Congenital+Myasthenia

Movement involves communication between neurons which is carried out through the signals of neurotransmitters. Congenital Myasthenic Syndromes (CMS) involve genetic defects that disrupt this communication path at the neuromuscular junction. The resulting disruption in neuron communication results in skeletal muscle weakness and fatigue [3]. Weakness is especially emphasized by exertion. Unlike Myasthenia Gravis, CMS is genetic. Onset normally occurs at or shortly after birth or in early childhood. Cardiac and smooth muscle are usually not involved. The severity and course of the disorder is highly variable; symptoms range from minor nuisances to disabling weakness [1]. CMS are inherited disorders, most often classified as autosomal recessive in which a mutated gene in both parents must be passed on to get the disorder. Only in rare cases is CMS autosomal dominant where only one mutated gene needs to be present. These disorders are typically categorized into several subtypes based on the specific genetic mutation and its location in the neuromuscular junction [2].
 * Introduction **

Key terms:
 * Functional Anatomy **
 * Presynaptic Membrane (knob/terminal): membrane of motor neuron ending
 * Postsynaptic Membrane: membrane of muscle fiber
 * Synaptic Cleft: space in neuromuscular junction between post and presynaptic membrane
 * Neurotransmitter: chemicals released from presynaptic terminal that allow for neuronal communication
 * Motor End Plate: bulb like expansion of axon terminal

The **neuromuscular junction** is a synapse that connects the axon terminal of a motor neuron with a specific skeletal muscle fiber. The function of the neuromuscular junction is to transmit signals from the motor neuron to the muscle fiber to ensure skeletal muscle contraction, therefore producing voluntary movement. Neurotransmitters are chemicals that allow information to be passed on from one cell to the next. For neurotransmitters to be effective, the nerve must release the neurotransmitter properly, and the muscle cell must be able to detect the neurotransmitter and respond to its signal properly. [2,7] Their effects depend on its postsynaptic receptor. Some are excitatory (Glutamate) and some are inhibitory (GABA & Glycine) [9].

1) ** Motor Neuron: ** Lower motor neurons extend from the spinal cord to a muscle fiber. Terminal buttons at the end of these axons are bulbous swellings that contain synaptic vesicles, each of which contains the neurotransmitter acetylcholine (ACh). These vesicles bind to the motor end plate of the terminal button to release ACh. [8]

2) ** Muscle fiber: ** Muscle fibers receive neurotransmitters on the postsynaptic membrane receptors and are either excited (EPSP) or inhibited (IPSP) by the electrochemical change in membrane potential. Excitation or inhibition results from the receptor’s reaction to the certain neurotransmitter involved. [8]



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[8]
 * 1) An action potential is sent down an axon via concentration gradient Na+ channels opening, eventually ending at motor nerve terminal which contains synaptic vesicles filled with neurotransmitters, ACh [7].
 * 2) As Na+ influx reaches the axon terminal, it triggers Ca2+ channels to open.
 * 3) Ca2+ influx into the axon terminal.
 * 4) Ca2+ binds to synaptic vesicles containing ACh.
 * 5) Vesicle moves toward the motor end plate to be released.
 * SNARE protein on the vesicles and presynaptic membrane help vesicle bind to motor end plate to allow for exocytosis of the neurotransmitter.
 * Synaptobrevin & Synaptotagmin are located on the vesicle and Syntaxin & SNAP-25 are located on the plasma membrane
 * Ca2+ binds with Synaptotagmin which allows for fusion of the vesicle to the membrane.
 * <span style="font-family: Times New Roman,Times,serif;">Synaptobrevin twist together with Syntaxin & SNAP-25 that pull the other closer.
 * 1) <span style="font-family: Times New Roman,Times,serif;">The neurotransmitter, acetylcholine, is released via exocytosis into the synaptic cleft.
 * 2) <span style="font-family: Times New Roman,Times,serif;">ACh bind to receptors on the postsynaptic membrane, the muscle fiber.
 * 3) <span style="font-family: Times New Roman,Times,serif;">Muscle fiber is excited

