Ion Channels: Implication in Pathological Conditions

UNIVERSIDAD CENTRAL DEL CARIBE SCHOOL OF MEDICINE Bayamón Puerto Rico

NEUROSCIENES COURSE APRIL 2019

Ion Channels: Implication in Pathological Conditions

PRESENTATIONS OF FIRST YEAR MEDICAL STUDENTS (Second semester 2018) -----

Summary of Presentations -----

Content Schizophrenia ..................................................... 2 Creutzfeldt-Jakob Disease .............................. 6 Guillain-Barré Syndrome ............................ 10 Hypocalcemia .................................................. 14 Esclerosis Lateral Amiotrófica .................. 17 Huntington’s Disease .................................... 21 Alzheimer’s disease ....................................... 25 Myotonia Congenita: Thomsen’s and Becker’s Disease ............................................. 29 Parkinson’s Disease....................................... 33

Dr. Legier V. Rojas, Ed. Acknowledgments: Thanks for suggestion of Crystal M. Rivera Pérez, MSI and for manuscript edition to Lyanne Colón Maldonado.

compulsive disorder, social phobia, panic attacks, and certain personality disorders, are also risk factors. Psychosocial risk factors, on the other hand, may also present as early manifestations of the illness. These include social adjustment difficulties in childhood and adolescence, delayed childhood development (motor, cognitive, or social), declining school performance, and unemployment.

(Compton, 2005).

According to the World Health Organization (WHO), schizophrenia affects more than 23 million people worldwide. The WHO reports that there are more reported cases amongst males (12 million) than females (9 million), suggesting varying incidence propensity based on gender. Male patients also present with symptom onset at an earlier age (Fact Sheets: Schizophrenia, 2018).

However, this condition has received a lot of attention across all healthcare professions due of its debilitating symptoms. Specifically, the considerable impairments to patients’ educational and occupational performance make 40-60% of them more likely to die at an early age (Thomas, 2013).

Schizophrenia By Orlando Arce, Gina Cardona, Christian López-Ashby, Natalia Ramírez, Fabiola Ruiz, Fernando Rivera, Calé Pagán, William Ríos

Introduction Schizophrenia is a widely discussed psychological disorder, characterized by abnormal behaviors and altered understandings of reality. The mechanism of disease development is also widely debated, but mostly centered on molecular ionic imbalances. The most commonly of these mechanisms correlates overstimulation and misfiring of dopaminergic receptors with the positive and negative affective symptoms present in these patients. (Schizophrenia, 2018).

Epidemiology Risk factors for schizophrenia are multifactorial. Studies have found that risk factors associated with the development of this condition include genetic, behavioral, and environmental influences that operate both individually and synergistically (Fact Sheets: Schizophrenia, 2018).

Family history of schizophrenia, older paternal age, microdeletions of chromosome 22q11, prenatal exposure to pathogens (such as influenza and toxoplasmosis), prenatal exposure to maternal stress, Rh incompatibility, and childhood infections of the central nervous system are some of the biological or genetic risk factors. Psychopathological conditions, including obsessive-

Clinical Presentation As mentioned above, schizophrenia is characterized by its positive, negative, and cognitive symptoms. Positive symptoms are new features, which have no physiologic or normal counterpart. Delusions, hallucinations, fragmented pattern of thinking, and grossly disorganized or abnormal motor behavior (including catatonia) are considered positive symptoms, which are commonly referred to as psychotic symptoms. In contrast, negative symptoms are represented by a diminution in what is considered normal 2

behavior or emotions. Reduced emotional expression, avolition, alogia, and anhedonia are negative symptoms frequently noted in these patients.

Cognitive symptoms associated with this disorder affect memory and learning and are more difficult to notice. Diminished ability to learn and use new information and trouble focusing are considered cognitive symptoms (American Psychiatric Association, 2013).

Patients with schizophrenia may also present with additional limitations and comorbidities, like substance-abuse disorders (Harrison, Charles & Britt, 2015). Patients with schizophrenia are also at a higher risk for anxiety, depression, obsessive-compulsive disorder, and panic, which can worsen the symptoms in the disorder (Dixon, Postrado, Delahanty, Fischer & Lehman, 1999).

To diagnose schizophrenia, patients must present with at least two of the following: delusions, hallucinations, fragmented pattern of thinking, and disorganized speech or abnormal motor behavior (including catatonia), and negative symptoms. At least one of the symptoms must be delusions, hallucinations, or disorganized speech.

The final requirement is that the symptoms must persist for at least six months (American Psychiatric Association, 2013).

active in the prefrontal cortex and the hippocampus of the brain, facilitating key neurological functions like language formation and memory formation. On the other, dopamine has been identified as a partial regulator of potassium channel activity, suggesting its excess and dysregulation might also contribute to symptom development, although the precise mechanism has not been identified (Carr, 2016).

At the neuronal level, potassium channels help to control when the cells produce an action potential and stimulate adjacent neurons. Specifically, these channels allow the passive passage of potassium ions out of the cell. In the CNS, the chemical messenger dopamine partly regulates this process by binding to D2 cell surface receptors and increasing potassium conductance across cells, thus exerting an inhibitory influence on neuronal tissue. In other words, dopamine increases potassium passage to the outside of the cell, generating a hyperpolarizing effect that sends the neuron into a refractory period and prevents further stimulation (Einhorn, 1991).

