Congenital myasthenic syndrome

Last updated Dec. 4, 2024, by Marisa Wexler, MS
Fact-checked by Joana Carvalho, PhD

Congenital myasthenic syndrome (CMS), also known as congenital myasthenia, is a group of rare genetic disorders marked by muscle weakness that worsens with physical activity, similar to myasthenia gravis (MG).

Both conditions are characterized by muscle weakness caused by problems with nerve-muscle communication. However, the mechanisms behind them are different.

In MG, an autoimmune response leads to the production of self-reactive antibodies that attack proteins, most commonly acetylcholine receptors, involved in nerve-muscle communication. In contrast, CMS results from genetic mutations that patients are born with, which impair neuromuscular communication.

The spectrum of symptoms that can develop in CMS broadly resembles that of MG. Myasthenia gravis usually manifests in adulthood, however, while symptoms of CMS typically become apparent in early childhood, often soon after birth. Still, there are cases of late-onset CMS, in which symptoms do not become evident until adolescence or adulthood. These patients typically will have milder forms of the disease.

Despite their similarities, CMS and MG are considered different disease entities, each with distinct underlying causes and treatment approaches.

Types of CMS

There are various types of CMS, classified based on how the genetic defect underlying them disrupts nerve-muscle communication at the neuromuscular junction. This junction is a specialized synapse where a nerve cell comes into close contact with a muscle cell and releases chemical signals to trigger muscle contractions. A broadly used term, synapse refers to the region where nerves communicate with other cells, including other nerve cells and muscles.

When a nerve impulse is sent to direct a muscle to contract, a nerve cell releases a signaling molecule called acetylcholine into the neuromuscular junction. Acetylcholine then binds to acetylcholine receptors on muscle cells, causing an ion channel to open, and allowing for an influx of positively charged molecules that generate an electrical impulse, which then triggers muscles to contract.

CMS can be classified as:

presynaptic, if the genetic defect impairs the nerve cell’s ability to release sufficient amounts of acetylcholine
postsynaptic, if the genetic defect affects the muscle cell’s ability to respond to acetylcholine
synaptic, if the mutation affects the synapse and prevents acetylcholine from effectively traveling across the neuromuscular junction.

Presynaptic CMS

Presynaptic CMS is caused by mutations that affect the nerve side of the neuromuscular junction, rendering nerve cells unable to release sufficient amounts of acetylcholine into the junction. This may happen due to problems in acetylcholine production, recycling, or packaging, or its release into the space between a nerve and a muscle cell.

The least common form of the condition, presynaptic CMS accounts for about 5%-10% of all cases. It usually manifests earlier than postsynaptic forms of the disease, generally at birth or during the prenatal period.

The CHAT gene, needed to produce acetylcholine, is the most common cause of presynaptic CMS, found in about 5% of patients. Other genes that may be implicated in presynaptic CMS include:

SLC5A7
SLC18A3
SNAP25
VAMP1
SYT2
MYO9A
MUNC13-1.

Postsynaptic CMS

In postsynaptic CMS, the most common form of these diseases, muscle cells can not effectively respond to acetylcholine. This usually happens when the muscle cells have either too few acetylcholine receptors or the receptors are defective. It also may be caused by problems with other molecular machinery needed for the receptors to appropriately respond to acetylcholine signaling.

There are several subtypes of postsynaptic CMS, depending on the effects of the specific mutations a person has. These include:

fast-channel CMS, which occurs when mutations cause acetylcholine receptors not to stay open long enough, disrupting the electrical current needed to trigger muscle contraction
slow-channel CMS, occurring when mutations cause acetylcholine receptors to stay open too long, also disrupting the electrical current needed to trigger muscle contraction
acetylcholine receptor deficiency, which occurs when mutations reduce the number of acetylcholine receptors present in muscle cells, impairing nerve-muscle communication
inadequate acetylcholine receptor clustering, which occurs when mutations interfere with the process through which acetylcholine receptors group together in clusters at the surface of muscle cells to form functional neuromuscular junctions
glycosylation disorders, occurring when mutations affect glycosylation — a chemical modification in which a sugar molecule is added to a protein or a fatty molecule — that’s crucial for the function of neuromuscular junctions.

