Myasthenia Gravis is an autoimmune disease in which the body's immune system mistakenly attacks the receptors in muscles that pick up acetycholine, a chemical messenger that transmits the signal from the nerves to the muscles. Antibodies block and progresively destory the signal and interrupt the nerve-muscle communication. This causes fluctuating levels of weakness that vary from patient to patient and day to day as the immune process, along with other factors, invariably alter the patient's ability to experience sustained contraction. It is classically defined as an autoimmune, anti-body mediated, T-cell dependent, immunological attack on the post synaptic membrane of the neuromuscular junction.
Myasthenia Gravis has a hallmark presentation of worsening with repetitive activity and improving with rest. A few examples of repetitive activity include talking, chewing, extended periods of standing or walking, cooking, showering, blow drying hair, gardening and driving. In some cases, medication allows for an almost full return to repetitive activity but for many, even with pharmaceutical management, activity requires significant modification, frequent rest and sometimes, abstaining altogether. (It should also be noted that activity, even when accompanied by significant rest, can cause the patient to require days of recovery after, regardless of the type of activity that the patient engages in.)
For some Myasthenics, even with medical intervention, their symptoms are poorly controlled and require significant changes to their lifestyles. Quality of life is a continual issue for those who struggle with Myasthenia Gravis. In spite of advancing treatments, many patients still struggle with fatigue, general weakness and emotional loss as they find themselves dealing with an unpredictable disease, sometimes harsh side effects from treatment and lack of clinical understanding that can put Myasthenics in harm's way.
Unfortunately, Myasthenia Gravis lacks consensus on salient information and even the fundamental basics are often misunderstood or altogether misconstrued by the clinical world, which more often than not leads to incorrect patient education and expectation, poses the risk for delay in treatment, withdrawal of care, misdiagnosis (often anxiety, depression and/or somatic disorders), diminishes clinical understanding of the potential severity of the disease and how to correctly and quickly triage a patient in emergency status (which can lead to invalidation and dismissal of the disease itself) and poorly conveys very normal emotional aspects wrought by the disease.
It is estimated that the prevalence rate is 20 individuals per 100,000 worldwide but the known incident rate is not a complete picture with under diagnosed individuals falling through the statistical cracks due to lack of access and appropriate medical education, although advancements in clinical knowledge is helping allay this issue.
While there is presently no cure, there is the hope of remission and asymptomatic relief.
The Myasthenia Gravis Hope Foundation believes that appropriate education, better research and increased patient resource access can bring the promise of a cure but will also change the present circumstances and obstacles faced by so many in the community today.
Congenital myasthenic syndrome is a group of conditions characterized by muscle weakness (myasthenia) that worsens with physical exertion. The muscle weakness typically begins in early childhood but can also appear in adolescence or adulthood. Facial muscles, including muscles that control the eyelids, muscles that move the eyes, and muscles used for chewing and swallowing, are most commonly affected. However, any of the muscles used for movement (skeletal muscles) can be affected in this condition. Due to muscle weakness, affected infants may have feeding difficulties. Development of motor skills such as crawling or walking may be delayed. The severity of the myasthenia varies greatly, with some people experiencing minor weakness and others having such severe weakness that they are unable to walk.
Severity and course of disease are highly variable, ranging from minor symptoms to progressive disabling weakness. In some subtypes of CMS, myasthenic symptoms may be mild, but sudden severe exacerbations of weakness or even sudden episodes of respiratory insufficiency may be precipitated by fever, infections, or excitement. Major findings of the neonatal-onset subtype include: respiratory insufficiency with sudden apnea and cyanosis; feeding difficulties; poor suck and cry; choking spells; eyelid ptosis; and facial, bulbar, and generalized weakness. Arthrogryposis multiplex congenita may also be present. Stridor in infancy may be an important clue to CMS. Later childhood-onset subtypes show abnormal muscle fatigability with difficulty in activities such as running or climbing stairs; motor milestones may be delayed; fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness are common presentations.
Some individuals have episodes of breathing problems that may be triggered by fevers or infection. Severely affected individuals may also experience short pauses in breathing (apnea) that can lead to a bluish appearance of the skin or lips (cyanosis).
Mutations in many genes can cause congenital myasthenic syndrome. Mutations in the CHRNE gene are responsible for more than half of all cases. A large number of cases are also caused by mutations in the RAPSN, CHAT, COLQ, and DOK7 genes. All of these genes provide instructions for producing proteins that are involved in the normal function of the neuromuscular junction. The neuromuscular junction is the area between the ends of nerve cells and muscle cells where signals are relayed to trigger muscle movement.
Gene mutations lead to changes in proteins that play a role in the function of the neuromuscular junction and disrupt signaling between the ends of nerve cells and muscle cells. Disrupted signaling between these cells results in an impaired ability to move skeletal muscles, muscle weakness, and delayed development of motor skills. The respiratory problems in congenital myasthenic syndrome result from impaired movement of the muscles of the chest wall and the muscle that separates the abdomen from the chest cavity (the diaphragm).
Mutations in other genes that provide instructions for proteins involved in neuromuscular signaling have been found to cause some cases of congenital myasthenic syndrome, although these mutations account for only a small number of cases. Some people with congenital myasthenic syndrome do not have an identified mutation in any of the genes known to be associated with this condition.
This condition is most commonly inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
Exhaustive genetic testing, EMG electrodiagnostic testing and sometimes live tissue muscle biopsies can all help diagnose a patient with CMS.
Most individuals with CMS benefit from AChE inhibitors and/or the potassium channel blocker 3,4-diaminopyridine (3,4-DAP); however, caution must be used in giving 3,4-DAP to young children and individuals with fast-channel CMS (FCCMS). Individuals with COLQ and DOK7 pathogenic variants usually do not respond to long-term treatment with AChE inhibitors. Some individuals with slow-channel CMS (SCCMS) are treated with quinidine, which has some major side effects and may be detrimental in individuals with AChR deficiency. Fluoxetine is reported to be beneficial for SCCMS. Ephedrine and albuterol have been beneficial in several individuals, especially as a therapeutic option for those with DOK7 or COLQ pathogenic variants.
Prevention of primary manifestations: Prophylactic anticholinesterase therapy to prevent sudden respiratory insufficiency or apneic attacks provoked by fever or infections in those with pathogenic variants in CHAT or RAPSN. Parents of infants are advised to use apnea monitors and be trained in CPR.
Special thank you to Angela Abicht, MD, Juliane Müller, S, PhD, and Hanns Lochmüller, MD.
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