Recent studies suggest that mutations in the KCNH2 gene generate the potassium channel isoform KCNH23.1, which is characterized by fast deactivation that results in a decreased repolarization magnitude and refractory period length. A decrease in these two variables allows neurons to become overactive, leading to the development of positive affective symptoms typical schizophrenia (Carr, 2016).

Molecular Lesion The cause of schizophrenia is still largely unknown. However, mutations in the KCNH2 gene that encodes for a large family of potassium channels, as well as excess dopamine in the CNS have been linked to the development of this condition. On one hand, the channels encoded by the KCNH2 gene are primarily

Treatment Pharmacological treatment is usually centered on the administration of antipsychotic drug, the most common of 3

which is Clozapine (Schizophrenia, 2018).

These medications present affinity for 5HT D2 receptors, specifically functioning as antagonists for dopaminergic receptors found in mesolimbic system (Sullivan et al., 2015). Blockage of these receptors alleviates the positive symptoms that patients present in this disorder, although the specific mechanism is not understood (Schizophrenia, 2018).

Once these bioactive drugs bind to the dopamine receptor, dopamine can no longer activate its G protein pathway, thus preventing it from achieving its general function of regulating potassium channel activity (Sullivan et al., 2015).

Interestingly, an increase in dopamine blockage at the level of D2 receptors also increases GABA activity, decreasing the activity of overactive neurons (Belousov, 2019).

from https://www.physiology.org/doi/full /10.1152/jn.1997.78.2.674 Carr, Gregory V, et al. “KCNH2-3.1 Expression Impairs Cognition and Alters Neuronal Function in a Model of Molecular Pathology Associated with Schizophrenia.” Molecular Psychiatry, U.S. National Library of Medicine, Nov. 2016, www.ncbi.nlm.nih.gov/pmc/articles/ PMC4980295/ Compton, M.T. Risk Factors and Risk Markers for Schizophrenia. Medscape.

2005;10(2).

Dixon, L., Postrado, L., Delahanty, J., Fischer, P. J., & Lehman, A. (1999). The association of medical comorbidity in schizophrenia with poor physical and mental health. The Journal of nervous and mental disease, 187(8), 496-502.

Einhorn, L., Gregerson, K., & Oxford, G. (1991). D2 dopamine receptor activation of potassium channels in identified rat lactotrophs: Whole-cell and single-channel recording. The Journal of Neuroscience, 11(12), 37273737. doi:10.1523/jneurosci.11-1203727.1991 Fact Sheets: Schizophrenia. World Health Organization. https://www.who.int/newsroom/factsheets/detail/schizophrenia Published April 9, 2018. Accessed March 25, 2019.

Harrison, C., Charles, J., & Britt, H. (2015).

Comorbidities and risk factors among patients with schizophrenia.

Australian family physician, 44(11), 781.

Patel, K. R., Cherian, J., Gohil, K., & Atkinson, D. (2014). Schizophrenia: overview and treatment options.

Pharmacy and Therapeutics, 39(9), 638.

Conclusion Schizophrenia is still considered one of the most complex enigmas in neuroscience. Because of the severity of its symptoms and the drastic effect it has on the lives of patients affected, its molecular and ionic basis should be studied in great detail to provide better quality of care to those affected.

References American Psychiatric Association.

Diagnostic and Statistical Manual of Mental Disorders. Fifth ed.

Washington, DC: American Psychiatric Association; 2013. Schizophrenia and other psychotic disorders; pp. 89–122.

Belousov, A. B., & Van Den Pol, A. N. (2019, March 19). Dopamine Inhibition: Enhancement of GABA Activity and Potassium Channel Activation in Hypothalamic and Arcuate Nucleus Neurons. Retrieved 4

Schizophrenia. (2018, April 10). Retrieved from https://www.mayoclinic.org/diseases -conditions/schizophrenia/diagnosistreatment/drc-20354449 Sullivan, L. C., Clarke, W. P., & Berg, K. A. (2015). Atypical antipsychotics and inverse agonism at 5-HT2 receptors.

Retrieved from https://www.ncbi.nlm.nih.gov/pmc/a rticles/PMC5543701/#S6title Thomas, S. P. (2013). World Health Assembly Adopts Comprehensive Mental Health Action Plan for 2013– 2020. Issues in Mental Health Nursing,34(10), 723-724. doi:10.3109/01612840.2013.831260

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Creutzfeldt-Jakob disease has a distinctive clinical course and gray matter pathology. This disease is transmissible and induced by an abnormal form of the prion protein that is resistant to physical and chemical inactivation.

paper on the new diseases that he concluded that Creutzfeldt's case refers to a “nosologically very closely connected if not identical affection”.

However, even of Jakob's five cases, only two are what we understand today as CJD. C. L. Masters was able to reexamine the original slide preparations of Jakob's cases still preserved in the archives of the department of neurology at the University of Hamburg, and he found that only the third and fifth of Jakob's cases fall within the present diagnostic criteria. Five of six subsequent cases published from Jakob's laboratory, however, under his supervision, showed the typical changes of spongiform encephalopathy.

History

Statistics

Creutzfeldt-Jakob Disease By Daniel Álvarez, Grecia Arroyo, Daniela Ortega, Sasha Ortiz, Nikitas Rodríguez, Néstor Suria, Beltrán Torres, Abraham Torres

Introduction

Creutzfeldt-Jakob Disease (CJD) is a sporadic disease that occurs worldwide, including the United States. It affects people roughly at a rate of 1 to 1.5 cases per 1 million population per year, although rates a little higher of two cases per million are not unusual. In the United States, there are about 350 cases per year.