Unlike other neurotransmitters, ACh in synaptic cleft are not terminated by reuptake, but by a hydrolytic enzyme, AChE [11]. Acetylcholinesterase in the synaptic cleft hydrolyses acetylcholine and limits the temporal and spatial effects of the release ACh, ensuring precision of muscle control. [7] It is important to clear the neurotransmitter from the junction in order to recycle them back into the synaptic vesicles. If they stay in the synapse for an extended period of time, they are vulnerable to hydrolyzing enzymes that could destroy them, resulting in a depletion in the number of neurotransmitter available for use.

media type="youtube" key="lRJd56BCidg" width="560" height="315" https://www.youtube.com/watch?v=lRJd56BCidg <span style="font-family: Times New Roman,Times,serif;">Video above describes the process of Synaptic Transmission in detail with visual references.

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Depending on the subtype of the disorder and its onset, symptoms can range from mild to severe. The classic symptoms that are presented in all forms of the disorder include: [3,4]
 * Symptoms **
 * <span style="font-family: Times New Roman,Times,serif;">Skeletal muscle weakness (especially during continuous activity) *
 * <span style="font-family: Times New Roman,Times,serif;">Fatigue
 * <span style="font-family: Times New Roman,Times,serif;">Ptosis (droopy eyelids)
 * <span style="font-family: Times New Roman,Times,serif;">Delayed development of motor skills

Symptoms usually appear in the first few years of life, however it may not be recognized until much later.
 * __ Infancy: __**
 * <span style="font-family: Times New Roman,Times,serif;">Floppiness
 * <span style="font-family: Times New Roman,Times,serif;">Failure to meet developmental milestones (rolling over and sitting up)
 * <span style="font-family: Times New Roman,Times,serif;">Feeding difficulties (bulbar weakness)
 * <span style="font-family: Times New Roman,Times,serif;">Multiple joint contractures
 * <span style="font-family: Times New Roman,Times,serif;">Respiratory insufficiency (impaired muscles of chest wall and diaphragm)
 * Episodes of choking
 * <span style="font-family: Times New Roman,Times,serif;">Apnea
 * <span style="font-family: Times New Roman,Times,serif;">Cyanosis

<span style="font-family: Times New Roman,Times,serif;"> [1,2]
 * __ Childhood: __**
 * <span style="font-family: Times New Roman,Times,serif;">Weakness during physical activity
 * <span style="font-family: Times New Roman,Times,serif;">Inability to perform age-appropriate actions (e.g. running & climbing etc…)
 * <span style="font-family: Times New Roman,Times,serif;">Possible ptosis
 * <span style="font-family: Times New Roman,Times,serif;">Difficulty speaking or swallowing
 * <span style="font-family: Times New Roman,Times,serif;">Spinal deformity or muscle atrophy

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<span style="font-family: Times New Roman,Times,serif; font-size: 120%;">**CMS in detail** The diagnosis of CMS can be confirmed by molecular analyses in eight genes whose mutations are known to cause CMS: [5] All of these genes provide instructions for producing proteins that are involved in the normal function of the neuromuscular junction. Mutations in the CHRNE gene are responsible for more than half of all cases. [4]. The two predominant genes in postsynaptic CMS are CHRNE and RAPSN [5]. Specific diagnoses of CMS occur at different locations in the neuromuscular junction. Each of the mutations cause the dysfunction of neuromuscular transmission [5] 1) **P** ** resynaptic: ** generally caused by anomaly of choline acetyltransferase (ChAT)
 * Four of the genes encode the various ACh receptor subunits **(CHRNE, CHRNA1, CHRNB1, CHRND)**
 * ** RAPSN **
 * ** COLQ ** (collagen tail of acetylcholinesterase)
 * ** CHAT ** (choline acetyltransferase)
 * ** SCN4A **
 * ChAT: affects synaptogenesis and coordinates synaptic maturation
 * Defects in Ach resynthesis (AR)
 * Scarcity of synaptic vesicle
 * Lambert- Eaton like CMS
 * Diminished AP markedly potentiated by tetanic stimulation [5]

2) **S** ** ynaptic: ** corresponding to anomaly of acetylcholinesterase deficiency
 * <span style="font-family: Times New Roman,Times,serif;">Partial or complete deficiency of the enzyme located in synaptic basal lamina
 * Observations that lead to diagnosis: autosomal recessive heredity, repetitive compound muscle action potential (CMAP) after single stimulation, absence of response to cholinesterase inhibitors and slowed, inconsistent pupil responses to light [5].

