Diseases and Ion Channels 2nd Semester 2017

UNIVERSIDAD CENTRAL DEL CARIBE SCHOOL OF MEDICINE Bayamón, Puerto Rico

Diseases and Ion Channel PRESENTATIONS OF FIRST YEAR MEDICAL STUDENTS (2017-2021) ……

Summary of Presentations Contents Hyperkalemia .............................................. 2 Multiple Sclerosis ........................................ 5 Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage ............................................... 8 Epilepsy ..................................................... 11 Brugada Syndrome.................................... 13 The effects of calcium ion channels (Amyloid β- protein) on the development of Alzheimer disease ..................................... 15 Startle disease (Hyperekplexia) ................ 18 Botulism .................................................... 21 Cystic Fibrosis ............................................ 23 Malignant Hyperthermia .......................... 25

| NEUROSCIENCES COURSE | NOVEMBER 2017 Ed. Dr. LV. Rojas

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Myasthenia Gravis .................................... 27

Presentations MS 2017 Medical Students First Year, UCC

mmol/L of blood or greater (Mayo Clinic, 2014). Most common symptoms are tiredness, feeling of numbness, nausea, trouble breathing and chest pain. Mild hyperkalemia often goes unidentified because it often appears without symptoms but some patients may develop muscle weakness (Mayo Clinic, 2014).

Hyperkalemia Vilmarys Figueroa; Valeria A. Martínez; Luis C. Rivera Martínez; Rafael Rivera; Antonio Santos; Janice García; Heriberto Casanova Hyperkalemia is an electrolyte disorder with a high plasma potassium (K) concentration of >5mmol/L (normal strict value are from 3.55mmol/L). The causes for this disorder is a decreased excretion, excessive intake, or shift of potassium from inside the cells to extracellular space. The ratio of intracellular to extracellular potassium is important for generation of action potentials. Specifically, for normal functions of neurons, skeletal muscles and cardiac muscles.

The regulation of potassium in the body is achieved by two mechanisms, which are: 1) Excretion of potassium through the kidneys and intestines; 2) Shifting of potassium from the extracellular fluid into the cells by the sodium/potassium pump. Impairment in these levels may lead to disturbance in regulation. The pump is mainly regulated by hormones such as insulin and catecholamines. (Bucaj, M., 2017) Clinical Presentation of Problems For many reasons the level of potassium in your blood can get high. A normal range of potassium is between 3.6-5.2 (mmol/L) of blood (Mayo Clinic, 2014). A potassium level higher than these values can be life threatening. Symptoms do not become apparent until levels of potassium are 6.5

Potassium is a mineral that is extremely important for the optimal and normal functioning of the body, especially in heart muscle cells. It is mainly taken up by dietary intake and the correct level of potassium is crucial. The kidneys are the key players in maintaining the body’s total potassium content by balancing its intake and excretion (American Heart Association, 2017). If the intake outweighs the excretion, the kidney function decreases. Therefore, there is more potassium in plasma and hyperkalemia occurs. An above normal level of potassium can cause different types of heart arrhythmias. (American Heart Association, 2017).

Causes There are different causes that can lead to hyperkalemia, the most common being kidney failure. One of the many functions of the kidneys is to excrete excess salts and in the case of hyperkalemia; the kidneys fail to remove excess potassium, which lead to a buildup of potassium. Other causes of hyperkalemia can be due to supplements that are high in potassium or adrenal gland (Addison’s disease). The adrenal gland secretes hormones such as aldosterone, which regulates retention of potassium excretion as well as fluid and sodium retention (Melissa Conrad Stöppler). This eventually leads hyperkalemia due to a decrease in potassium excretion due to less production of aldosterone.

Implication of ion channels Hyperkalemia is a disease that involves increased serum potassium levels. The levels

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of potassium and sodium are critical for maintaining the resting membrane potential of the cell and are regulated by the Na/K pump. This change in the concentration gradient has two effects on the pump. First, it decreases the value of the resting membrane potential making the cell more likely to fire an action potential and reduces the amount of sodium channels available. The reduction in the available sodium channels results in a slower influx of sodium and slower impulse conduction. Finally, these changes can be seen in the EKG of patients with Hyperkalemia as evidenced in changes in the amplitude and frequency of the waves.

(Parham, Mehdirad, Biermann and Fredman, 2006)

salbutamol may be more effective than either treatment alone (Elliot et al., 2010).

Treatment

References

There are different ways to treat hyperkalemia. The most used treatment option is insulin as it stimulates Na/K ATP pump, promoting intracellular shift of potassium. It may take as soon as 15 minutes to lower serum potassium. Calcium based salts, such as calcium chloride or calcium gluconate, are other treatment option as they antagonize cardiac membrane excitability preventing a possible cardiac complication due to high potassium levels in the blood (Elliot etal., 2010). Salbutamol binds to Betareceptors in liver and muscle cells, stimulating adenylate cyclase to convert ATP to 3’ 5’ cyclic adenosine monophosphate (Ahee & Crowe, 2000). This stimulates the Na/K ATP pump resulting in intracellular K uptake. This treatment is not recommended for patients who use Beta-blockers as the response in decreasing potassium levels is attenuated. The main difference between insulin and salbutamol is the time of action, as insulin acts faster in lowering potassium concentration. Hemodialysis is the most effective treatment option for patients with severe hyperkalemia as it rapidly lowers plasma potassium concentrations in the first hour. Combination treatments may be better options in the future as some studies have shown that simultaneous use of insulin and

Ahee P, Crowe AV. The management of hyperkalemia in the emergency department.

Emergency Medicine Journal 2000;17: 188191.

Conclusion Hyperkalemia is characterized by high serum potassium levels. This in turn causes the resting membrane potential to become more depolarized. For this reason, membranes of Hyperkalemia patients are more susceptible to fire action potentials, leading to abnormal functions of neurons, skeletal muscles and cardiac muscles. Therefore, it is important to treat this condition by stimulating the use of the Na/K ATP pump, to maintain the adequate ratio of potassium ions inside and outside of the cell.

Bucaj, M., Clemente-Fuentes, R. Hyperkalemia. Retrieved November 08, 2017, from https://www.unboundmedicine.com/ucentra l/view/5-Minute-ClinicalConsult/116295/all/Hyperkalemia?q=hyper kalemia&ti=0 Elliott, M. J., Ronksley, P. E., Clase, C. M., Ahmed, S. B., & Hemmelgarn, B. R. (2010).

Management of patients with acute hyperkalemia. CMAJ : Canadian Medical Association Journal, 182(15), 1631–1635. http://doi.org/10.1503/cmaj.100461 High potassium (hyperkalemia). (2014, November 25). Retrieved November 09, 2017, from https://www.mayoclinic.org/symptoms/hyp erkalemia/basics/definition/sym-200507 Conrad, M. Hyperkalemia (High Blood Potassium) Causes, Symptoms, TreatmentHyperkalemia

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Causes. https://www.emedicinehealth.com/hyperkal emia/page2_em.htm Hyperkalemia (High Potassium). (2016, October). Retrieved November 08, 2017, from http://www.heart.org/HEARTORG/Condition s/HeartFailure/TreatmentOptionsForHeartF ailure/Hyperkalemia-HighPotassium_UCM_488806_Article.jsp#.WgPMf 7opDmoh Parham, W. A., Mehdirad, A. A., Biermann, K. M., & Fredman, C. S. (2006). Hyperkalemia Revisited.

Texas Heart Institute Journal, 33(1), 40–47.

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Multiple Sclerosis Agnes Cruz; Asdrúbal Rivera; Paola A. Colón Bonilla; Paola Figueroa; Kenneth Avilés; Carla Fernández & Roberto D.; Kutcher Díaz Introduction Multiple sclerosis has been classified as a chronic and progressive autoimmune disease in which the myelin sheaths around the axons of the brain and spinal cord are damaged. The demyelination of the axons leads to a poor nerve impulse, which disrupts the flow of information within the brain and body. As a result, wide varieties of symptoms are produced that increase the disabilities for the normal body function. Multiple sclerosis symptoms include numbness, vision problems, walking difficulty, fatigue, weakness, pain, muscle spasms, among others.

Statistics Recent statistics have shown MS affects around 2.5 million people worldwide (Healthline, 2015). According to a recent study published in 2016, the total number of insured patients diagnosed with MS between 2008 and 2012 was more than 400,000 with a median age between 45 and 49 years (Dlokthornsakul et al, 2016), with about 200 new cases diagnosed each week (Healthline, 2015). In Puerto Rico, the prevalence rate was estimated to be 52 per 100,000 residents (Chinea, 2012). One interesting fact about MS is that the prevalence rate increases at higher latitudes (Healthline, 2015). MS diagnosis worldwide is normally higher for women than men; this trend is also true for Puerto Rico and the United States (Healthline, 2015).

Finally, it is important to recognize the costs associated with the disease, which can range from around $8,000 to more than $50,000 per year (Adelman, 2013).

