Congenital myasthenic syndrome (CMS) refers to a group of disorders that cause muscle weakness, or fatigable weakness that worsens with physical exertion. This disorder may be mistaken for spinal muscular atrophy (SMA), which also causes weakness as well as fatigue with physical activity. Furthermore, both disorders are neuromuscular (they affect the meeting point between nerve cells and muscle cells), and both are caused by inherited genetic mutations.
Despite their similarities, CMS and SMA are two separate disorders with different causes. This article explores the overlap and differences between CMS and SMA, including each disorder’s causes, symptoms, and treatments.
The characteristic symptom of both CMS and SMA is muscle weakness, but there are slight differences between the two. SMA causes progressive muscle loss over time, resulting in weakness. However, during the day or during an activity, people with SMA also experience muscle fatigue, which may be confused with a similar symptom of CMS known as fatigable weakness.
Fatigable weakness refers to muscle weakness that worsens because of physical activity and improves with rest. It is the hallmark symptom of CMS and related disorders such as myasthenia gravis. A person with CMS will feel their muscles become increasingly weak as they perform exercises or exert themselves with activities of daily living. Making the distinction less clear, however, is the fact that some people with CMS have permanent weakness, similar to SMA.
People with SMA experience muscle fatigue. This term can vary in meaning within the scientific community. Fatigue is the feeling or perception of exhaustion or tiredness. Additionally, the term muscle fatigability is defined as a decrease in muscle performance over time. Individuals with SMA tend to experience both of these symptoms. For example, an individual with SMA may feel increasingly exhausted during a walk. They may also find the power of their muscles decreasing during repetitive daily activities like chewing.
Both SMA and CMS can cause a variety of similar symptoms depending on the severity and type of SMA or CMS a person has. Fatigable weakness in CMS and progressive muscle loss in SMA may cause a person to have problems with muscle coordination in the throat leading to difficulty swallowing (dysphagia) or speaking. Both conditions can also cause weakness of the facial muscles (including the eyes and eyelids).
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The term “congenital” refers to a health condition that is present at the time of birth. As its name implies, CMS is congenital — it is not a disease that is caught or developed later in life. The same is true of SMA. However, depending on the type of SMA or CMS a person has, they may not show symptoms until they are well into adulthood.
Both CMS and SMA are caused by inherited genetic mutations (faulty genes) that are passed down from parent to child. CMS, in particular, may result from many different gene mutations. More than half of all instances of CMS are caused by changes to the CHRNE gene, but the disorder may also result from mutations in the CHAT, COLQ, DOK7, and RAPSN genes. Each of these mutations affects the proteins involved in the meeting point between nerves and muscles (neuromuscular junction) and disrupts the signals sent between the two (neuromuscular transmission). These changes result in problems with the coordination of the skeletal muscles (muscles that connect to bones to allow movement) as well as delayed motor skill development and muscle weakness.
SMA types 0 to 4 make up nearly all cases of SMA. They are caused by a mutation in the survival motor neuron (SMN) genes on both copies of chromosome 5. SMN genes tell the body to make SMN protein. This protein is crucial for the function of nerve cells that transmit signals from the brain and spinal cord to the muscles (motor neurons). Without sufficient SMN protein, motor neurons die, and the brain cannot signal the muscles to function.
The two SMN genes on chromosome 5 are SMN1 and SMN2. A mutation on both copies of a person’s SMN1 gene determines whether they will have SMA. The type of SMA a person develops, the severity of symptoms, and life expectancy are often, but not always, related to the number of SMN2 copies they have.
Because the signs and symptoms of SMA and CMS can overlap with those of other rare diseases and neuromuscular disorders, doctors need to perform tests to determine the right diagnosis. They will start by reviewing a person’s personal and family medical history, asking about their signs and symptoms, and conducting a physical exam.
Several laboratory tests can be used to confirm a diagnosis of SMA. The condition may also be diagnosed during pregnancy if there is a family history of SMA.
When an individual’s muscles are deteriorating, they release an enzyme called creatine kinase into the bloodstream. A protein and enzyme blood test checks for high or elevated levels of creatine kinase, which may point to a diagnosis of SMA.
In the United States, all newborn babies undergo blood testing to identify any metabolic or genetic abnormalities. Some states include testing for issues with the SMN1 gene as part of this panel.
An electromyogram is used to record electrical activity in the muscles (which indicates how responsive the muscles and nerves are).
A nerve conduction study measures the strength and speed of nerve signals.
Although rarely used, muscle biopsy can help reveal atrophy (loss of muscle) caused by conditions like SMA. This test involves removing a small amount of the muscle cells and muscle tissue for lab analysis.
Diagnosing CMS may also rely on electromyography, but electromyograms alone cannot tell which type of CMS a person has. Genetic testing is used to determine the particular gene mutation present, which can indicate which subtype of CMS a person has and which treatment will be most effective. As the National Organization for Rare Disorders notes, genetic diagnosis is crucial in people with CMS because certain treatments that may benefit one type of CMS may cause another type to worsen.
Recently, three disease-modifying therapies were approved for the treatment of SMA. Continued research is necessary to learn more about SMA and develop more therapies for the condition. Assessment tools, like the Hammersmith functional motor scale, may be a part of that research. Different therapies or assistive devices may also be used to help a person with SMA get around, complete everyday tasks, or perform functions like breathing or eating.
Because CMS is so rare (particular subtypes of the disorder have been identified in only a few individuals), there is no one standard approach to treating the disorder. In addition, treatment depends on the particular gene mutation the person with CMS has. More clinical trials will be necessary to determine what treatments may benefit those with CMS. Some therapies currently being used include drugs called acetylcholinesterase inhibitors (pyridostigmine), adrenergic agonists (albuterol and ephedrine), and blockers of acetylcholine receptors (fluoxetine and quinidine). As with SMA, certain mobility and assistive devices can help those with CMS complete daily functions like eating, breathing, moving around, and getting supplemental nutrition.
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