3) **P** ** ostsynaptic: ** secondary to an anomaly of acetylcholine receptor or rapsyn
 * <span style="font-family: Times New Roman,Times,serif;">Slow channel syndrome: prolonged opening time of acetylcholine receptor
 * Mutations are located in the two transmembrane domains taking part in the formation of the acetylcholine receptor pore through which passes sodium
 * //__ Rapsyn __//// : // postsynaptic cytoplasmic protein. It participates in acetylcholine receptor assembly at neuromuscular junction. It also allows its anchoring to the cytoskeleton. [5]

Neurologists will test various muscles to determine if they grow weaker with repeated activity. Diagnostic strategy includes two successive steps: the association of a clinical electrophysiological picture of myasthenic syndrome and data in favor of congenital origin, and the recognition of the pathophysiological type. The different subtypes of CMS share common clinical presentation and the onset is generally early. Rare cases have been reported of appearance in adolescence and adulthood. [5]
 * Diagnosis **


 * **// Electromyography //**
 * o The electrophysiology of neuromuscular transmission is determinant for CMS diagnosis. Testing includes the search for neuromuscular block, repetitive motor responses and increments. Observation neuromuscular transmission block affirms myasthenic syndrome*. Increment greater than 100% in amplitude and in tested area is suggestive of presynaptic origin [5].
 * o Individuals should be testes for decremental EMG response of CMAP on low-frequency stimulation. In addition, a single-fiber EMG is a good determinant of neuromuscular transmission defect [1]
 * **// Muscle Biopsy //**[5]
 * This testing eliminates the diagnosis of myopathy. Predominance of type 1 fibers and marked atrophy of type 2 fibers is suggestive of CMS. Testing looks for two main things, first, to see if acetylcholinesterase is absent at neuromuscular junction and second, to see if there is significant reduction in the number of acetylcholine receptors on the postsynaptic membrane.
 * **// Molecular Genetics //**[5]
 * The diagnosis of CMS can be confirmed by molecular analyses in eight genes whose mutations are known to cause CMS.
 * ** CHRNE, CHRNA1, CHRNB1, CHRND, RAPSN, COLQ **, **CHAT**, **SCN4A**
 * //**<span style="font-family: Times New Roman,Times,serif;">Serial -Single Gene Testing **//
 * The mutation of a particular gene accounts for a large proportion of the disease. [1]
 * **// Response to AChE Inhibitors //**
 * Positive response to Acetylcholinesterase inhibitors is suggestive of the disorder. [1]

Prognosis is difficult to assess given that each person has an individualized case with a certain subtype of the disorder along with varying ages of onset and involved symptoms. [2,5] The earlier the onset of the disorder, the more severe the symptoms tend to be [3]. Genetic mutations that effect the facial muscles can lead to difficulty breathing, feeding and swallowing which can leave the affected person vulnerable to pneumonia or respiratory failure [2]. Normal life expectancy occurs in most cases in which the respiratory function is not compromised. however, in the cases where the facial muscles and diaphragm are not functioning properly, the disorder will progress over time and lead to other, more severe health problems [2].
 * Prognosis **

Possibilities for treatment depend on the specific subtype of the disorder. Most treatments are aimed at improving the signaling between nerve and muscle cells. There are no treatments to cure the genetic abnormality of CMS at this time. Drugs to improve cell signaling: [2,10]
 * Treatment **
 * // Fluoxetine & Quinidine //: long-lived open channel blocker
 * // Ephedrine //
 * // 3,4- Diaminopyridine //
 * // Prydiostigmine //
 * This specific drug is a long-lived open channel blocker of acetylcholine receptor.