Causes The exact cause for multiple sclerosis is unknown, but it is related to genetic and environmental factors. In multiple sclerosis, the immune system attacks the myelin sheath of the oligodendrocytes. The T-cells pass through the blood-brain barrier (BBB) and attaches to the myelin. This activates the Tcells and acts on the BBB to express more receptors. Later, cytokines are released and the vessels dilate to allow B-cells and macrophages to get through the BBB. B-cells synthesize antibodies that mark the myelin sheath proteins. Macrophages recognize these markers and begin to engulf and destroy the oligodendrocytes. Consequently, degeneration of the neuron is caused by lack of myelin sheath. Some risk factors include:  Gender (women are two times more likely to be affected)  Family history  Ethnicity (Caucasians have a higher risk)  Age (20-40 years old) Multiple sclerosis can be divided in 4 different types. Each type depends on the pattern of disabilities throughout time, starting with the appearance of the first symptom. These are: Relapsing-Remitting MS (RRMS): Is considered the most common form of multiple sclerosis. Those with RRMS experience temporary periods or relapses in which the person experiences new symptoms.

Secondary-Progressive MS (SPMS): With or without the occurrence of relapses the symptoms worsen more constantly throughout time. Most people with RRMS later on develop SPMS. Primary-Progressive MS (PPMS): The person experiences a slow and steady worsening of the symptoms without relapses.

Progressive-Relapsing MS (PRMS): Rarest form of MS. The person experiences steadily worsening symptoms accompanied by acute relapses without recovery.

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Normal Action Potential In normal myelinated neurons in the Central Nervous System, the axon is isolated with myelin — a substance produced by oligodendrocytes. Myelin is arranged in sheaths, internodes, along the axon with regions rich in voltage dependent channels, called Nodes of Ranvier. This arrangement allows the neuron to propagate the action potentials down to the axon terminal in a faster and efficiency manner when compared to a demyelinated —a phenomenon called saltatory conductance. Saltatory conductance allow the neuron to reach threshold and follow a normal action potential pattern, where Vm during depolarization tends to sodium equilibrium potential and subsequently following depolarization where the Vm tends to potassium equilibrium potential and back to resting state. When the myelin sheaths are damaged, the neuron loses the ability to propagate the action potentials as fast.

Unmyelination When the axon become unmyelinated, this leads to inefficient signal transmission and even death of the neurons, due to the fact that myelin not only helps in signal transmission but also protecting the integrity of the neurons axon. Myelin increases membrane resistance and decreases membrane capacitance, which allows the signal to travel in a higher-speed rate than signals observed in unmyelinated axons. Increasing membrane resistance forces the current to flow along the path of least resistance of the axon interior.

The decreased membrane capacitance decreases the time constant, how quickly a cell membrane depolarizes in response to inward current. Thus, in the breaks of the myelin sheath, the axonal membrane depolarizes faster in response to inward current (Costanzo, 2010). Therefore, in patient with multiple sclerosis the axons become unmyelinated, due to that antibodies attack myelin, and this natural mechanism of signal transmission is interrupted and signal

transmission does not occur in a feasible way.

Furthermore, antibodies are also believed to attack oligodendrocyte cells, which produce the myelin, hence, the axon cannot be remyelinated and function to the neurons will not regenerate properly. This leads to the degenerative symptoms observed in multiple sclerosis patients.

Treatments Currently, there is no cure for multiple sclerosis. Treatment is directed towards faster recovery after attacks, slowing the progression of the disease and managing the severity of the symptoms. Common medications for progressive primary and relapsing-remittent MS may include:  Ocrelizumab (Ocrevus)- the only FDA approved disease modifying therapy. Its mechanism of action involves targeting CD20 marker on B-lymphocytes and may be considered an immunosuppressant drug. It protects neurons and myelin from attacks of the immune system.  Beta interferons- intravenous medication used for the reduction in severity and frequency of relapses.  Glatiramer Acetate (Copaxone)- helps block the autoimmune attack on myelin.  Natalizumab(Tysabri)- designed to block the movement of potentially damaging immune cells from the bloodstream into the brain or spinal cord.

References Centonze, D., Muzio, L., Rossi, S., Furlan, R., Bernardi, G., & Martino, G. (2009). i. The link between inflammation, synaptic transmission and neurodegeneration in multiple sclerosis. Cell Death And Differentiation, 17(7), 1083-1091. http://dx.doi.org/10.1038/cdd.2009.

179.

Chinea A1, Pérez N, Perez-Canabal A, Rojas F, Torres J, Poser C., (2012). The Puerto Rico

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study for the prevalence of multiple sclerosis.

Bol Asoc Med PR, 2012 Sep-Dec;104(4):4-9.

Costanzo, L. (2010). Physiology. Philadelphia, PA: Saunders/Elsevier.

Dilokthornsakul, P., Valuck, R. J., Nair, K. V., Corboy, J. R., Allen, R. R., & Campbell, J. D. (2016). Multiple sclerosis prevalence in the United States commercially insured population. Neurology, 86(11), 1014– 1021. http://doi.org/10.1212/WNL.000000000000 2469 Pietrangelo, A., Higuera, V. and Kim, MD, S. (2015). Multiple Sclerosis by the Numbers: Facts, Statistics, and You. [online] Healthline. Available at: https://www.healthline.com/health/multiple -sclerosis/facts-statistics-infographic [Accessed 10 Nov. 2017].

R, T. (2017). Multiple sclerosis- diagnosis, management and prognosis. - PubMed NCBI. Ncbi.nlm.nih.gov. Retrieved 8 November 2017, from https://www.ncbi.nlm.nih.gov/pubmed/221 46321 Types of MS and MS Treatment Options— multiplesclerosis.com. (2017).

Multiplesclerosis.com. Retrieved 8 November 2017, from https://www.multiplesclerosis.com/us/treat ment.php What is Multiple Sclerosis? (2017). YouTube.

Retrieved 8 November 2017, from: https://www.youtube.com/watch?v=qgySDm RRzxY.

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Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage Camila Pabón; Janelly Simons; Paola Caldas; Ivana García; Guillermo García; Gonzalo Monasterio; Gabriel Laguillo Amyotrophic lateral sclerosis (ALS) is a progressive fatal disorder due to a group of neurological attacks that degenerate the neurons that are in charge of controlling voluntary muscles.1 It has been known that only 5-10% of the patients affected by this disease acquire it by genetics and the other 90% of the cases are sporadic.1 The main cause of ALS is an abnormal activity of motor neurons that results in an abnormal and spontaneous twitching of muscle fibers.1 Dying cells spontaneously discharge as a result of imbalances of K+ and Na+ channels.2 Risk factors for ALS are genetic, age, and sex.

Development of Familial ALS is highly correlated to patients whose parents have been diagnosed with ALS. The chance to acquire ALS increases as age increases, especially after the age of 40 and it have been found that males have a higher risk to acquire ALS than women.3 The environmental risk factors for acquiring ALS are smoking, occupational exposure to toxins (such as fertilizers, pesticides, metals/dust/fibers/fumes/gas/radiation, military service), and medical conditions such as head trauma, metabolic diseases, and cancer.4 Although the cause of ALS is not known, numerous pathways are thought to be

impacted by its onset. The purpose of the genes thought to be involved in ALS is broad but a number of them revolve around the function of K+ voltage-gated channels, glutamate transporters, and kinase enzyme activity. Within our research, the focus was on DPP6, FGGY, ITPR2, C9orf72, SLC1A2, SOD1, KCNA1, KCNA2, and KCNQ2 with specific focus on the latter 3 (Chio, 2009).

One of the most noticeable symptoms of ALS is fasciculations. Fasciculations are a combination of sustained spasms and muscle tremor due to the spasms. A group of Japanese scientists decided to study anomalies in axonal membranes of motor neurons through electrophysiological experiments. Methods used included measurements of depolarization and action potentials of the median nerve in the wrist.

Cohort included 58 patients with ALS and 25 age-matching control patients. Results of the studies show hyperexcitability of the neurons due to membrane abnormalities. These are due to defective potassium channels in the axonal membrane, specifically related to genes KCNA1 and KCNA2.2 The potassium conductance decreases, which leads to an increase in potassium concentration intracellularly. Membrane potential then assimilates that of potassium which makes the cell hyperpolarized. Hyperpolarization makes it more difficult to reach threshold and fire an action potential. This process is further complicated due to an increase in sodium conductance. When threshold is finally reached difficult, hardly due to hyperpolarization, an action potential is fired and a great amount of sodium enters the cell.

Since there is a great amount of potassium intracellularly, depolarization is sustained until neurotransmitters are depleted from the pre-synaptic vesicles. Since neurotransmitters are being liberated into the neuromuscular junction, the muscle contracts continually and spasms occur. This depolarizations might be irreversible and could lead to cellular death.

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Amyotrophic lateral sclerosis presents as a gradual onset muscle atrophy and paralysis.