The genes most commonly involved in postsynaptic CMS are CHRNA1, CHRNB1, CHRND, and CHRNE. These four genes code for the five subunits that make up nicotinic acetylcholine receptors, which are the primary mediators of muscle contraction at the neuromuscular junction.

Mutations in these genes collectively account for about half of all CMS cases. Depending on how the mutations impact the resulting proteins, they can cause either acetylcholine receptor deficiency, fast-channel CMS, or slow-channel CMS.

Other genes that may be implicated in postsynaptic CMS include:

RAPSN
DOK7
LRP4
MUSK
PLEC
SCN4A.

Synaptic CMS

Synaptic congenital myasthenic syndrome, or synaptic CMS, is characterized by problems in the way acetylcholine crosses the gap between the nerve ending and the muscle cell.

Most cases arise from defects in acetylcholinesterase function, which is needed to break down acetylcholine and terminate neuromuscular transmission. When acetylcholinesterase is absent or not working properly, acetylcholine accumulates in the neuromuscular junction, leading to prolonged signaling that disrupts effective communication between nerves and muscles.

Mutations in the COLQ gene, which codes for a protein needed for anchoring acetylcholinesterase to the neuromuscular junction’s basal lamina, account for most cases of synaptic CMS. The basal lamina is a matrix of proteins and other molecules that envelops the edge of a muscle cell at the neuromuscular junction.

Mutations in COL13A1, which disrupt that extracellular matrix, have also been reported to cause this form of CMS.

Inheritance

Congenital myasthenic syndrome usually is inherited in an autosomal recessive manner, meaning that the disease only develops if both copies of a person’s gene — one from each biological parent — contain a mutation. In these cases, an individual carrying one mutated copy of the gene and one normal copy is called a carrier. A carrier will not develop the disease, but may still pass the mutated gene on to any biological children.

In this type of inheritance, if two carriers have biological children, there is a 25% chance that any offspring will develop CMS, a 50% chance each child would also be a carrier, and a 25% chance any child will not have CMS nor be a carrier. In a situation in in which someone with CMS has biological children with a carrier, there would be a 50% chance any offspring would have CMS and a 50% chance each child would be a carrier.

More rarely, such as in some cases of slow-channel CMS, the disease is inherited in an autosomal dominant manner. That means that just one mutated copy of a gene is sufficient to cause the disease. If a person with autosomal dominant CMS has biological children, there is a 50% chance any child would also have CMS.

Autosomal dominant CMS also can occur due to spontaneous mutations, which appear randomly in the development of sperm or egg cells and are then passed on when those cells are used to conceive a child.

Symptoms

Similar to MG, the hallmark symptom of CMS is muscle weakness. It mainly affects skeletal muscles, which are voluntary muscles that a person has conscious control over, and are used to move certain parts of the body. In addition to affecting muscles in the limbs, CMS may affect ocular muscles, or those that control eye movements, as well as other facial muscles.

CMS often presents at birth or soon after a baby is born. Early symptoms of the disease can include:

difficulty breathing or bouts of apnea, or periods when breathing stops, which can lead to symptoms like cyanosis, marked by blue skin discoloration
stridor, or a high-pitched sound during breathing that occurs due to a narrowing of the airways
trouble feeding
poor suck and cry
choking spells
ptosis, or eyelid droopiness
contractures, or stiff, immobile joints that are caused by lack of fetal movement in the womb
ocular, facial, or bulbar weakness, which refers to signs of weakness in the muscles of the face and neck
other generalized signs of muscle weakness, such as moving around less than usual.

In some cases, CMS symptoms don’t reveal themselves until later in childhood or even early adulthood. When CMS symptoms arise later on in life, they often follow a limb-girdle pattern. That means that weakness primarily affects muscles close to the torso, such as those in the shoulders and hips. Symptoms of CMS in older individuals can include:

delays in reaching typical motor milestones, such holding the head upright, sitting, crawling, or walking
delayed development of fine motor skills required for using utensils or brushing teeth
ptosis and poor eye control, often leading to double vision
nasal speech
trouble breathing
difficulty swallowing, chewing, and coughing
deformities of the spine, joints, and feet
muscle atrophy, or wasting.

