroidThe thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
diseases, including Hashimoto's thyroiditisHashimoto's thyroiditisHashimoto's thyroiditis or chronic lymphocytic thyroiditis is an autoimmune disease in which the thyroid gland is gradually destroyed by a variety of cell- and antibody-mediated immune processes. It was the first disease to be recognized as an autoimmune disease...
and Graves' diseaseGraves' diseaseGraves' disease is an autoimmune disease where the thyroid is overactive, producing an excessive amount of thyroid hormones... - Diabetes mellitus type 1Diabetes mellitus type 1Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...
- Rheumatoid arthritisRheumatoid arthritisRheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
- LupusSystemic lupus erythematosusSystemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
, and - Demyelinating CNS diseasesDemyelinating diseaseA demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This impairs the conduction of signals in the affected nerves, causing impairment in sensation, movement, cognition, or other functions depending on which nerves are involved.The term...
Seropositive and "double-seronegative" patients often have thymoma
Thymoma
Thymoma is a tumor originating from the epithelial cells of the thymus. Thymoma is an uncommon tumor, best known for its association with the neuromuscular disorder myasthenia gravis. Thymoma is found in 15% of patients with myasthenia gravis. Once diagnosed, thymomas may be removed surgically...
or thymic hyperplasia. However, anti-MuSK positive patients do not have evidence of thymus pathology.
In pregnancy
In the long term, pregnancyPregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
does not affect myasthenia gravis. The mothers themselves suffer from exacerbated myasthenia in a third of cases, and in those for whom it does worsen, it usually occurs in the first trimester of pregnancy. Signs and symptoms in pregnant mothers tend to improve during the second and third trimesters. Complete remission can occur in some mothers. Immunosuppressive therapy should be maintained throughout pregnancy, as this reduces the chance of neonatal muscle weakness, as well as controls the mother's myasthenia.
Up to 10% of infants with parents affected by the condition are born with transient (periodic) neonatal myasthenia (TNM), which generally produces feeding and respiratory
Respiratory system
The respiratory system is the anatomical system of an organism that introduces respiratory gases to the interior and performs gas exchange. In humans and other mammals, the anatomical features of the respiratory system include airways, lungs, and the respiratory muscles...
difficulties. TNM usually presents as poor suckling and generalized hypotonia
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
(low muscle tone). Other reported symptoms include a weak cry, facial diplegia
Diplegia
Diplegia, when used singularly, refers to paralysis affecting symmetrical parts of the body. This should not be confused with hemiplegia which refers to spasticity restricted to one side of the body, or quadriplegia which requires the involvement of all four limbs but not necessarily...
(paralysis of one part of the body) or paresis
Paresis
Paresis is a condition typified by partial loss of voluntary movement or by impaired movement. When used without qualifiers, it usually refers to the limbs, but it also can be used to describe the muscles of the eyes , the stomach , and also the vocal cords...
(impaired or lack of movement) and mild respiratory distress. A child with TNM typically responds very well to acetylcholinesterase inhibitor
Acetylcholinesterase inhibitor
An acetylcholinesterase inhibitor or anti-cholinesterase is a chemical that inhibits the cholinesterase enzyme from breaking down acetylcholine, increasing both the level and duration of action of the neurotransmitter acetylcholine.- Uses :Acetylcholinesterase inhibitors:* Occur naturally as...
s. Very rarely, an infant can be born with arthrogryposis multiplex congenita, secondary to profound intrauterine weakness. This is due to maternal antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
that target an infant's acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
receptors. In some cases, the mother remains asymptomatic
Asymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
.
Diagnosis
MG can be a difficult diagnosis, as the symptoms can be subtle and hard to distinguish from both normal variants and other neurological disorders. A thorough physical examinationPhysical examination
Physical examination or clinical examination is the process by which a doctor investigates the body of a patient for signs of disease. It generally follows the taking of the medical history — an account of the symptoms as experienced by the patient...
can reveal easy fatiguability, with the weakness improving after rest and worsening again on repeat of the exertion testing. Applying ice
Ice
Ice is water frozen into the solid state. Usually ice is the phase known as ice Ih, which is the most abundant of the varying solid phases on the Earth's surface. It can appear transparent or opaque bluish-white color, depending on the presence of impurities or air inclusions...
to weak muscle groups characteristically leads to improvement in strength of those muscles. Additional tests are often performed, as mentioned below. Furthermore, a good response to medication can also be considered a sign of autoimmune pathology.