Not all people experience the same symptoms or the same sequence of progression. Primary symptoms can begin in muscles that control speech and swallowing or in the hands, arms, legs or feet. Other early symptoms include tripping, dropping things, abnormal fatigue of the arms and/ or leg, muscle cramps and twitches, and uncontrollable periods of laughing or crying. As symptoms progress, severe complication arise. Speaking becomes very difficult to understand. Eating problems due to damage of swallowing muscles, makes them need feeding tube to avoid aspiration.

Fronto -temporal dementia has been associated with ALS. Over time, patients may need to have a tracheostomy, and respiratory failure is the most common death for patients.

ALS usually strikes between the ages of 40 to 70 years and the mean survival is three to five years.

Currently Riluzole and Edaravone are the only therapeutic agents for treating ALS patients. There is no cure for ALS, however Riluzole (marketed as Rilutek) and Edaravone (marketed as Radicava) help treat the symptoms. The precise mode of action of Riluzole has yet to be discovered. It is believed to act on the glutamate system, by activating a G-protein-dependent process that inhibits glutamate release and by blockade of postsynaptic NMDA glutamate receptors.5 In mice, it blocks Na+ channels and removes excess Na+. It also activates various types of K+ channels and inhibits slow inactivation of voltage-dependent K+ channels. This results in an increase of K+ currents in neurons, which can be associated with the inhibition of glutamate release and with neuroprotection.

Given these findings, Potassium Channel Activators should be considered as a potential target against many neuronal diseases including ALS. Treatment for ALS includes breathing care, physical therapy, occupational therapy, speech therapy, nutritional support, psychological support, and social support.

Patients eventually will have more difficulty breathing as muscles become weaker and will need a mechanical ventilator. A physical therapist can address pain, walking, mobility, bracing and equipment needs that help to stay independent. Low-impact exercises are also recommended. In addition, occupational therapist can help in find ways to remain independent despite hand and arm weakness.

Adaptive equipment can help you perform daily activities such as dressing, grooming, eating and bathing. Speech therapists can also help to explore other methods of communication, such as an alphabet board, ASL, pen and paper, computers with text-tospeech applications or computer-based equipment with synthesized speech that may help you communicate. Nutritional support is important to ensure you're eating foods that are easier to swallow and meet your nutritional needs. Eventually will need a feeding tube. Psychologists, social workers and others may provide emotional support for the person with ALS and your family.

References Cronin, S, et al. (2008). Screening for replication of genome-wide SNP associations in sporadic ALS. Department of Clinical Neurological Sciences, Dublin, Ireland.

Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/189 87618.

Yu Yu, F, et al. (2014). Environmental Risk Factors and Amyotrophic Lateral Sclerosis (ALS): A Case-Control Study of ALS in Michigan. University of Michigan, Ann Arbor, MI. Retreived from: http://journals.plos.org/plosone/article/aut hors?id=10.1371/journal.pone.0101186.

Ingre, C, et al. (2015).

Risk factors for amyotrophic lateral sclerosis.

Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.

Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4334292/

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Chio,A et al. (2009). A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis. Department of Neuroscience, University of Turin, Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/191 93627 . https://academic.oup.com/brain/articlelookup/doi/10.1093/brain/awl024

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Epilepsy Jonathan Cárdenas; María Rocío Reyes; Marcos Pérez; Arnaldo Santa Cruz; María Gabriela Rodríguez; José Henríquez; Antonio Mondríguez Epilepsy is a condition that is characterized by the presence of over-excitable neuronal networks which provoke seizures of varying severity. Although its causes are mostly unknown, brain trauma, genetics, and abnormal development inside the uterus have been established as some known causes of the disease. Epilepsy causes multiple physiologic changes in the brain such as mutated ion channels that lead to abnormalities in the transport of certain ions such as Na+ K+, and Cl-. Other molecular mechanisms that are affected is neuronal transmission involving neurotransmitters, specifically GABA. Epilepsy is the fourth most common neurodegenerative disorders characterized by unpredictable seizures and abnormal electrical activity in the brain. A person is typically diagnosed with epilepsy when that person has at least 2 unprovoked seizures.

This means that the these attacks were not caused by a known or reversible medical condition, such as alcohol withdrawal or low blood sugar. Since Epilepsy is a spectrum disorder, these seizures can have many different effects on the brain of the affected person. Some of these effects, which are also termed as symptoms are: uncontrollable jerking movements of the limbs, loss consciousness, prolonged staring states, temporary confusion, psychic symptoms of fear, anxiety, etc. These symptoms/effects are then used to categorize the type of seizure the affected individual has. The two broadest types are Focal Seizures (which focus on one area of the brain) and General Seizures (which affect almost the entire brain). These same classifications have many different subtypes in which the patient can be further localized. Also important to consider is how

epilepsy can affect almost every person.

However, incidence rates are greatest among young children and older adults.

Normal physiological neuronal function involves the flow of sodium, potassium and chloride ions across the axonal membrane via integral membrane proteins of the voltage & ligand-gated ion channels type (other ions such as calcium are present, however, they do not participate in generating an action potential). Concentration gradients of each ion are different and establish the dynamic activity. Sodium and chloride ions are at a higher concentration outside the neuronal cell while potassium is at a higher concentration on the inside the cell, for example. Furthermore, there are different mechanisms to establish concentration gradients such as the sodium/potassium pump (primary active transport) and potassium leak channels. The propagation of an action potential occurs in a sequential fashion beginning at the axon hillock upon the receipt of a signal. The end product of the neuronal propagation events culminates with the release of neurotransmitters at a synapse where another neuron receives the signal that further propagates it to other neurons.

The major inhibitory neurotransmitter receptors in the brain is the GABA receptor. It is multi-subunit integral protein made up of two alpha, two beta and two gamma subunits grouped around the central pore that allows flow of ions. The chloride ions flow through using the following mechanism: The GABA component binds to its two binding sites between the alpha and beta subunits. This produces a conformational change which locks GABA in the binding socket in a state known as the flipped state. Addition conformational changes open the ion pore allowing the flow of chloride ions in. Any impairments to the GABA transmissions induces epileptic seizures. Mutations on the gamma and alpha subunits can lead to increased sensitivity to heat or weakened integrity of the receptors which disrupts inhibition in the CNS. Chemical agents can

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also block inhibition. For example, the chemical Picrotoxin binds the ion pore portion of the receptor; thus, preventing the flow of chloride ions.

GABA has two major receptor subtypes: GABAA receptors and GABAB receptors.

GABAA receptors are permeable to Chloride ions, which hyperpolarize the cell and form the basis for neuronal inhibition. Normally GABA binds to its GABAA receptor causing an influx of Cl- ions, which hyperpolarize the membrane and as a result inhibit action potentials from forming. Seizures are caused by the loss of balance of GABAA receptor inhibition. Seizure initiation is characterized by 2 concurrent events: high frequency bursts of action potentials, and hypersynchronization of a neuron population.

Sustained neuronal depolarization results in the burst of action potential spikes and a plateau-like depolarization, then a rapid repolarization followed by hyperpolarization of the membrane. This sequence of events is known as the paroxysmal depolarizing shift, where the normal refractory period between action potentials is no longer seen. The propagation of a seizure is caused by the activation of a neighboring neurons and loss of surrounding inhibition. Normally, the propagation of bursts of action potentials is prevented by intact hyperpolarization and inhibitory neurons. But in epileptic seizures, the burst of action potentials leads to an increase in extracellular K+ which reduces the hyperpolarizing outward K+ currents, causing neighboring neurons to depolarize and.

the cell and hyperpolarizing it. Vigabatrin and Tiagabine act on the GABA Transporter to avoid the reuptake of the neurotransmitter and prolong the inhibitory response in the post-synaptic cell. Vigabatrin is an irreversible inhibitor of the GABAT. Tiagabine on the other hand, is a competitive inhibitor of the transporter that binds with high affinity.

References “Epilepsy | MedlinePlus.� MedlinePlus Trusted Health Information for You, medlineplus.gov/epilepsy.html.

Las Benzodiacepinas: Mecanismo de accin y cm o suspender la ingestin, C Ashton, 2002, www.benzo.org.uk/espman/bzcha01.ht m#8 Rogawski, M & Loscher, W. 2004. The Neurobiology of Antiepileptic Drugs. Nature Revies-Neuroscience (5)- 553.

An Introduction to Epilepsy. Bromfield EB, Cavazos JE, Sirven JI. American Epilepsy Society (2006). Chapter 1, Basic Mechanisms Underlying Seizures and Epilepsy. https://www.ncbi.nlm.nih.gov/boo ks/NBK2510/

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Epilepsy of this type is treated with benzodiazepines, vigabatrin and tiagabine.