The risk of this disease increases with age, and in persons aged over 50 years of age. On the other hand, CJD tends to affect younger individuals, with an average onset of around 28 years of age, compared to sporadic CJD, which tends to affect middle-aged and elderly individuals. However, both progress with the individual’s age.

In 1921, the Hamburg neuropathologist Alfons Maria Jakob (1884-1931) published three papers, “Über eigenartige Erkrankunbgen des Zentralnervensystems mit bemerkenswertem anatomischen Befunde” (“On peculiar illnesses of the central nervous system with remarkable anatomical findings”). In these, and in a paper published in 1923 (ref. 4), he described the cases of two men and three women aged between 34 and 51 who progressively developed disturbances of motor functions, speech and emotion. All of them with obvious personality changes and loss of memory; eventually they were unable to move, stand or speak, and died in dementia between a few weeks and a year after the start of more serious symptoms.

In 1920, the Breslau neurologist Hans Gerhard Creutzfeldt (1885-1964) had described “a peculiar focal illness of the central nervous system” of the patient Berta E.5. Jakob writes in his second

Biochemistry behind CJD Creutzfeldt Jakob’s is understood to be caused by what we call prions.

Prions are proteins that we can already find within our body, particularly in the nervous system, especially in the cell membrane of neurons. The function of 6

these proteins is not fully understood but it is believed they play a role in the uptake of copper into the cell and they might help in the transmission of action potentials.

We can become infected iatrogenically, or by consuming infected ailments. Upon infection with a mutant Prion this protein will induce a change in the normal prion proteins in the surface of the neurons of the CNS. A mutant prion protein is characterized by containing a large amount of beta platelet sheets as opposed to the normal prion protein (PrP) which is mainly made of alpha helices. The mutant form is resistant to proteases, which are proteins within the body in charge of degrading other proteins for optimal homeostasis; if this system fails, accumulation of the defective PrP proteins will occur within the nervous system and lead to neuronal apoptosis.

Eventually the cell death within the brain will leave cysts causing the patient to suffer from loss of higher brain functions.

The result is what we know as spongiform encephalopathy as the brain is left looking like a sponge secondary to the holes left behind by apoptosis.

As the disease progresses, mental symptoms worsen. Most people eventually lapse into a coma. Heart failure, respiratory failure, pneumonia or other infections are generally the cause of death. Death usually occurs within a year.

How is it transmitted?

Creutzfeldt-Jakob disease may be acquired from infected individuals through bone graft or neurologic transplants. Thus, it is a disease that usually has an iatrogenic etiology. This disease, however, can also be due to an inherited mutation of proteins in the human body. It is not communicable by blood or body fluids.

Diagnosis A diagnosis of Creutzfeldt-Jakob disease (CJD) is confirmed only with a brain autopsy. However, usually the diagnosis can be made based on medical history, symptoms and a series of tests.

Early in the disease, a nervous system and mental examination will show memory and thinking problems. Later in the disease, a motor system examination may show abnormal reflexes, increase in muscle tone, strong startle response and muscle weakness. Additionally, an eye exam may show areas of blindness that the person is not even aware off.

Tests used to diagnose this condition may include: 1. Blood tests to rule out other forms of dementia and to look for markers that sometimes occur with the disease 2. CT scan of the brain 3. Electroencephalogram (EEG) 4. MRI of the brain 5. Spinal tap to test for a protein called 14-3-3

Signs and Symptoms Creutzfeldt-Jakob disease is marked by rapid mental deterioration, usually within a few months. Initial signs and symptoms typically include: · Personality changes · Anxiety · Depression · Memory loss · Impaired thinking · Blurred vision or blindness · Insomnia · Difficulty speaking · Difficulty swallowing · Sudden, jerky movements

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Treatment Although there is no known cure for this condition, different medications have been tried to slow the disease, such as antibiotics, blood thinners, antidepressants, etc. However, none works well. For this reason, doctors often decide to help alleviate the pain and other symptoms in order to help the patients feel more comfortable.

chlorine for an hour minimum and then wash in a normal fashion after each use.

6. Any instrument that has come in contact with the person should be soaked in undiluted chlorine for an hour, minimum, and then autoclaved (pressure cooker) to be sterilized with distilled water at 132134 degrees Celsius for at least an hour.

Ongoing Research Currently there are various research projects directed towards understanding different aspects of Creutzfeldt-Jakob disease (CJD) such as its methods of transmission, abnormal prion formation, its replication patterns, and various forms treatment. Including the development of non-invasive methods of identification. One of the treatments being tested is the use of the anti-malaria drug Quinacrine, which has been shown to clear abnormal prion proteins from cell cultures.

Previously the only way to study the abnormal prion proteins was solely through bovine variants. Now modified pluripotent stem cell can be infected with the CJD prions of CJD patients [5], making it easier for researchers to analyze modes of transmission. Finally, a team of researchers [4] have developed called protein misfolding cyclic amplification assay in order to identify variant CJD.