__** Summary **__ Congenital Myasthenic Syndromes (CMS) involve genetic defects that disrupt this communication path at the neuromuscular junction. The resulting disruption in neuron communication results in skeletal muscle weakness and fatigue [3]. Weakness is especially emphasized by exertion. Ptosis and delayed developmental milestones of motor skills are also common symptoms of the disorder. It is mainly an autosomal recessive disorder in which both parents must supply a defected copy of the affected gene. It is a rare inherited disorder, with initial onset of symptoms usually occurring in the first few years of life. Specific genetic mutations effect proteins and neurotransmitters at the neuromuscular junction between motor neurons and muscle fibers. For neurotransmitters to be effective, the nerve must release the neurotransmitter properly, and the muscle cell must be able to detect the neurotransmitter and respond to its signal properly. There are eight genes known to be involved in CMS if a mutation is present: CHRNE, CHRNA1, CHRNB1, CHRND, RAPSN, COLQ, CHAT and SCN4A. All of these genes provide instructions for producing proteins that are involved in the normal function of the neuromuscular junction. Specific diagnoses of CMS occur at different locations in the neuromuscular junction. Mutations in presynaptic and postsynaptic membranes as well as the synaptic cleft all result in disruption of synaptic transmission of neurotransmitters. Diagnosis is completed through a series of physical examinations. Electromyography is the most important of the tests, it distinguishes whether there is neurotransmitter disruption and its precise location in the neuromuscular junction. Muscle biopsies, Molecular genetics, serial single-gene testing and response to Acetylcholinesterase inhibitors are all ways through which a practitioner can gain information toward a diagnosis of CMS. Prognosis is difficult to assess given that each person has an individualized case with a certain subtype of the disorder along with varying ages of onset and involved symptoms. The earlier the onset of the disorder, the more severe the symptoms tend to be. Normal life expectancy occurs in most cases in which the respiratory function is not compromised. There is no treatment that can cure the genetic mutation, however there are several medications that can work to improve cell signaling and reduce the negative symptoms to an extent.

<span style="font-family: Times New Roman,Times,serif;">Additional Information

media type=youtube key=GPy52MdcTpE width=560 height=315 width="560" height="315" https://www.youtube.com/watch?v=GPy52MdcTpE In depth description of CMS definition, key signs and symptoms, diagnosis, prognosis and treatment options.

media type=youtube key=JDsV3BhbLM8 width=560 height=315 width="560" height="315" [] Presentation on CMS that includes pictures and diagrams of the neurological implications of the disorder.

__** Glossary of Terms: **__ 1) __Heterogeneous__: having its source or origin outside the organism; foreign origin 2) __Congenital__: at or near birth 3) __ChAT__: presynaptic protein localized in the nerve terminals where it catalyzes acetylcholine production 4) __Bulbar__: relating to neck and jaw 5) __AChE__: Acetylcholinesterase. Enzyme that catalyzes the breakdown of acetylcholine in the synaptic cleft so the next nerve impulse can be transmitted across the junction.


 * Quiz **


 * 1) ** True or false, neurotransmitters always excite the cell to which they synapse.


 * 2) ** How is Congenital Myasthenia different from Myasthenia Gravis?
 * ** A. **<span style="font-family: Times New Roman,Times,serif;"> It results in less severe muscle weakness than Myasthenia Gravis
 * **B.** Its symptoms appear later in life
 * **C.** It is genetically inherited
 * ** D. ** It doesn’t involve neurotransmitter problems

**3)** A symptom NOT frequently found in CMS:
 * **A.** Missing motor milestones
 * ** B. ** Ptosis
 * ** C. ** Weakness
 * ** D. ** Negative affect


 * 4) ** True or false, CMS involves skeletal, cardiac and smooth muscle.


 * 5) ** True or false, the cause of neuromuscular disruption in CMS is caused by gene mutations involved in protein function at junction.


 * 6) ** True or false, life span is shortened with CMS in most cases.

1) Describe the key characteristic symptom involved in CMS and when it is maximized. 2) Name the major anomalies that cause CMS at each of the three main locations of the neuromuscular junction. 3) What are three different tests that can be used to diagnose CMS?
 * Short answer: **


 * Essay: ** Describe the steps involved in Synaptic Transmission through which a motor neuron signals a muscle fiber.

__** Answers: **__ F, C, D, F, T, F

__** Short answer: **__ 1) The key symptom in CMS is generalized skeletal muscle weakness. It can be seen as “floppiness” in infancy and missed developmental milestones in early childhood. It is maximized with continuous activity.