Some CMS patients also experience other symptoms that aren’t directly related to muscle weakness, such as unusual facial features, kidney problems, numbness or tingling in the extremities, seizures, hearing loss, and cognitive issues.

The severity and course of CMS can vary widely from person to person, even among individuals with the same type of disease, caused by mutations in the same gene. Some people with CMS may have very mild weakness that’s only noticeable when exercising, while others may have severe weakness that makes it hard to engage in day-to-day activities.

The severity of symptoms can even change over time in the same individual. For example, people with CMS may experience sudden worsening in muscle weakness or their breathing abilities in the presence of factors such as fever, infection, or stress.

Diagnosis

Diagnosing CMS involves tests to identify typical disease-related changes in neuromuscular function, and to rule out other conditions that may cause similar symptoms.

The diagnostic process for CMS usually begins with a rigorous physical examination to look for disease symptoms and signs. Clinicians will usually also conduct a detailed family history. Because the mutations that cause CMS can be passed from parents to their biological children, the disease often affects multiple members of the same family — making an up-to-date family history especially helpful to have.

A blood test for abnormal antibodies may be requested to discard the possibility of immune-mediated MG. Still, because some MG patients have no detectable antibodies in their bloodstream, a lack of self-reactive antibodies cannot completely rule out a diagnosis of MG, and other tests will be needed.

Nerve conduction tests also may be used to identify CMS. In particular, an electromyography or EMG, which measures the electrical activity of muscle cells in response to nerve stimulation, can help to identify the type of neuromuscular dysfunction that usually occurs in congenital myasthenia.

A diagnosis is typically confirmed with genetic testing to identify the specific mutation causing the disease. Because treatments that are beneficial to some forms of the disease may be detrimental to others, genetic tests to identify the specific form of congenital myasthenia is critical.

Checking to see how patients respond to certain medications also can be a useful way to help narrow down a person’s CMS type in the absence of confirmative genetic results.

Treatment and prognosis

No cure is available for congenital myasthenia, and no treatments exist that can address the underlying cause of the disease. Instead, treatment for CMS generally relies on medications that work to normalize acetylcholine signaling, which can help improve muscle strength and ease disease symptoms among patients.

Presynaptic CMS and fast-channel CMS may be treated with amifampridine or cholinesterase inhibitors like pyridostigmine (sold as Mestinon and generics). These medications increase the amount of acetylcholine available at the neuromuscular junction.

However, they are often ineffective and may even worsen other forms of congenital myasthenia, such as slow-channel CMS, that are marked by excessive acetylcholine signaling.

Instead, this type of CMS may be treated with the antidepressant fluoxetine (sold as Prozac, among other brand names), which blocks acetylcholine receptors and reduces the time they remain open. Quinidine, a compound that alters the electrical activity of muscles and is used to manage heart arrhythmias, may also sometimes be effective for this type of CMS. However, it also may worsen the disease in people with certain specific mutations, making it crucial for this medication to be given with care.

Treatment options for synaptic congenital MG are limited, but ephedrine and albuterol may have beneficial effects. Across types, it’s common for some trial and error to be necessary to find the optimal medication(s) to control CMS symptoms.

Some of the medications named here may also be used to treat MG. However, because CMS is caused by genetic mutations rather than an autoimmune attack, treatments that suppress the immune system and are widely used to manage MG are not effective in CMS.

Beyond medications, other medical interventions, such as physical, occupational, and respiratory therapy may help CMS patients manage symptoms and maintain independence in daily life.

CMS is usually associated with a favorable prognosis when its symptoms start in childhood or adulthood and the disease is diagnosed early and treated adequately. But successful treatment can vary depending on the disease’s underlying causes and symptoms.

For some individuals, CMS will cause only mild symptoms and won’t have a major effect on overall health or life expectancy. But CMS can also be life-threatening or even fatal if it severely impairs breathing or other essential bodily functions.

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