Safety and Precautions

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There are different ways in which the transmission of CJD can be kept at an already low risk. For example, if a person has any suspects of having acquired CJD or has a confirmed diagnostic of CJD, this person should not donate blood, organs or tissues. This applies to people that have an increased risk due to family history, a dura mater graft, amongst other factors. It is important to understand that normal cleaning and sterilization procedures practiced in a typical household like cooking, cleaning, and/or boiling do not destroy prions. The following precautions should be taken in order to avoid the spreading of the disease: Always wear gloves when working with any tissue sample, fluids, or covering up a wound.

Any cuts or lesions should be covered with waterproof dressings.

Handle sharp instruments contaminated with the person’s blood with care and avoid cutting or stabbing oneself mistakenly Use face protection if there is a possibility of unwanted spurts of contaminated fluids like blood or CSF Use disposable bed sheets and other disposable cloth-like pieces for contact with the person. If cloth are indispensable, soak them in undiluted

References Creutzfeldt-Jakob Disease Fact Sheet.

(2018, May). Retrieved March 24, 2019, from https://www.ninds.nih.gov/Disorder s/Patient-Caregiver-Education/FactSheets/Creutzfeldt-Jakob-DiseaseFact-Sheet Creutzfeldt-Jakob Disease. Retrieved March 25,2019 from 8

https://www.mayoclinic.org/eses/diseases-conditions/creutzfeldtjakob-disease/diagnosistreatment/drc-20371230 Treatment for CJD (2018, June) https://www.nhs.uk/conditions/cre utzfeldt-jakob-diseasecjd/treatment/ ScienceDaily. (2019). New research could lead to blood test to detect Creutzfeldt-Jakob disease. [online] Available at: https://www.sciencedaily.com/relea ses/2016/12/161221152752.htm [Accessed 25 Mar. 2019] ScienceDaily. (2019). Brain cell advance brings fresh hope for Creutzfeldt-Jakob disease therapies: Experts have developed a way of studying the disease in the lab using brain cells derived from human stem cells. [online] Available at: https://www.sciencedaily.com/relea ses/2017/11/171120111306.htm [Accessed 25 Mar. 2019].

Centers for Disease Control and Prevention. Creutzfeldt-Jakob Disease, Classic (CJD). [online] Available at: https://www.cdc.gov/prions/cjd/occ urrence-transmission.html [Accessed 25 Mar. 2019].

European Centre for Disease Prevention and Control. Facts about variant Creutzfeldt-Jakob disease. [online] Available at: https://ecdc.europa.eu/en/vcjd/fact s [Accessed 25 Mar. 2019].

Masters, C. L. & Gajdusek, D. C. in Recent advances in Neuropathology Vol. 2 (eds Smith, W. T. & Cavanagh, J. B.) 139-163 (Churchill Livingstone, Edinburgh, 1982).

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By Alejandra V. García Ferré, Julián Maldonado Alers, José J. Hermina Pérez, Crystal M. Rivera Pérez, Stefan A. Lugo, Camille L. Anderson Díaz, Luis A. Vélez Figueroa, Karla M. García Ortiz, Jesús A. Merced Román

In addition to muscle weakness, common symptoms of GBS include tingling or prickling sensations in fingers, toes, ankles or wrists, unsteady walking or inability to walk or climb stairs, and difficulty with eye or facial movements (including speaking, chewing or swallowing) (NIH, 2018). Patients with GBS could also experience severe lower back pain, difficulty breathing, loss of bladder control, fast heart rate, and paralysis.

Introduction

Statistics

Guillain-Barré Syndrome

Guillain-Barré syndrome (GBS) is an infrequent neurological disorder in which the individual’s immune system attacks sections of its peripheral nervous system. GBS can vary in severity, ranging from the patient experiencing brief episodes of weakness and tingling to having paralysis and being unable to breathe independently. Most of the individuals affected with GBS eventually recover, although some may continue to experience some degree of weakness. GBS can affect anyone at any age with both sexes being equally affected. (Mayo Clinic, 2018).

GBS is a rare disorder that affects 1 in every 100,000 people every year worldwide. (Mayo Clinic, 2018).

Causes The exact cause of GBS is not known. Up until now, GBS is considered an autoimmune disease that develops from a bacterial or viral infection, which attacks the peripheral nervous system (PNS), such as Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus and Mycoplasma pneumoniae (Kuwabara, 2004). Other factors such as surgery and vaccinations have been linked also to an increased risk of suffering this disease (NIH, 2018).

Symptoms The first symptom experienced by GBS patients is a tingling sensation that usually begins in the feet and legs, and spreads gradually to the upper body and arms. (Mayo Clinic, 2018) These symptoms can progress very rapidly. The most significant weakness can occur within 2-4 weeks after first symptoms appear. In many reported cases, the disease has become serious in just a few hours. As the syndrome progresses, muscle weakness can evolve into paralysis. (Mayo Clinic, 2018)

Pathophysiology GBS is a heterogeneous syndrome with variant forms. The two major forms are acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and acute motor axonal neuropathy (AMAN), which have a different pathophysiology (Vriesendorp, 2018) (Figure 1).