2) ChAT defects in presynaptic membrane that affects synaptic maturation. Acetylcholinesterase deficiency in the synapse, less ACh reuptake. Defect of acetylcholine receptor or rapsyn allows for prolonged receptor opening on postsynaptic membrane.

3) There are several tests that can be done to diagnose CMS, multiple tests including Muscle Biopsies, Electromyography and response AChE Inhibitors should be examined in order to properly diagnose the patient. Diagnosis of CMS cannot be determined by a singular test.

__** Essay: **__ Action potential is sent down an axon via concentration gradient Na+ channels opening, eventually ending at motor nerve terminal which contains synaptic vesicles filled with neurotransmitters, ACh. As Na+ influx reaches the axon terminal, it triggers Ca2+ channels to open. Ca2+ influx into the axon terminal. Ca2+ binds to synaptic vesicles containing ACh. Vesicle moves toward the motor end plate to be released. SNARE protein on the vesicles and presynaptic membrane help vesicle bind to motor end plate to allow for exocytosis of the neurotransmitter. Synaptobrevin & Synaptotagmin are located on the vesicle and Syntaxin & SNAP-25 are located on the plasma membrane. Ca2+ binds with Synaptotagmin which allows for fusion of the vesicle to the membrane. Synaptobrevin twist together with Syntaxin & SNAP-25 that pull the other closer. The neurotransmitter, acetylcholine, is released via exocytosis into the synaptic cleft. ACh bind to receptors on the postsynaptic membrane, the muscle fiber and it results in muscle fiber excitation.

**<span style="font-family: Times New Roman,Times,serif; font-size: 110%;">References ** [1] Abicht, A, Müller J, Lochmüller H. (May 3, 2003) [Updated July 14, 2016]. Congenital Myasthenic Syndromes [Online]. GeneReviews. University of Washington, Seattle. [|https://www.ncbi.nlm.nih.gov/books/NBK1168/#cms.Diagnosis] __ [29 Nov. 2017].

[2] American Academy of Neurology (2017). Congenital Myasthenia [Online]. National Institute Neurological Disorders and Stroke. [] [28 Nov. 2017].

[3] Congenital Myasthenic Syndromes (CMS) (2017) [Online]. Muscular Dystrophy Association Inc. [] [28 Nov. 2017].

[4] Genetics Home Reference. (November 28, 2017). congenital myasthenic syndrome [Online]. U.S National Library of Medicine. [|https://ghr.nlm.nih.gov/condition/congenital-myasthenic-syndrome#genes] [29 Nov. 2017].

[5] Hantai D, Richard P, Koenig J, Eymard B. (2004). Congenital myasthenic syndromes [Online]. [] [28 Nov. 2017].

[6] Nicole et al. (November 21, 2017). Congenital Myasthenic Syndromes or Inherited Disorders of Neuromuscular Transmission: Recent Discoveries and Open Questions. [Online]. Journal of Neuromuscular Diseases Vol. 4. []

[7] Hong I, Etherington S. (2011) [Updated 2017]. Neuromuscular Junction. [Online]. John Wiley & Sons Inc, Wiley Online Library. [] [30 Nov. 2017].

[8]https://www.khanacademy.org/science/health-and-medicine/human-anatomy-and-physiology/introduction-to-muscles/v/neuromuscular-junction

[9] Neurotransmitters and receptors (2017). Khan Academy [Online]. [] [30 Nov 2017].

[10] Engel A. (2017). Congenital Myasthenic Syndromes. [Online]. https://rarediseases.org/rare- diseases/congenital-myasthenic-syndromes/ [1 Dec 2017].

[11] Purves D, Augustine GJ, Fitzpatrcik D et al., editors. (2001). Acetylcholine [Online]. Neuroscience 2nd edition. Sinauer Associates. [] [2 Dec 2017].

[] Diagram of neuromuscular junction with labeled steps of passing a neurotransmitter through the terminal button through the synaptic cleft and synapsing on the postsynaptic receptors.
 * Picture references **

[] Diagram of neuromuscular junction and the three types of defects that occur with Congenital Myasthenic Syndromes.

[] Picture representing ptosis.

[] Picture displaying the difference between a normal baby and a hypertonic, “floppy” baby suffering from CMS.