Physical examination
Muscle fatigability can be tested for many muscles. A thorough investigation includes:- looking upward and sidewards for 30 seconds: ptosisPtosis (eyelid)Ptosis is a drooping of the upper or lower eyelid. The drooping may be worse after being awake longer, when the individual's muscles are tired. This condition is sometimes called "lazy eye", but that term normally refers to amblyopia...
and diplopiaDiplopiaDiplopia, commonly known as double vision, is the simultaneous perception of two images of a single object that may be displaced horizontally, vertically, or diagonally in relation to each other... - looking at the feet while lying on the back for 60 seconds
- keeping the arms stretched forward for 60 seconds
- ten deep knee bends
- walking 30 steps on both the toes and the heels
- five situps, lying down and sitting up completely
- "Peek sign": after complete initial apposition of the lid margins, they quickly (within 30 seconds) start to separate and the sclera starts to show
Blood tests
If the diagnosis is suspected, serologySerology
Serology is the scientific study of blood serum and other bodily fluids. In practice, the term usually refers to the diagnostic identification of antibodies in the serum...
can be performed in a blood test
Blood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....
to identify certain antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
:
- One test is for antibodies against the acetylcholine receptorAcetylcholine receptorAn acetylcholine receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.-Classification:...
. The test has a reasonable sensitivity of 80–96%, but in MG limited to the eye muscles (ocular myasthenia) the test may be negative in up to 50% of the cases.
- A proportion of the patients without antibodies against the acetylcholine receptor have antibodies against the MuSK proteinMuSK proteinMuSK is a receptor tyrosine kinase required for the formation of the neuromuscular junction. It is activated by a nerve-derived proteoglycan called agrin.-MuSK is required for formation of the Neuromuscular Junction:...
.
- In specific situations (decreased reflexes which increase on facilitation, coexisting autonomic features, suspected presence of neoplasm, especially of the lung, presence of increment or facilitation on repetitive EMG testing) testing is performed for Lambert-Eaton syndrome, in which other antibodies (against a voltage-gated calcium channelCalcium channelA Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:...
) can be found.
Electrodiagnostics
Muscle fibers of patients with MG are easily fatigued, and thus do not respond as well as muscles in healthy individuals to repeated stimulation. By stimulating a nerve-muscle motor unit with short sequences of rapid, regular electrical impulses, before and after exercising the motor unit, the fatiguability of the muscle can be measured. This is called the repetitive nerve stimulation test. In single fiber electromyographyElectromyography
Electromyography is a technique for evaluating and recording the electrical activity produced by skeletal muscles. EMG is performed using an instrument called an electromyograph, to produce a record called an electromyogram. An electromyograph detects the electrical potential generated by muscle...
(SFEMG), which is considered to be the most sensitive (although not the most specific) test for MG, a thin needle electrode is inserted into different areas of a particular muscle to record the action potentials from several samplings of different individual muscle fibers. Two muscle fibers belonging to the same motor unit are identified and the temporal variability in their firing patterns are measured. Frequency and proportion of particular abnormal action potential patterns, "jitter" and "blocking," are diagnostic. Jitter refers to the abnormal variation in the time interval between action potentials of adjacent muscle fibers in the same motor unit. Blocking refers to the failure of nerve impulses to elicit action potentials in adjacent muscle fibers of the same motor unit.
Edrophonium test
Edrophonium
Edrophonium is a readily reversible acetylcholinesterase inhibitor. It prevents breakdown of the neurotransmitter acetylcholine and acts by competitively inhibiting the enzyme acetylcholinesterase, mainly at the neuromuscular junction...
(Tensilon, Reversol) or neostigmine (Prostigmin), drugs that block the breakdown of acetylcholine by cholinesterase
Cholinesterase
In biochemistry, cholinesterase is a family of enzymes that catalyze the hydrolysis of the neurotransmitter acetylcholine into choline and acetic acid, a reaction necessary to allow a cholinergic neuron to return to its resting state after activation.-Types:...