In AIDP and AMAN there is an immune response towards the peripheral nerve components known as molecular mimicry (Vriqesendorp, 2018). Molecular mimicry “occurs when similarities 10

between foreign and self-peptides favor an activation of autoreactive T or B cells by a foreign-derived antigen in a susceptible individual� (Rojas, et al., 2018). In AIDP, the immune system reacts against target epitopes in Schwann cells or myelin resulting in demyelination (Kiwabara, 2004). Those target epitopes have not yet been identified, but they could be myelin proteins (P0, P2 and PMP22) and node of Ranvier proteins (gliomedin, contactin, TAG-1, moesin and neurofascin) (Willison, et al., 2016). In AMAN, the immune system reacts against the gangliosides GM1, GM1b, GD1a and GalNAc-GD1a that are expressed on the motor axolemma (Kiwabara, 2004). This type of neuropathy causes axon degeneration (Kiwabara, 2004).

evaluates the patient, deep tendon reflex in the legs (knee jerk) are usually lost. In order to confirm GBS, spinal tab (lumbar puncture) is performed to extract cerebrospinal fluid (CSF). CSF test for GBS patients look for high levels of certain proteins such as albumin but low levels of immune cells. In addition, electromyography and nerve conduction studies are performed in order to access muscle activity and conduction velocity.

Electromyography is a study when the physician inserts thin needles electrodes into the muscles to measure muscle activity. In GBS patients, there are low conduction velocity and muscle activity due to neurons demyelination.

Treatments There is no cure for GBS, however, there are two main treatment that have proven to reduce the severity of the illness, and speed recovery (Mayo Clinic, 2018). The most commonly used is the administration of intravenous immunoglobulins. This treatment is made from donated blood from healthy patients with antibodies that can prevent the harmful antibodies damaging the myelin in the patient (Mayo Clinic, 2018). The second possible course of treatment is a plasma exchange, or plasmapheresis. This option involves the removal of blood from a vein and filtration with a machine connected to the patient. This eliminates the antibodies that are attacking the nerves from the system (NHS, 2018).

Other treatments, such as breathing machines, painkillers, feeding tube and urinary catheter may be needed in particular cases.

Figure 1. Major Guillain-BarrĂŠ syndrome subtypes (From Willison, et al., 2016).

Diagnostic GBS could be difficult to diagnose in its earliest stages due to the first symptoms presented. Symptoms can be confused with others neurological disorders. However, when the clinical scenario gets worse, the physician could suspect this type of neurological disorder.

In the HPI, a history of infection illness appeared and when the physician 11

Prognosis

PNS resulting in a polyneuropathy or general degeneration of peripheral nerves (Rubin, 2019). The two main types of GBS (AMAN and AIDP) have different pathophysiology in which AIDP reacts against target epitopes in Schwann cells or myelin resulting in demyelination and in AMAN, the immune system reacts against specific gangliosides. As previously stated, there is no cure for the condition discussed. From the two most utilized treatments, the administration of intravenous immunoglobulins (IVIG) which is the treatment via donated blood from healthy patients with antibodies that can prevent the harmful antibodies damaging the myelin in the patient is the most frequently used. Estimated prognosis depends on severity and type of the syndrome.

Early in the development of GBS, the Schwann cells compensate for the loss of myelin by making more. This process is referred to as remyelination. However, over time, the PNS’s Schwann cells are unable to maintain a steady rate of remyelination and there is an irreversible damage to these cells. The fact that there is a lack of myelin sheath results in the nerve conductions being slow and partly ineffective (NIH, 2018). As mentioned previously, there is first ankle and muscle weakness followed by loss of reflexes in the patellar, arm, etc. In severe cases the nerves that innervate the respiratory system, such as the diaphragm, can be affected which can lead to death. A positive prognosis for GBS relies mostly at which time in the development of this pathology it is resisted with treatment.

According to the NIH, approximately 70% of patients with GBS experience a full recovery if careful and intensive treatments are provided (NIH, 2018).

Specifically, those patients with generally poor prognosis seem to benefit with more intensified treatments (van Doorn, 2013).

What normally varies is the amount of time it takes for patients to stabilize after initial symptoms – this can range from weeks, months, and up to several years (NIH, 2018). Approximately 15% experience an ongoing weakness due to this disease and 3% of patients with can experience a relapse after treatment is completed (NIH, 2018).

References “Guillain-Barré Syndrome Fact Sheet.”

National Institute of Neurological Disorders and Stroke, U.S. Department of Health and Human Services, www.ninds.nih.gov/Disorders/Patient -Caregiver-Education/FactSheets/Guillain-Barre-SyndromeFact-Sheet#3139_9 Kuwabara, S. (2004). Guillain-Barré syndrome: Epidemiology, pathophysiology and management.

Retrieved March 24, 2019, from https://www.ncbi.nlm.nih.gov/pubme d/15018590 Mayo Clinic. (2018, May 18). GuillainBarre syndrome - Diagnosis and treatment - Mayo Clinic. Retreated March 22, 2019, from https://www.mayoclinic.org/diseases -conditions/guillain-barresyndrome/diagnosis-treatment/drc20363006

Conclusions GBS occurs via myelin acute inflammation formed by Schwann cells in the PNS occurring after infectious illnesses such as a gastrointestinal or respiratory illness. The inflammation impairs the transmission of axons in the 12

NHS website. (2018, October 3).

Treatment for Guillain-Barre.

Retreated March 22, 2019, from https://www.nhs.uk/conditions/guill ain-barre-syndrome/treatment/ Rojas, M., Restrepo-Jiménez, P., Monsalve, D. M., Pacheco, Y., Acosta-Ampudia, Y., Ramírez-Santana, C., Anaya, J. (2018, December). Molecular mimicry and autoimmunity. Retrieved March 24, 2019, from https://www.ncbi.nlm.nih.gov/pubme d/30509385 Rubin, M. (n.d.). Polyneuropathy - Brain, Spinal Cord, and Nerve Disorders.