Increase of the gamma butarytic acid (GABA) effect on neurons is used to treat epileptic seizures. Benzodiazepines drugs are positive allosteric modulators that bind to the gamma subunit of the GABA receptors to increase the affinity of the neurotransmitter to the GABA receptor. As a result, the receptor is activated for a prolonged time, letting Cl- into

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Brugada Syndrome Natalia Rodríguez; Gabriela L. Navarro; Víctor Martínez; Gladys Viera; Fabio Squicimari; Alexander Meléndez; Javier Ruiz According to the NIH, Brugada syndrome is an autosomal dominant disease with incomplete penetrance that disrupts the heart’s normal rhythm (Wilde, et al., 2002) (Dumaine, et al., 1999). Unfortunately, the disease can lead to major complications like fainting, seizures, difficulty breathing, or even sudden death. When the person is asleep or resting, he or she is more vulnerable to these complications. Sudden death, which is due to cardiac complications due to atrial fibrillation, usually does not occur until the person is 40 years old. (Priori, et al., 2002). In most cases, complications do not occur until adulthood. Patients may also experience nightmares or thrashing at night, fever (which is known to trigger or worsen complications listed above), and abnormal elevation of ST-segment (Dizon, 2017).

However, complications may arise during childhood. It is important to note as well that this although the frequency of this disease is unknown, it is estimated that it affects 5 in 10,000 individuals, most of which are of Asian descent. (Priori, et al., 2002) In 30% of Brugada syndrome cases, the mutated gene is SCN5A. There is a frameshift mutation due to a misplaced stop codon. This gene normally encodes for a wild type cardiac sodium channel which plays an important role in maintaining a normal heart rhythm (Dumaine, et al., 1999). The NIH explains that this channel signals the start of each heartbeat, coordinates the contractions of the upper and lower chambers of the heart, thus maintaining a normal heart rhythm. Other causes are still unknown because of a lack of research into this rare autosomal disease (Antzelevitch, 2006). When the individual is

febrile, the sodium channels deactivate. The symptoms, thus, are more likely to be expressed when this is going on.

Although not much research has gone into Brugada syndrome, some treatments have been found to cause moderate relief in patients. One of these is an implantable cardioverter-defibrillator (ICD) which is the only proven effective device treatment thus far. This device monitors the patient’s heart rhythm and delivers electrical shocks when needed to control abnormal heartbeats. It is inserted into a major vein under or near the collarbone guided with x-ray images to heart.

Although effective, this treatment is notoriously expensive and not a viable option for many affected individuals. It is also not very effective in children and infants. Another treatment in the US specifically is an agent called quinidine. This agent normalizes the ST segment of the ECG preventing heart rhythm complications. Finally, catheter ablation over the anterior right ventricular outflow tract epicardium has been found to relieve some symptoms (Nademanee, et al., 2011). However, these treatments usually only prolong death, not necessarily prevent it (Antzelevitch, 2006).

Brugada syndrome is not necessarily fatal and may be asymptomatic, which is probably why not much research is going into it. The current treatments are moderately effective, but do not necessarily help when the patient is febrile. It mostly affects poor areas of Asian populations, and probably will not get much attention soon (Antzelevitch, 2006).

References Antzelevitch, C., & Fish, J. M. (2006). Therapy for the Brugada syndrome. In Basis and Treatment of Cardiac Arrhythmias (pp. 305330). Springer Berlin Heidelberg.

Dizon, J. & Nazif, T. (2017) Brugada Syndrome Guidelines. Retrieved from https://emedicine.medscape.com/article/16 3751-guidelines#g1

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Dumaine, R., Towbin, J. A., Brugada, P., Vatta, M., Nesterenko, D. V., Nesterenko, V. V., ... & Antzelevitch, C. (1999). Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circulation research, 85(9), 803-809.

Nademanee, K., Veerakul, G., Chandanamattha, P., Chaothawee, L., Ariyachaipanich, A., ‌ & Ngarmukos, T. (2011). Prevention of Ventricular Fibrillation Episodes in Brugada Syndrome by Catheter Ablation Over the Anterior Right Ventricular Outflow Tract Epicardium. Circulation, 12701279.

Priori, S. G., Napolitano, C., Gasparini, M., Pappone, C., Della Bella, P., Giordano, U., ... & Ronchetti, E. (2002). Natural history of Brugada syndrome. Circulation, 105(11), 1342-1347.

Wilde, A. A., Antzelevitch, C., Borggrefe, M., Brugada, J., Brugada, R., Brugada, P., ... & Priori, S. G. (2002). Proposed diagnostic criteria for the Brugada syndrome.

Circulation, 106(19), 2514-2519.

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The effects of calcium ion channels (Amyloid βprotein) on the development of Alzheimer disease Alejandra Figueroa; Nelson Álvarez; Keila Mestey; Waldo Santiago; Fabiola Garau; Erik Grodus; Alexander Moreira Introduction Alzheimer’s is a progressive disease that destroys important mental functions; it is a leading cause for dementia. A pathologic representation of AD is the formation of senile plaques made from amyloid beta peptide. The amyloid beta peptide begins destroying synapses of the neurons before it clumps into plaques that lead to nerve cell death; it also forms unusual ion channels in the neurons, which allow an increase cation uptake inducing neuronal abnormality, leading to the main causes of AD. There are many other studies looking into the relationships of the amyloid beta accumulation and their relations to the Alzheimer’s disease (Selkoe DJ et al, 2016).

Clinical presentation of the problem Alzheimer disease is characterized by gradual onset and progressive decline in cognition.

There is a notable decrease in sensory and motor functions in later stages of the disease.

The average course of AD is approximately a decade, with a range of 3 to 20 years’ duration from diagnosis to death, but the rate of progression is variable (Small et al 1997).

Memory loss, short-term or long-term, is present all throughout the disease, and distant memories are lost. AD patients experience problems learning new things and retaining information. Cognitive impairment affects the patient’s daily life and includes: aphasia, apraxia, disorientation, visuospatial

dysfunction, and impaired judgement and executive functioning. Social skills usually remain intact until later stages of the disease.

There are significant behavioral and mood changes. Patients may experience anxiety, personality changes, irritability, depression in early stages of the disease, and they may also experience delusions, hallucinations, aggression, and wandering in middle or late stages of the disease.

This disease can be diagnosed by brain imaging techniques like Aβ-PET, which is an imagining marker that detects the cognitive impairment to dementia due to Alzheimer’s disease. It relies on the use of the Pittsburgh compound B (PiB), which is a radioactive carbon 11 analogue of the fluorescent amyloid dye thioflavin- T62 (Masters et al, 2015). This compound is able to bind to fibrillar Aβ with high affinity as it crosses through the blood-brain barrier. Patients with a positive Aβ-PET scan have great amounts of Aβ depositions in their brain that leads to brain atrophy and cognitive decline.

Aβ-PET is feasible and has helped improved the cohort selection for clinical trials (Masters et al, 2015).

Another technique used relies on the collection of cerebrospinal fluid (CSF) by lumbar puncture to detect specific Alzheimer’s biomarkers such as Aβ42, T-Tau, and P-Tau (Masters et al, 2015). CSF levels of Aβ42 correlate with amyloid ligand retention in the brain seen by Aβ-PET imaging. The CSF levels of T-Tau increase in Alzheimer’s disease and other neurodegenerative disease.

These T-Tau levels reflect the intensity of neuronal and axonal degeneration. Lastly, PTau correlates with the rate of hippocampal atrophy in the brain. These biomarkers are sensitive and specific and help differentiate between Alzheimer’s and other diseases such as Parkinson’s and Lewy body dementia.

Implication of ion channels The transmembranal amyloid B-protein is a precursor of the amyloid B-protein precursor

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(APP) that is generally related with Alzheimer’s disease. It has the potential of forming selective Ca2+ cation channels in the cellular membrane. This protein can form aberrant cation channels that could lead to cellular death by amyloid neurotoxicity. The amyloid channel activity exhibits multiple conductance levels, cation selectivity and sensitivity to tromethamine. The amyloid Bprotein disrupt Ca2+ homeostasis in the neuron, by an increase in the intracellular concentration of Ca2+ (Arispe & Rojas, 1993).

Treatments (status) Two types of medications are primarily used to help with symptom relief, as there is no definitive cure. They may be used in conjunction at times. The first one used is Memantine (Namenda) and it works to slow the symptomatic progression of moderate to severe Alzheimer’s disease. It specifically blocks the NMDA receptors of the glutamatergic system. Common side effects include but are not limited to: headache, drowsiness, agitation, dizziness, insomnia, constipation, confusion, and hallucinations.

The second type of medication used is cholinesterase inhibitors works on the enzyme acetylcholinesterase. The normal function of acetylcholinesterase is to break down acetylcholine in the synaptic cleft after signal transmission. If this enzyme is inhibited, then there is more acetylcholine available to be passed to the next nerve cell.

Patients taking this medication may find improvement with: memory, behavioral symptoms, and daily life functions. Common side effects include but are not limited to: vomiting, nausea, diarrhea, fatigue, insomnia, dizziness, and loss of appetite.

Occasionally anti-depressant and anti-anxiety medications may be used to combat behavioral symptoms. These should be used with severe caution as they may actually exacerbate symptoms. For example, sleeping medications may increase confusion and the risk of falls (Mayo Clinic, 2011). Also, exercise and proper nutrition are vital as well.