(cholinesterase inhibitors) and temporarily increases the levels of acetylcholine at the neuromuscular junction
Neuromuscular junction
A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...
. In people with myasthenia gravis involving the eye muscles, edrophonium chloride will briefly relieve weakness.
Imaging
Chest X-ray
In medicine, a chest radiograph, commonly called a chest X-ray , is a projection radiograph of the chest used to diagnose conditions affecting the chest, its contents, and nearby structures...
is frequently performed; it may point towards alternative diagnoses (e.g. Lambert-Eaton syndrome due to a lung tumor) and comorbidity. It may also identify widening of the mediastinum
Mediastinum
The mediastinum is a non-delineated group of structures in the thorax, surrounded by loose connective tissue. It is the central compartment of the thoracic cavity...
suggestive of thymoma
Thymoma
Thymoma is a tumor originating from the epithelial cells of the thymus. Thymoma is an uncommon tumor, best known for its association with the neuromuscular disorder myasthenia gravis. Thymoma is found in 15% of patients with myasthenia gravis. Once diagnosed, thymomas may be removed surgically...
, but computed tomography
Computed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
(CT) or magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
(MRI) are more sensitive ways to identify thymomas, and are generally done for this reason.
Pulmonary function test
SpirometrySpirometry
Spirometry is the most common of the pulmonary function tests , measuring lung function, specifically the measurement of the amount and/or speed of air that can be inhaled and exhaled...
(lung function testing) may be performed for the assessing of respiratory function if there are concerns about a patient's ability to breathe adequately. The forced vital capacity
Vital capacity
Vital capacity is the maximum amount of air a person can expel from the lungs after a maximum inspiration. It is equal to the inspiratory reserve volume plus the tidal volume plus the expiratory reserve volume....
may be monitored at intervals so as not to miss a gradual worsening of muscular weakness. Acutely, negative inspiratory force may be used to determine adequacy of ventilation. Severe myasthenia may cause respiratory failure
Respiratory failure
The term respiratory failure, in medicine, is used to describe inadequate gas exchange by the respiratory system, with the result that arterial oxygen and/or carbon dioxide levels cannot be maintained within their normal ranges. A drop in blood oxygenation is known as hypoxemia; a rise in arterial...
due to exhaustion of the respiratory muscles.
Pathological findings
Muscle biopsy is only performed if the diagnosis is in doubt and a muscular condition is suspected. ImmunofluorescenceImmunofluorescence
Immunofluorescence is a technique used for light microscopy with a fluorescence microscope and is used primarily on biological samples. This technique uses the specificity of antibodies to their antigen to target fluorescent dyes to specific biomolecule targets within a cell, and therefore allows...
shows IgG antibodies on the neuromuscular junction. (The antibody which causes myasthenia gravis does not fluoresce, but rather a secondary antibody directed against it.) Muscle electron microscopy shows receptor infolding and loss of the tips of the folds, together with widening of the synaptic
Chemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...
clefts. Both these techniques are currently used for research rather than diagnostically.
Treatment
Treatment is by medication and/or surgery. Medication consists mainly of cholinesterase inhibitors to directly improve muscle function and immunosuppressant drugs to reduce the autoimmune process. ThymectomyThymectomy
A thymectomy is an operation to remove the thymus. It usually results in remission of myasthenia gravis with the help of medication including steroids...
is a surgical method to treat MG. For emergency treatment, plasmapheresis
Plasmapheresis
Plasmapheresis is the removal, treatment, and return of blood plasma from blood circulation. It is thus an extracorporeal therapy...
or IVIG can be used as a temporary measure to remove antibodies from the blood circulation.