Retrieved from https://www.merckmanuals.com/enpr/home/brain,-spinal-cord,-andnerve-disorders/peripheral-nervedisorders/polyneuropathy Van Doorn, P. A. (2013) “Diagnosis, Treatment and Prognosis of GuillainBarré Syndrome (GBS).” Presse Medicale (Paris, France: 1983), U.S. National Library of Medicine. www.ncbi.nlm.nih.gov/pubmed/2362 8447 Vriesendorp, F. J., MD. (n.d.). GuillainBarré syndrome: Pathogenesis.

Retrieved March 24, 2019, from https://www.uptodate.com/contents /guillain-barre-syndromepathogenesis#H2 Willison, H. J., Jacobs, B. C., & Doorn, P. A. (2016). Guillain-Barré syndrome. The Lancet,388(10045), 717-727. https://www.thelancet.com/journals/ lancet/article/PIIS01406736(16)003391/fulltext#seccestitle40

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ectodermal and cardiac changes; it may also affect the smooth muscles, and mental status of the patient.

Hypocalcemia

Causes

By Keishla M. Figueroa, Yarely Gierbolini, Eduardo J. Malavé Santiago, Alejandro Jiménez, Monique Huertas, Manuel Del Río; Ricardo Pérez, Andrea Soto

Hypocalcemia is a disease in which patients suffer the effects of low levels of free calcium in blood. The low levels of calcium may be due to defective parathyroid glands, which are producing low levels of parathyroid hormone (PTH).

Without an adequate supply of parathyroid hormone (PTH), the body will not be able to absorb calcium from the kidney’s ascending loop of Henle, intestines or bone. Being unable to respond to normal levels of parathyroid hormone (pseudohypoparathyroidism) also causes hypocalcemia, which is mainly due to defective PTH receptors. Having low levels of magnesium and vitamin D will also present effects of hypoparathyroidism. Vitamin D is mainly obtained from sunlight and from our diet, but it could also be the case that if a patient suffers from renal failure, vitamin D will not be able to be synthesized in renal tubules. Iatrogenic effects of some medications like rifampin, anticonvulsants, bisphosphonates, corticosteroids, chloroquine and plicamycin can also cause hypocalcemia (Cooper, Gittoes, 2008).

Introduction Our body's nerve reactions and muscle function are dependent upon the proper exchange of electrolyte ions outside and inside cells. When the exchange or levels of ions are affected, these changes are reflected in the function of various tissues and cells.

Hypocalcemia is an electrolyte imbalance and is indicated by a low level of calcium in the blood (Chemocare, 2019). The normal adult range for calcium in blood is 2.1–2.6 mmol/L or 8.5 to 10.3 mg/dL. Levels less than 2.1 mmol/l are defined as hypocalcemia. Calcium is important for maintaining healthy bones and teeth, and for normal muscle and nerve function.

Over 99% of total body calcium is found in teeth and bones and 1% circulates in the blood. About 40% of the calcium in blood is bound to protein, mainly albumin, which acts as a reserve source of calcium for the cells but has no active function in the body. Only ionized calcium (unbound) affects the body’s functions.

Thus, hypocalcemia causes problems only when the level of unbound calcium is low.

Therefore, an accurate measurement of the ionized calcium level is the best assessment of hypocalcemia.

Hypocalcemia may result from a problem with the parathyroid glands, diet, kidney, or certain drugs. Clinical features associated with hypocalcemia are neuromuscular irritability, neurological,

Implication of ion channels The low levels of calcium in hypocalcemia are detrimental for the functioning of calcium channels. Voltagegated calcium channels are the primary mediators of depolarization-induced calcium entry into neurons for neurotransmitter release and muscle contraction. Given these important physiological processes, it can be assumed that neuromuscular excitability 14

is reduced. However, the effect of low calcium levels is paradoxical given that it is presented clinically by tetany, seizures and bronchospasm. By having low ionized calcium levels in extracellular fluid, the permeability of the neuronal membrane to sodium is increased, causing a progressive depolarization and increased action potentials. This physiological effect increases the excitability of the neuron, which explains these clinical manifestations (Simms, Zamponi, 2014).

requires treatment with intravenous calcium. Intravenous calcium gluconate is administered for over ten minutes.

Calcium gluconate is the preferred form of intravenous treatment because calcium chloride is more likely to cause irritation.

Most of the time, this only offers temporary relief and continuous administration is required in order to prevent recurrence of hypocalcemia.

Calcium supplements should be given concurrently and if the patient is deficient in parathyroid hormone, calcitriol should also be given (Rao, Shoback, 2018).

In the case of vitamin D deficiency, oral calcium, vitamin D3 and D4 are suggested. This can easily be found in vitamin D supplements, which are combined with calcium and generally supply 400 IU of vitamin D daily. This is recommended in cases of people with mild hypocalcemia. However, when vitamin D deficiency becomes symptomatic, higher doses are suggested, such as 50,000 IU weekly for eight weeks of 300,000 IU intramuscularly every trimester.