Exercise can help with maintenance of cardiac and muscular health along with improving mood. Alzheimer patients should have healthy shakes/smoothies along with plenty of water, juice, and other healthy beverages as they may forget to eat. Caffeine should be avoided as it can exacerbate restlessness and prevent sleeping (Mayo Clinic, 2011). Another important aspect of the treatment is the holistic approach such as creating a safe place for the patient. It is important to make the house more secure with guardrails and removing extra furniture.

Essential items such as wallets, keys, and phones should be left in the same place. Also, see if your physicians can change dosing of medications to once a day.

References Arispe, N., Rojas E., et al. (1993, November) Giant multilevel cation channels formed b Alzheimer disease amyloid β- protein [ AβP(1-40)] in bilayer membranes. Medical Sciences, 90 (22), 10573-10577. Retrieved November 08, 2017 from https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC47819/ Masters, Colin., et al. (2015, October) Alzheimer’s Disease. Nature Review Disease Primer, 1(15), 1–15. https://www.nature.com/articles/nrdp2015 56 Mayo Clinic. (2017, August 11). Alzheimer's disease- Symptoms and causes. Mayo Clinic.

Retrieved November 08, 2017 from https://www.mayoclinic.org/diseasesconditions/alzheimersdisease/symptoms-causes/syc-20350447 Selkoe, D. J., & Hardy, J. (2016, March 29). The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Molecular Medicine, 8(6), 595-608. Retrieved November 08, 2017 from http://embomolmed.embopress.org/content /8/6/595

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Small GW, Rabins PV, Barry PP, et al. (1997, October 22). Diagnosis and Treatment of Alzheimer Disease and Related Disorders Consensus Statement of the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society. JAMA. 278(16), 1363– 1371. Retrieved November 08, 2017 from https://www.ncbi.nlm.nih.gov/pubmed/934 3469

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Startle disease (Hyperekplexia) Liana Lladó; Alan Montiel; Sarah Rivera; Katherine Quiñones; Otilio Rivera; Carlos Dohse; Darinelys Figueroa Introduction Startle disease, also called hyperekplexia, is a rare autosomal dominant neurological disorder characterized by excessive startle reflexes due to tactile or acoustic stimuli. In most severe cases, it also presents hypertonia during infancy. It is frequently misdiagnosed initially as spastic quadriplegia, and later as epilepsy due to the similar symptoms presented in these diseases. Molecularly, hiperekplexia disease is related to mutations in the glycine receptors, as demonstrated by Shiang and colleagues (1993).

Clinical presentation of the problem Hyperekplexia is characterized by generalized stiffness after birth that normalizes during the first years of life, excessive startle reflex stimuli and a short period of stiffness following the startle response in which voluntary movements are not possible. Some patient present exaggerated head-retraction reflex consisting of extension of the head followed by flexor spasms of limbs and neck (Tijssen and Rees, 2007). There are two types of hyperekplexia: major and minor. Patients who present the major form are characterized by an unusual extreme startle reaction to an unexpected noise, movement or touch, spastic jerking movements, which can occur when the patient is trying to fall asleep, or falling stiffly to the ground. Infants who suffer from the major form exhibit extreme muscle tension, especially at birth and hypokinesia. Patients who exhibit the minor form usually exhibit irregular exaggerated startle reflex with few or none of the other symptoms. The intensity of the reflex can be affected by stress or

anxiety (National Organization for Rare Disorders, N.d). This disease can affect infants as newborns or prior to birth but it can also be present in adolescence or adulthood.

Implications of ion channels Glycine is a major inhibitory neurotransmitter in the brainstem and spinal cord, where it can act on both motor and sensory neurotransmission. When glycine is released from the vesicles of the pre-synaptic neuron, they bind to glycine receptors, on the post-synaptic membrane and causes them to open. The influx of Cl- ions into the cell causes hyperpolarization of the postsynaptic membrane, thus decreasing the chance of generating an action potential. Glycine, therefore, causes an inhibitory post-synaptic potential (IPSP). In the human startle disease or hyperekplexia, these inhibitory glycinergic synapses are deficient because the human glycine receptor (hGlyR) chloride channel is mutated. Therefore, disruptions in the inhibitory glycinergic synapses increases the general level of excitability of motor neurons, which accounts for neonatal hypertonia. With time, patients with this disease develop compensatory mechanisms for the enhanced excitability of neurons, but cannot deal with the high demand of inhibitory transmission during sudden, unexpected auditory or tactile stimuli.

Mutations that cause hyperekplexia The normal glycine receptor is a pentameric cys-loop ligand-gated ion channel receptor.

The glycine receptor consists of α subunits (α1 – α4) and one β subunit; they can arrange in α homomers or αβ heteromers (2:3 or 3:2 stoichiometry). The mutations in human startle disease can be either on the GLRA1 gene, (α subunit) of the hGlyR or by mutations in the GLRB gene (β subunit). In autosomal recessive GLRA1, the nonsense and frameshift mutations cause a loss of protein expression at the cell surface, but the unaffected allele generates sufficient quantities to maintain normal glycinergic

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neurotransmission (Bode, 2014). On the other hand, autosomal dominant mutations are caused by missense mutations that affect the hGlyR in different ways. Some GLRA1 mutations result in spontaneous channel activation destabilization the open state of the channel, cause the glycine receptor to shift towards the inactivated state rapidly after activation or prolongs the time glycine receptors take to go from the inactivated state back to the resting state. All these mutations will decrease the amount of inhibitory post-synaptic action potential and there will be no counteraction and therefore excess excitatory post-synaptic current.

Hyperekplexia can also be caused by mutations in SLC6A5 which codes for a Na+ /Cldependent glycine transporter (GlyT2), a transporter found in glycinergic axons (Davies et.al, 2010). This transporter is responsible for recapturing glycine from the synaptic cleft and maintaining a high concentration of glycine in the presynaptic vesicles (Carta et.al, 2012). Thus, mutations in this transporter or its coding gene (SLC6A5) will limit glycine clearance in glycinergic synapses and/or the presynaptic cell’s ability to produce the high vesicular concentrations of glycine required for proper glycine neurotransmission (Carta et.al, 2012). This is proved by Gomenza, et al, and and Rees, which knocked out the GlyT2 in mice and mutated the SCL6A5, respectively, and both actions displayed symptoms similar as those seen in hyperekplexia (Rees et.al, 2006). The particular reason mutations in the SLCA65 gene is related to hyperekplexia is due to the responsibility of glycinergic neurons in controlling the startle reflex. When the inhibitory glycinergic neurotransmission is disrupted, the startle reflex is not controlled and becomes exaggerated -a common feature of the Hyperekplexia neurological disorder.

(Zafra, IbaĂąez and Gimenez, 2016) Treatment The most commonly used treatment for hyperekplexia is by the use of clonazepam.

Clonazepam acts as a GABA agonist thus

increases the function the the glycine receptor. GABA is the major inhibitory neurotransmitter of the brain. Because of how complex hyperekplexia is, not all patients will respond to this particular medication. Other treatment options include valproic acid with hydroxytryptophan and piracetam, which functions similarly to clonazepam. If the patient shows symptoms of apnea or cardiac disturbances, may have to treat with resuscitation. (Mineyko, A., Whiting, S., & Graham, G. E, 2011) References Andermann, F., Keene, D. L., Andermann, E., & Quesney, L. F. (1980). Startle Disease Or Hyperekplexia Further Delineation Of The Syndrome. Brain, 103(4), 985-997. doi:10.1093/brain/103.4.985 Bode, A., & Lynch, J. W. (2014). The impact of human hyperekplexia mutations on glycine receptor structure and function. Molecular Brain,7(1), 2. doi:10.1186/1756-6606-7-2 Carta, E., Chung, S., James, V. M., Robinson, A., Gill, J. L., Remy, N., and Harvey, R. J. (2012).

Mutations in the GlyT2 Gene (SLC6A5) Are a Second Major Cause of Startle Disease.

Journal of Biological Chemistry, 287(34), 28975-28985. doi:10.1074/jbc.m112.372094 Davies, JS., Chung, SK., Thomas, RH., Robinson, A., Hammond, CL., Mullins, JG., Carta E., Pearce BR., Harvey K., Harvey RJ. and Reese, MI. (2010). The glycinergic system in human startle disease: a genetic screening approach. Frontiers in Molecular Neuroscience. doi:10.3389/fnmol.2010.00008 Mineyko, A., Whiting, S., & Graham, G. E. (2011). Hyperekplexia: treatment of a severe phenotype and review of the literature.

Canadian Journal of Neurological Sciences, 38(3), 411-416.