Medication
- Acetylcholinesterase inhibitorAcetylcholinesterase inhibitorAn acetylcholinesterase inhibitor or anti-cholinesterase is a chemical that inhibits the cholinesterase enzyme from breaking down acetylcholine, increasing both the level and duration of action of the neurotransmitter acetylcholine.- Uses :Acetylcholinesterase inhibitors:* Occur naturally as...
s: neostigmineNeostigmineNeostigmine is a parasympathomimetic that acts as a reversible acetylcholinesterase inhibitor.- Synthesis :Neostigmine was first synthesized by Aeschlimann and Reinert in 1931....
and pyridostigminePyridostigminePyridostigmine is a parasympathomimetic and a reversible cholinesterase inhibitor. Since it is a quaternary amine, it is poorly absorbed in the gut and does not cross the blood-brain barrier, except possibly in stressful conditions.-Mode of action:...
can improve muscle function by slowing the natural enzyme cholinesteraseCholinesteraseIn biochemistry, cholinesterase is a family of enzymes that catalyze the hydrolysis of the neurotransmitter acetylcholine into choline and acetic acid, a reaction necessary to allow a cholinergic neuron to return to its resting state after activation.-Types:...
that degrades acetylcholineAcetylcholineThe chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
in the motor end plate; the neurotransmitter is therefore around longer to stimulate its receptor. Usually, doctors will start with a low dose, e.g. 3x20mg pyridostigmine, and increase until the desired result is achieved. If taken 30 minutes before a meal, symptoms will be mild during eating. Side effects, such as perspiration and diarrhea, can be countered by adding atropineAtropineAtropine is a naturally occurring tropane alkaloid extracted from deadly nightshade , Jimson weed , mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects...
. Pyridostigmine is a short-lived drug, with a half-life of about four hours.
- Immunosuppressive drugs: prednisonePrednisonePrednisone is a synthetic corticosteroid drug that is particularly effective as an immunosuppressant drug. It is used to treat certain inflammatory diseases and some types of cancer, but has significant adverse effects...
, cyclosporine, mycophenolate mofetilMycophenolate mofetilMycophenolate mofetil is an immunosuppressant and prodrug of mycophenolic acid, used extensively in transplant medicine. It is a reversible inhibitor of inosine monophosphate dehydrogenase in purine biosynthesis, which is necessary for the growth of T cells and B cells...
and azathioprineAzathioprineAzathioprine is a purine analogue immunosuppressive drug. It is used to prevent organ rejection following organ transplantation and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease , multiple sclerosis, autoimmune hepatitis, atopic...
may be used. Patients are commonly treated with a combination of these drugs with a cholinesterase inhibitor. Treatments with some immunosuppressives take weeks to months before effects are noticed. Other immunomodulating substances, such as drugs that prevent acetylcholine receptor modulation by the immune system, are currently being researched.
Plasmapheresis and IVIG
If the myasthenia is serious (myasthenic crisis), plasmapheresisPlasmapheresis
Plasmapheresis is the removal, treatment, and return of blood plasma from blood circulation. It is thus an extracorporeal therapy...
can be used to remove the putative antibodies from the circulation. Also, intravenous immunoglobulin
Intravenous immunoglobulin
Intravenous immunoglobulin is a blood product administered intravenously. It contains the pooled IgG extracted from the plasma of over one thousand blood donors. IVIG's effects last between 2 weeks and 3 months...
s (IVIGs) can be used to bind the circulating antibodies. Both of these treatments have relatively short-lived benefits, typically measured in weeks.
Surgery
Thymectomy, the surgical removal of the thymusThymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
, is essential in cases of thymoma
Thymoma
Thymoma is a tumor originating from the epithelial cells of the thymus. Thymoma is an uncommon tumor, best known for its association with the neuromuscular disorder myasthenia gravis. Thymoma is found in 15% of patients with myasthenia gravis. Once diagnosed, thymomas may be removed surgically...
in view of the potential neoplastic effects of the tumor. However, the procedure is more controversial in patients who do not show thymic abnormalities. Although some of these patients improve following thymectomy, some patients experience severe exacerbations and the highly controversial concept of "therapeutic thymectomy" for patients with thymus hyperplasia is disputed by many experts, and efforts are underway to unequivocally answer this important question.