In the case of hypoparathyroidism, this dosage is unproductive given that parathyroid hormone is necessary to convert 1,25-dihydroxyvitamin D. Therefore, calcitriol and alfacidol is needed at a starting dose of 0.5 Îźg of calcitriol or 1 Îźg of alfacalcidol and incrementing doses until serum calcium levels are within reference range. The main risk for this option is development of nephrocalcinosis because of hypercalciuria. This should be corrected by using thiazide diuretics to decrease urinary calcium excretion.

If hypocalcemia is being caused by malabsorption, the underlying problem must be treated in order to properly treat this case of hypocalcemia (Cooper, Gittoes, 2008).

Clinical presentation Calcium is an important ion in the human body for blood clotting, muscle contraction, nerve impulses, and cell metabolism. In order for the symptoms of hypocalcemia to be presented by the patient, the blood calcium levels must decrease less than 8.5 mm/dL. However, hypocalcemia can be asymptomatic. This condition, chronic or acute, can be life threatening. Symptoms of hypocalcemia can be subdivided in different categories (neuromuscular, mental status, epidermal, ophthalmic, cardiovascular), and most commonly include paresthesia, muscle spasms, cramps, tetany, circumoral numbness, and seizures.

Hypocalcemia can also present with laryngospasm, neuromuscular irritability, cognitive impairment, personality disturbances, prolonged QT intervals, electrocardiographic changes that mimic myocardial infarction, or heart failure.

(Fong J, Khan A, 2012).

Treatments The treatment for hypocalcemia depends on the cause of the condition, speed of onset, biochemical severity, and clinical severity. Acutely presenting hypocalcemia (< 1.9 mmol/l) presents with neuromuscular irritability and it 15

Simms, B. A., & Zammponi, G. W. (2014).

Neuronal Voltage-Gated Calcium Channels: Structure, Function, and Dysfunction. Retrieved from: https://doi.org/10.1016/j.neuron.201 4.03.016 Trinidad B, Pengchang H, Jiong S. (2015).

Hypocalcemia-Induced Seizure. doi:10.1177/1759091415578050

Conclusion Hypocalcemia is a disease that is distinguished by a deficiency of calcium in the bloodstream. When your serum calcium levels are too low your nervous system and muscles cannot function properly. The main symptoms hypocalcemia will demonstrate are neuromuscular irritability, neurological, ectodermal and cardiac changes. The best way to treat this deficiency is to administer intravenous calcium gluconate. Most of the time this treatment is only temporary, and the patient needs to be treated regularly to keep appropriate calcium blood levels.

References Cleveland Clinic Cancer. (2019).

Chemocare. Retrieved from http://chemocare.com/es/default.asp x Cooper MS, Gittoes NJ (2008). Diagnosis and management of hypocalcaemia.

Retrieved from https://www.ncbi.nlm.nih.gov/pmc/a rticles/PMC2413335/ Fong J, Khan A. (2012) Hypocalcemia: Updates in diagnosis and management for primary care. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/a rticles/PMC3279267/ Murphy E, Williams GR. (2009) Hypocalcaemia. Medicine; 37(9):4658.

Rao MN, Shoback DM. (2018) Hypocalcemia. Retrieved from: https://www.ncbi.nlm.nih.gov/books /NBK344077/ Schafer AL, M.D. and Shoback DM, M.D. (2016) Hypocalcemia: Diagnosis and Treatment. From: Retrieved from: https://www.ncbi.nlm.nih.gov/books /NBK279022/ 16

didácticas para lograr una transmisión efectiva de la información.

Esclerosis Lateral Amiotrófica

Mecanismo Estudios han demostrado que la causa más común de ELA es una mutación en un gen que codifica para una enzima antioxidante conocida como superoxide dismutase 1 (SOD1). Mutaciones en esta enzima provocan que la molécula no pueda alcanzar su estructura funcional, evitando que esta trabaje eliminando desperdicios metabólicos que pueden dañar o afectar el funcionamiento de la célula (Zarei, S. et al, 2015). Hasta el día se han encontrado más de 100 mutaciones diferentes de SOD1 que han sido relacionadas con ELA heredado. La gran mayoría de las mutaciones cambian la secuencia de amino ácidos en una sola posición. (ALS Association, 2019) Existen múltiples propuestas en relación a la patogénesis de ELA, entre estas se incluye: la excito-toxicidad de glutamato, anormalidades en las mitocondrias, problemas en el transporte axonal y estrés por radicales oxidativos libres. La excito-toxicidad de glutamato se debe a que la mutación en SOD1 provoca que la cantidad de transportadores de glutamato presentes en las células astrogliales sea mínima. Estos transportadores son los que remueven el glutamato del espacio sináptico, por ende, existirá mayor cantidad de glutamato presente, mayor sobre-estimulación de los receptores de glutamato y una degeneración neuronal debido a la excito-toxicidad. La segunda propuesta son las anormalidades en las mitocondrias espinales causadas por la mutación en SOD1, esto provocará funcionamiento anormal en la producción de ATP, problemas en la homeostasis de calcio, problemas en el transporte axonal mitocondrial y apoptosis. La homeostasis

By Isabel Colón, Héctor García, Jorge Lázaro, Diego Ortiz, Nicole Pabón, Cayra Ramírez, Coral Reyes, Fernando Viera

Introducción Esclerosis Lateral Amiotrófica (ELA), también conocida como ALS por sus siglas en inglés, es un trastorno motor caracterizado por la pérdida progresiva de las neuronas motoras superiores e inferiores a nivel espinal. Es considerado una enfermedad neurodegenerativa que afecta las neuronas motoras con una incidencia de 1 sobre 100,000 personas.