National Organization for Rare Disorders (Ed.). (n.d.). Hyperekplexia. Retrieved

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November 12, 2017, from https://rarediseases.org/rarediseases/hyperekplexia Rees, M. I., Harvey, K., Pearce, B. R., Chung, S., Duguid, I. C., Thomas, P. and Harvey, R. J. (2006). Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease. Nature Genetics, 38(7), 801-806. doi:10.1038/ng1814 Shiang, R., Ryan, S. G., Zhu, Y. Z., Hahn, A. F., O'Connell, P., & Wasmuth, J. J. (1993).

Mutations in the α1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia. Nature genetics, 5(4), 351-358.

Tijssen MAJ, Rees MI. Hyperekplexia. 2007 Jul 31 [Updated 2012 Oct 4]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors.

GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 19932017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK12 60/ Zafra, F., Ibañez, I., & Gimenez, C. (2016).

Glycinergic transmission - Glycine transporter GlyT2 in neuronal pathologies.

Neuronal Signaling. doi:10.1042/ns2016000

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Botulism Amin Hussein; Andrea Otero; Arturo Fossas; Carolina Rodriguez; Carlos Ramirez; Jean Paul Godreau; Raymond Gerena Brief Introduction Botulism is an illness caused by a toxin released by the bacterium Clostridium botulinum. Although its rate of incidence has dramatically decreased since its discovery in 1895 (Erbguth, 2004), recent outbreaks in the U.S. as well as some Northern European countries have caused the need for improved surveillance and detection methods by the World Health Organization (WHO). Even if its incidence is low, without adept and immediate treatment, the mortality rate is extremely high, and even in those that are treated, 5-10% of the cases are fatal (WHO).

Clinical Presentation The toxins produced by the bacterium strive in anaerobic conditions, where they are able to form spores that contain the botulinum toxin. Out of the 7 exotoxins the bacterium is able to produce, four of these (A, B, E, and F) are responsible for human botulism (WHO).

All of the toxins produced by the bacterium are composed of a single polypeptide that has a light chain and a heavy chain linked together by a disulfide bond. The protein acts by preventing the release of Acetylcholine from the presynaptic vesicles in the periphery at the neuromuscular junctions and autonomic nerve terminals.

It does so by binding its heavy chain to receptors in the presynaptic terminal and is then taken up via endocytosis. Once inside the cytoplasm, the disulfide bond between the light and heavy chains is broken, allowing the light chain to interact with important vesicular fusion proteins like SNAP 25, VAMP, and Syntaxin 1. Because the light chain is an endoprotease, it cleaves segments of these

proteins before they are able to form SNARE complexes, thus inhibiting the binding of the presynaptic vesicles to the membrane, thereby preventing the exocytosis of Acetylcholine. Because Acetylcholine is not exocytosed, the postsynaptic membrane does not depolarize, and muscle contraction is not able occur.

In general, Botulinum toxin affects the intrinsic muscles of the mouth and throat region resulting in patient showing symptoms of dysphagia, dysarthria, and dysphonia, as well as, a suppressed gag reflex.

Additionally, the ocular and extraocular muscles are affected resulting in diplopia, nystagmus, ptosis, dilated fixed pupils, and extraocular muscle weakness or paresis. As toxicity progresses, symmetrical descending paralysis and ataxia can be seen. The affected patient will also have difficulty breathing, dry mucous membranes of mouth and throat and decreased or absent deep tendon reflexes (CDC, 2017). The autonomic nervous system is also involved causing a paralytic ileus advancing to severe constipation; gastric dilation; bladder distention advancing to urinary retention; orthostatic hypertension; reduced salivation and reduced lacrimation (Chan-Tack & Bartlett, 2017).

Treatment Treatment for Botulism is the quick administration of an intravenous antitoxin to prevent further spread of the toxin. However, once the toxin makes its way inside a neuromuscular junction, the site will not be able to fully return to its prior condition immediately after antitoxin administration; thus rehabilitation therapy is required to regain function of affected muscles. Early diagnosis and administration of the antitoxin is crucial to reduce the patient’s mortality rate and increase their chance of a full recovery.

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References Botulism. Centers for Disease Control and Prevention. (2017, May 08). Retrieved November 08, 2017 from https://www.cdc.gov/botulism/symptoms.ht ml Botulism. Chan-Tack, K. M., MD, & Bartlett, J., MD. (2017, May 23). (P. H. Chandrasekar MBBS, MD, Ed.). Retrieved November 08, 2017 from https://emedicine.medscape.com/article/21 3311-overview Botulism. Nigam P. K., Nigam, A., Indian J Dermatol (2010, Jan-Mar) 55 (1): 8-14 Retrieved November 07, 2017 from https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC2856357/#__ffn_sectitle Botulism. World Health Organization. (2017, Oct). Retrieved November 07, 2017 from http://www.who.int/mediacentre/factsheets /fs270/en/ Botulism. The Mayo Clinic (2017) Retrieved November 06, 2017 from https://www.mayoclinic.org/diseasesconditions/botulism/basics/treatment/con20025875 Historical notes on botulism, Clostridium botulinum, botulinum toxin, and the idea of the therapeutic use of the toxin. Erbguth, F. J. (2004, March 19). https://www.ncbi.nlm.nih.gov/pubmed/150 27048

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Cystic Fibrosis Moisés Hernández; Jonathan Vélez; Mark Miranda; María T. Ortiz; Andrés Rodríguez; Ilan Rosario; Grecia Santaella; Robert Robinson Introduction Cystic fibrosis is caused by genetic defects in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR). This chloride channel is a member of the ATP-binding cassette (ABC) family of transport proteins. Under normal circumstances, the CFTR moves chloride ions out of the cell to the mucus that covers the epithelium of different organs. The movement of chlorine ions out of the cell causes sodium ions to follow. This increases the electrolyte concentration resulting in water movement out of the cell thus making the mucous thinner. When the CFTR is mutated, it is unable to transport chlorine ions out of the cell thus reducing the effective thinning of the mucus and increasing the risk of infections.

Clinical presentation of the problem and implication of ion channels The phenotypic features for a positive diagnosis of Cystic Fibrosis includes Chronic Sino pulmonary diseases, gastrointestinal abnormalities and genital abnormalities in males. The Sino pulmonary disease includes the persistent infection with Staphylococcus aureus, Haemophilus influenza, Pseudomonas aeruginosas, Stenotrophomonas maltophilia y Burkholderia. Beside infection issues, chronic cough, chest radiograph abnormalities (bronchiectasis), obstruction of airway with air trapping and Nasal polyps.

Gastrointestinal abnormalities include the mal nutrition patterns in consequence of the ion re-distribution with hypoproteinemia.

Intestinal problems like meconium and rectal prolapse are present. Hepatic and pancreatic abnormalities are also present in patients with a positive diagnosis of Cystic Fibrosis.

This condition is dependent to an Ion Channel deficiency, which includes the poor performance of ABC transmembrane regulator proteins. This type of proteins regulates the efflux of chloride and inhibits the influx of sodium channels. This cause a regulated osmolality on lumen. If there is a mutation that cause an abnormal function of this protein, chloride ions are accumulated inside the cell and an increase influx of sodium cause dryness and thickness caused by increase mucositis and therefore its accumulation.

Treatments There is currently no cure for cystic fibrosis.

A clinician’s approach focuses on helping control the symptoms, prevent or reduce complications and making the condition easier to live with. The type and degree of severity of the condition’s symptoms differ greatly amongst patients. It’s precisely this wide range of symptoms that makes treatments more individualized, even though treatment plans contain some staple elements key for the course of action. Cystic fibrosis patients rely on therapies to help alleviate their symptoms. Some of which include airway clearance to help loosen and get rid of the thick mucus that can build up in the lungs, the use of high frequency vibrating inflatable vests, which help, loosen and thin mucus.

Some of the main medicines for cystic fibrosis patients include antibiotics to prevent and treat chest infections, bronchodilators to widen the airways and facilitate breathing, as well as steroids to treat nasal polyps. Drugs like Dornase Alfa, Hypertonic Saline and Dry Powder are common medicines used to thin mucus in the lungs. On the other hand, Ivacaftor is used limitedly (since it’s only suitable for 4-5% of patients because of its specificity to a certain mutation that causes cystic fibrosis and due to its high cost) to help reduce the levels of mucus.

Patients also depend on the use of inhaled medicines to open the airways or thin the mucus, such as antibiotics to fight lung

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infections and therapies to help keep the airways clear. Pancreatic enzyme supplement capsules and multivitamins are also used to improve the absorption of essential nutrients.

There are currently a range of experimental therapies and investigations being conducted in hopes of finding a cure for cystic fibrosis. In 2012, the first drug targeting a genetic defect in cystic fibrosis was approved by the US FDA. In 2015, the second drug to treat the condition’s main cause, which is a defective CFTR protein, was approved. The development of drugs based on CFTR modulation signals the possibility of extending the life expectancy for cystic fibrosis patients.