There are a number of surgical approaches to the removal of the thymus gland: transsternal (through the sternum, or breast bone), transcervical (through a small neck incision), and transthoracic (through one or both sides of the chest). The transsternal approach is most common and uses the same length-wise incision through the sternum (breast bone)used for most open-heart surgery. The transcervical approach, a less invasive procedure, allows for removal of the entire thymus gland through a small neck incision. There has been no difference in success in symptom improvement between the transsternal approach and the minimally invasive transcervical approach. For patients with a thymoma, though, complete tissue removal is important, as thymic tissue can regrow. Thymomas can be malignant and are thought to be the onset of other diseases, as well, so many surgeons will only recommend the full sternotomy approach to a thymectomy.
Thymoma is relatively rare in younger (<40) patients, but especially younger patients with generalized MG without thymoma benefit, paradoxically, from thymectomy. Resection is also indicated for those with a thymoma, but it is less likely to improve the MG symptoms.
Prognosis
With treatment, patients have a normal life expectancy, except for those with a malignant thymomaThymoma
Thymoma is a tumor originating from the epithelial cells of the thymus. Thymoma is an uncommon tumor, best known for its association with the neuromuscular disorder myasthenia gravis. Thymoma is found in 15% of patients with myasthenia gravis. Once diagnosed, thymomas may be removed surgically...
(whose lesser life expectancy is on account of the thymoma itself and is otherwise unrelated to the myasthenia). Quality of life can vary depending on the severity and the cause. The drugs used to control MG either diminish in effectiveness over time (cholinesterase inhibitors) or cause severe side effects of their own (immunosuppressants). About 10% of MG patients are found to have tumors in their thymus glands, in which case a thymectomy is a very effective treatment with long-term remission. However, most patients need treatment for the remainder of their lives, and their abilities vary greatly. MG is not usually a progressive disease; the symptoms may come and go, but do not always get worse as the patient ages. For some, the symptoms decrease after a span of three to five years.
Epidemiology
Myasthenia gravis occurs in all ethnic groups and both genders. It most commonly affects women under 40 and people from 50 to 70 years old of either sex, but it has been known to occur at any age. Younger patients rarely have thymoma. The prevalence in the United StatesUnited States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
is estimated at 20 cases per 100,000. Risk factors are the female gender with ages 20 – 40, familial myasthenia gravis, D-penicillamine ingestion (drug-induced myasthenia), and having other autoimmune diseases.
Three types of myasthenic symptoms in children can be distinguished:
- Neonatal: In 12% of the pregnancies with a mother with MG, she passes the antibodies to the infant through the placentaPlacentaThe placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
, causing neonatal myasthenia gravis. The symptoms will start in the first two days and disappear within a few weeks after birth. With the mother, it is not uncommon for the symptoms to even improve during pregnancy, but they might worsen after labor. - Congenital: Children of a healthy mother can, very rarely, develop myasthenic symptoms beginning at birth, congenital myasthenic syndromeCongenital myasthenic syndromeCongenital myasthenic syndrome is an inherited neuromuscular disorder caused by defects of several types at the neuromuscular junction...
or CMS. Other than myasthenia gravis, CMS is not caused by an autoimmune process, but due to synaptic malformation, which in turn is caused by genetic mutations. Thus, CMS is a hereditary disease. More than 11 different mutations have been identified, and the inheritance pattern is typically autosomal recessive. - Juvenile myasthenia gravis: myasthenia occurring in childhood, but after the peripartum period
The congenital myasthenias cause muscle weakness and fatigability similar to those of MG. The symptoms of CMS usually begin within the first two years of life, although in a few forms, patients can develop their first symptoms as late as the seventh decade of life. A diagnosis of CMS is suggested by the following:
- Onset of symptoms in infancy or childhood
- Weakness which increases as muscles tire
- A decremental EMG response, on low frequency, of the compound muscle action potential (CMAP)
- No anti-AChR or MuSK antibodies
- No response to immunosuppressant therapy
- Family history of symptoms which resemble CMS
The symptoms of CMS can vary from mild to severe. It is also common for patients with the same form, even members of the same family, to be affected to differing degrees. In most forms of CMS, weakness does not progress, and in some forms, the symptoms may diminish as the patient gets older. Only rarely do symptoms of CMS become worse with time.
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