Current research in cystic fibrosis includes inhibitors of neutrophil elastase in lungs and PTC 124 therapy. Cystic fibrosis may present inflammation on the respiratory tract epithelial surface due to neutrophil domination. This results in a chronic amounts of the neutrophil elastase. In this case, α1antitrypsin, which is the main inhibitor of neutrophil elastase in lung was been administered and showed suppression of the elastase in the epithelial lining fluid and restored its antineutrophil elastase capacity, giving indications of a possibility to increase host defense in cystic fibrosis.

Foundation Consensus Report. The Journal of Pediatrics, 153(2), S4–S14. http://doi.org/10.1016/j.jpeds.2008.05.005 Kerem, E., Hirawat, S., Armoni, S., Yaakov, Y., Shoseyov, D., Cohen, M., ... & Elfring, G. L. (2008). Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. The Lancet, 372(9640), 719-727. http://www.sciencedirect.com/science/articl e/pii/S014067360861168X Linsdell, P. (2014). Functional architure of the CFTR chloride channel. Molecular membrane biology, 31(1), 1-16. https://www.ncbi.nlm.nih.gov/pubmed/243 41413 McElvaney, N. G., Hubbard, R. C., Birrer, P., Crystal, R. G., Chernick, M. S., Frank, M. M., & Caplan, D. B. (1991). Aerosol α1-antitrypsin treatment for cystic fibrosis. The Lancet, 337(8738), 392-394. http://www.sciencedirect.com/science/articl e/pii/014067369191167S Spoonhower, K. A., & Davis, P. B. (2016).

Epidemiology of cystic fibrosis. Clinics in chest medicine, 37(1), 1-8. http://www.sciencedirect.com/science/articl e/pii/S0272523115001367

Another experiment focused on cystic fibrosis that results from nonsense mutations in the mRNA for CFTR (cystic fibrosis transmembrane conductance regulator), used the administration of PTC124, which is a molecule designed to induce ribosomes to selectively read through premature stop codons during mRNA translation, in order to produce a functional CFTR. References Farrell, P. M., Rosenstein, B. J., White, T. B., Accurso, F. J., Castellani, C., Cutting, G. R., Campbell, P. W. (2008). Guidelines for Diagnosis of Cystic Fibrosis in Newborns through Older Adults: Cystic Fibrosis

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Malignant Hyperthermia Nicolás Bezáres Oliveras; Natalia Cárdenas Suárez; Yomar Crispín Aponte; Emily Gardner; Julio Juliá Molina; Christian Pérez Torres; Alejandra Rodríguez Alemañy; Zuleika Rodríguez Santos Introduction Malignant hyperthermia (MH) is a disease with an acute onset. Diagnosis of MH is often difficult because of its nonspecific nature and variable incidence of many of the clinical signs and laboratory findings. Estimating the likelihood of MH in a patient is not currently standardized. The disease is most commonly triggered by volatile anesthetic gases. The time between the administration of anesthetics and onset of MH may vary between anesthetic agents. This disease is potentially life threatening if not treated correctly. Treatment must be instituted rapidly on clinical suspicion of the onset. It has been linked with RYR1 gene mutations.

Clinical Presentation Symptoms of malignant hyperthermia is mainly present when the susceptible patient is placed under general anesthesia. With administration of general anesthesia medications such as succinylcholine, isoflurane, sevoflurane or desflurane, the patient will begin to show symptoms immediately or have a delayed onset. The patient presents in a hypercatabolic state with most notable symptoms including very high temperature (105°F or higher), tachycardia, dark urine due to rhabdomyolysis, rapid breathing rate, muscle rigidity and aches, increased oxygen consumption, increased carbon dioxide production and subsequent mixed acidosis.

Implication of Ion Channels In malignant hyperthermia, a triggering agent induces prolonged opening of mutated

ryanodine receptors (RYR1). This mechanism results in an uncontrolled release of calcium from the sarcoplasmic reticulum and ongoing muscle activation, as portrayed in Figure 1.

Constant activation of aerobic and anaerobic metabolism in the muscle also results in increased oxygen consumption, which leads to: 1. Hypoxia 2. Progressive lactate acidosis 3. Excessive production of CO2 4. Increased body temperature.

Depletion of ATP could also result from malignant hyperthermia, given that calcium reuptake into the sarcoplasmic reticulum and sustained muscle contraction consume large amounts of ATP. It can lead to rhabdomyolysis; given that breakdown of membrane’s integrity results in release of the contents of cells (eg, potassium, creatine phosphokinase, myoglobin) into circulation.

Treatment Dantrolene, Malignant Hypertermia’s only specific treatment, is a hydantoin that attaches to the RYR1 in a specific site in the N-terminal. This binding prevents the ionotropic channel in the sarcoplasmic reticulum to form and sodium will not be able to exit the sarcoplasmic reticulum causing the maintained contraction. Dantrolene is commonly administered as Dantrolene sodium intravenously with a dose of 2 mg/Kg every 5 minutes until the symptoms are alleviated. A maximum dose of 20 mg/Kg is recommended. If there is no improvement of the symptoms and the maximum recommended dose has been reached, another diagnostic should be considered.

Dantrolene has some side effects, but the major one is muscle weakness. This muscle weakness is dangerous because the patient with Malignant Hyperthermia could develop difficulty swallowing and/or breathing and some measures should be taken if these side effects are severe. Other side effects of taking dantrolene sodium are: drowsiness, dizziness,

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low energy, tired feeling, injection site reactions, diarrhea, constipation, nausea, vomiting, stomach pain, problems with speech, difficulty with balance or walking, headache, confusion, vision problems, insomnia, sweating, drooling, or urinating more than usual.

Another measure that could be taken is to cover the person in cold-water covered blankets. This will help reduce the patient’s temperature and prevent some of the damage that Malignant Hyperthermia can produce.

566–568, https://doi.org/10.1093/bja/aew047 Malignant hyperthermia and muscle-related disorders. Zhou J, Bose D, Allen PD, Pessah.

Miller RD, ed. Miller's Anesthesia. 8th ed.

Philadelphia, PA: Elsevier Saunders; (2015):chap 43. https://doi.org/10.1016/09608966(92)90001-M

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References Critical Roles of intracellular RyR1 calcium release channels in skeletal muscle function and disease. Hernández-Ochoa, Erick Omar, et al. (2015). Frontiers in physiology, 6, 420. https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4709859/ Dantrolene in the treatment of malignant hyperthermia: a case report. Islander, G. BMC Anesthesiology,(2014), 14(1), A7. https://www.ncbi.nlm.nih.gov/pmc/articles /PMC4139685/ Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study. Klingler, W., Heiderich, S., Girard, T., Gravino, E., Heffron, J. J., Johannsen, S., Lehmann-Horn, F. Orphanet Journal of Rare Diseases, (2014), 9(1), 8. doi:10.1186/1750-1172-9-8. https://ojrd.biomedcentral.com/articles/10.

1186/1750-1172-9-8 Identification of variants of the ryanodine receptor type 1 in patients with exertional heat stroke and positive response to the malignant hyperthermia in vitro contracture test. N. Roux-Buisson, N. Monnier, E. Sagui, A. Abriat, C. Brosset, D. Bendahan, G. KozakRibbens, S. Gazzola, J.-L. Quesada, C. FoutrierMorello, J. Rendu, D. Figarella-Branger, P. Cozonne, M. Aubert, L. Bourdon, J. Lunardi, J. Fauré; , BJA: British Journal of Anaesthesia, Volume 116, Issue 4, 1 April (2016), Pages

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Myasthenia Gravis

probably need intubation, because of inability of breathing on their own.

Rafael Amador; Andres Avilés; Andrea Devaris; Carlos E. García Ocasio; Cristal Hernández Hernández; Valeria Lozada; Paola Roman Bonet; Valeria Lozada; Henry Ruberté

Diagnosis

Introduction Myasthenia Gravis is a chronic autoimmune disease where the antibodies produced by a patient’s immune system basically start attacking itself (NIH, 2016). The antibodies prevent communication between nerves and muscles, which causes weakness of the voluntary muscles such as eyes, face, neck and limbs (MDA, 2017). The amount of weakness felt by the patient increases when there is an increase in physical activity, such as sports, running or strenuous exercise.

Since there are many diseases, which can manifest as muscle weakness, such as muscular dystrophy, neurologic diseases and even neuropathy/myopathy, it is one of the main reasons why the disease is very hard to diagnose. Myasthenia Gravis is a highly treatable disease but the difficulty in diagnosis can negatively affect a patient’s outcome.

Classification Myasthenia Gravis can be classified depending on the degree of weakness the patient presents. The most common and mild type is known as Ocular Myasthenia, in which only ocular muscle weakness is present. Mld Generalized myasthenia gravis is present when the patient not only presents eye muscle weakness, but the conditions also involves muscle weakness in other parts of the body especially in the limbs. The most severe classes of this disease also involve muscle weakness in respiratory muscles and bulbar involvement, which involves muscles that are innervated by cranial nerves on the spinal medulla. In these cases, patients will

Myasthenia Gravis can be diagnosed with various methods. First, blood tests are performed to verify for high Acetylcholine Receptor Antibody or Anti-MuSK Antibody since there is an increase in antibody production from part of the immune system (NHS, 2017). Electromyography, which is a test where small needles are inserted around the eyes, forehead and arms, is done in order to measure electrical activity in the muscles (Mayo Clinic, 2017) . The lower the electrical activity, the higher the probability that there is a problem with the interactions between nerves and muscles. Third, a CT or MRI can be performed in order to determine the thymus gland size, which is part of the lymphatic system and tends to increase when the immune system is activated since there is an increase in T lymphocyte production. Finally, an Edrophonium test (Tensilon) can also be performed. During this test a patient is given Edrophonium Chloride, and is considered positive if the muscles strengthen after the injection. The tensilon test is considered high risk due to its side effects, which include a slow heartbeat and breathing problems (MedlinePlus, 2016). This condition has a prevalence of 14-40 per 100,000 individuals in the United States. It more frequently affects females than males. Symptom onset most commonly peaks in women during their 20s or 30s and in men during their 50s or 60s.

Reports indicate that the frequency of the disorder has appeared to increase over the last several decades; but this may be because of better diagnostic methods.

Causes Ordinarily, impulses travel down a nerve, and release a neurotransmitter that fits precisely into its receptor site. In the musculoskeletal system, this neurotransmitter is known as acetylcholine and its receptor is seen on muscle cells at the neuromuscular junction.

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When acetylcholine binds to its receptor, it causes the muscle to contract. In Myasthenia Gravis, the weakness and fatigability of skeletal muscles is thought to be due to interference with neuromuscular transmission that follows binding of an acetylcholine receptor antibody. In other words, it is caused by a breakdown in the normal communication between nerves and muscles. These antibodies are produced by the immune system, and block or destroy the acetylcholine receptor. The reduction in receptor site availability, diminishes the nerve signals being received, resulting in muscle weakness. Occasionally, there are antibodies that may block the function of a protein known as muscle-specific tyrosine kinase. This is an enzyme critical for neuromuscular junction formation. When antibodies block the function of this protein, it may lead to Myasthenia Gravis.

In adults with Myasthenia Gravis, it has been noted that the thymus gland is unusually large. This has led to the assumption that the thymus gland may trigger or maintain the production of antibodies against the acetylcholine receptor. It may give incorrect instructions to developing immune cells, resulting in autoimmunity and the production of the acetylcholine receptor antibodies. Most Myasthenia Gravis patients have thymus abnormalities, with more than 50% having thymus hyperplasia, and 10-15% having a thymus tumor.

Symptoms Myasthenia gravis is characterized because it weakens voluntary skeletal muscles. It symptoms may be variable, it can be limited to certain muscles or affect a multiple group of muscles. These aggravates with the constant use of the muscle, but they usually improve with rest. However, the symptoms tend to worsen as years pass after being diagnosed. The first symptoms that appear are the ones that affect the eye muscles: dropping one or both eyelids (ptosis), and double vision (diplopia); this one improves

when one eye is closed. In about 15 percent of people with myasthenia gravis, face and throat muscles get affected, causing: face paralysis, difficulty swallowing and breathing, problem chewing, altered speaking, and fatigue (Healthline, 2016). The neck and limbs muscles may also be weaken, making it hard to hold up the head and walk. Not everyone with this disease will present all the symptoms, and the degree of the muscle weakness can vary from day to day.

Mechanisms of the condition The pathology that characterizes this disease can be described through two mechanisms that alter the presence and functionality of nicotinic Acetylcholine receptors (nAChR) localized in the postsynaptic membrane of the neuromuscular junction. In the condition of Myasthenia Gravis (MG), these receptors are targeted by the immunological system of the body, specifically by the IgG immunoglobulins of the humoral response (Drachman, 1980).

The first mechanism involves the direct interaction between the IgGs and the nACh receptors. This mechanism can be divided into three sub mechanism. The first submechanism is realized through the binding of the variable region of the IgG and the active site of the nACh receptor. This prevents the ACh from binding to the respective active site in the receptor, inhibiting the conformational change that will promote the opening of the ion channel. The second sub-mechanism involves the activation of the immunological complement system, induced by IgGs, which promotes the formation of a complex known as the Membrane Attack Complex (MAC). The MAC proceeds to disrupt the morphology of the postsynaptic membrane, damaging the synaptic folds and reducing the density of receptors. The third sub-mechanism involves the endocytosis of nAChRs due to crosslinking of receptors by the IgGs. (Conti-Fine, 2006).

The second mechanism is based on an indirect action between the IgGs and a molecule known as Muscle-specific tyrosine kinase (MuSK). This tyrosine kinase promotes the clustering of nAChRs in the postsynaptic

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membrane and the development of the morphology of said membrane (Gomez, 2010; Engel, 2013). Through these two mechanisms originates the development of Myasthenia Gravis. We can see that both pathways reduce the neuromuscular junction’s efficiency in conducting an action potential toward the muscle tissue, which leads to the clinical symptoms of this disease.

Treatment Treatments for myasthenia gravis focus mainly in relieve of symptoms caused by the disease. These treatments will not cure myasthenia gravis, but they may improve muscle contraction and muscle strength.

Cholinesterase inhibitors are medications such as pyridostigmine (Mestinon) that enhance communication between nerves and muscles by preventing the degradation of acetylcholine at the synaptic cleft. Side effects of cholinesterase inhibitors include gastrointestinal upset, nausea, and excessive salivation and sweating. In addition, corticosteroids as prednisone inhibit the immune system, limiting antibody production. As side effects, these medications may cause bone thinning, weight gain, diabetes and increased risk of some infections. Furthermore, immunosuppressant such as azathioprine (Imuran), mycophenolate mofetil (CellCept), cyclosporine (Sandimmune, Neoral), methotrexate (Trexall) or tacrolimus (Prograf) may alter your immune system, limiting the immune attack against the acetylcholine receptor. Unfortunately, side effects of immunosuppressant can be serious and may include nausea, vomiting, liver and kidney damage, gastrointestinal upset, and increased risk of infection (Mayo Clinic Staff, 2017).

References Conti-Fine, B. M., Milani, M., & Kaminski, H. J. (2006). Myasthenia gravis: past, present, and future. Journal of Clinical Investigation, 116(11), 2843.

https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC1626141/ Drachman, D. B., Adams, R. N., Stanley, E. F., & Pestronk, A. L. A. N. (1980). Mechanisms of acetylcholine receptor loss in myasthenia gravis. Journal of Neurology, Neurosurgery & Psychiatry, 43(7), 601-610. https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC490627/ Engel, A. G. (2013). Why does acetylcholine exacerbate myasthenia caused by anti‐MuSK antibodies?. The Journal of physiology, 591(10), 2377-2377. https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3678029/ Gomez, A. M., Van Den Broeck, J., Vrolix, K., Janssen, S. P., Lemmens, M. A., Van Der Esch, E., ... & De Baets, M. H. (2010). Antibody effector mechanisms in myasthenia gravis— pathogenesis at the neuromuscular junction.

Autoimmunity, 43(5-6), 353-370. https://www.ncbi.nlm.nih.gov/pubmed/203 80584 Jaime Herndon. (2016). Myasthenia Gravis.

Retrieved from Healthline: https://www.healthline.com/health/myasthe nia-gravis#overview1 Mayo Clinic Staff. (2017, August 2).

Myasthenia gravis. Retrieved from Mayo Clinic: https://www.mayoclinic.org/diseasesconditions/myasthenia-gravis/diagnosistreatment/drc-20352040 Mayo Clinic (2017). Myasthenia Gravis Causes. Retrieved from Mayor Clinic: https://www.mayoclinic.org/diseasesconditions/myasthenia-gravis/symptomscauses/syc-20352036 Mayo Clinic. (2017). Electromyography (EMG). Retrieved from Mayo Clinic: https://www.mayoclinic.org/testsprocedures/electroconvulsivetherapy/basics/definition/PRC20014183?p=1

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MDA. (2017). Myasthenia Gravis. Retrieved from MDA: https://www.mda.org/disease/myastheniagravis Meriggioli M. N., Sanders D. B. Muscle autoantibodies in myasthenia gravis: beyond diagnosis? Expert Review of Clinical Immunology. 2012;8(5):427–438. doi: 10.1586/eci.12.34 Medlineplus (2016) . Myasthenia Gravis MG. Retrieved from Medline Plus: https://medlineplus.gov/myastheniagravis.ht ml MedlinePlus. (2016). Tensilon Test. Retrieved from Medline Plus: https://medlineplus.gov/ency/article/00393 0.htm NHS. (2017) Myasthenia Gravis Diagnosis.

Retrieved from NHS: https://www.nhs.uk/conditions/myastheniagravis/diagnosis/ Sultan Qaboos Medical Journal. (2012) “Misdiagnosis of Myasthenia Gravis and Subsequent Clinical Implication: A case report and review of literature”. Retrieved from NCBI: https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3286704/

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