Existen dos tipos de ELA: la esporádica y la familiar, ambas asociadas con la destrucción de las neuronas motoras. La forma esporádica no tiene componente genético evidente, a diferencia del tipo familiar el cuál si tiene un factor hereditario dominante (Zarei, S. et al. 2015). En este documento se estará explicando los mecanismos de la enfermedad, los síntomas, el diagnóstico y prognosis de la misma.

Métodos El proceso de desarrollo de este proyecto conllevó la recopilación de literatura primaria sobre el ELA obtenida mediante el buscador PubMed, el cual permite acceso a la base de datos biomédica Medline. Una vez estudiados y resumidos los conceptos fundamentales y detalles pertinentes sobre el ELA, se organizó una reunión grupal para entrelazar los distintos subtemas del trabajo escrito, al igual que coordinar y ejecutar la grabación del vídeo explicativo, el cual conllevó emplear estrategias 17

de calcio es importante debido a que Ca2+ es uno de los mensajeros intracelulares más importantes para el rol en los ciclos metabólicos, desarrollo neuronal y transmisión sináptica. Por otra parte, encontró que la mutación en SOD1 afecta el transporte retrogrado y anterógrado en el axón provocando acumulación de neurofilamentos, mitocondrias y autofagosomas en las neuronas motoras.

Por último, mutaciones en SOD1 también provocan una elevación de radicales libres en las células provocando citotoxicidad. (Zarei, S. et al. 2015)

tono vocal, tropezarse al caminar, perdida de agarre en las manos, fatiga no normal de los brazos y/o piernas, problemas de pronunciación, calambres musculares, empeoramiento de la postura, y dificultad sosteniendo la cabeza hacia arriba.

Diagnóstico La naturaleza compleja y heterogénea del ELA hacen retante su diagnóstico temprano. En promedio, existe un retraso de entre 13-18 meses desde el comienzo de los síntomas hasta la confirmación del diagnóstico (Elman, 2018). El diagnóstico del ELA se basa principalmente en la exclusión de otras causas de disfunción progresiva de neuronas motoras superiores e inferiores.

La falta de un marcador biológico establecido para el ELA, la variabilidad de síntomas y la sobre-posición patogénica con otras enfermedades neurodegenerativas también contribuyen a la dificultad del diagnóstico. Las dos herramientas de criterio diagnóstico empleadas son el Airlie House Criteria y el Awaji algorithm, utilizados para excluir diagnósticos diferenciales mediante el uso de laboratorios y para medir neurofisiológicamente la degeneración de las neuronas motoras inferiores, respectivamente.

Síntomas Los síntomas iniciales y el avance del ELA pueden variar de persona a persona. Las personas afectadas usualmente presentan debilidad focal asimétrica de las extremidades. Esta debilidad es generalmente indolora y se desarrolla gradualmente a través del tiempo. Cuando la enfermedad se da en los niveles cervicales inferiores, las personas pueden presentar una mezcla de debilidad fláccida y debilidad espástica ya sea en las extremidades superiores o inferiores dependiendo de dónde sea la lesión. Si ELA progresa superiormente partiendo de los niveles cervicales inferiores, las fibras nerviosas motoras del nervio frénico se pueden ver afectadas y esto compromete la respiración. Personas con ELA al nivel del tronco encefálico caudal pueden tener dificultad para tragar y hablar debido a debilidad de los músculos faríngeos o de la lengua, inervados por los nervios craniales X & XII. Por consiguiente, estas personas tienden a perder peso rápidamente y pueden sufrir de malnutrición (Mayo Clinic, 2019).

Otros síntomas pueden reflejarse como dificultad al agarrar un lápiz o levantar un vaso de agua o un cambio de

Tratamientos Los tratamientos que se recomiendan son para aliviar las complicaciones que los pacientes pueden presentar. El uso de las terapias físicas es recomendado para retrasar el deterioro muscular, evitar complicaciones y promover independencia funcional. La administración de medicamentos se utiliza de manera que mejore la calidad de vida para estos pacientes. Se utiliza riluzol para atrasar la necesidad de ventilación 18

asistida o traqueotomía. Para el dolor neuropático se utiliza gabapentina y pregabalina. NSAIDS y opioides para dolor nociceptivo. Antidepresivos y ansiolíticos.

Ya que en muchos se les dificulta el tragar, se utilizan medicamentos para disminuir la secreción de saliva como atropina. Para la espasticidad muscular se utiliza baclofeno y diazepam (Mayo Clinic, 2019).

percutánea. Este método es asociado con un mejoramiento de calidad de vida y sobrevivencia.

Prognosis y conclusión Un 20% de pacientes con ELA puede llegar a un máximo de 10 años de supervivencia (Mateen et al., 2010). A mayor edad y mayor deficiencia en funcionamiento pulmonar, menor será la predicción de supervivencia. Por ejemplo, hay un subtipo de ELA que específicamente afecta a mujeres mayor de 65 años, causando dificultades respiratorias y de tragado, principalmente. Este se debe por deterioro en neuronas motoras inferiores (Wijesekera et al, 2009). La ELA aún no tiene cura y la mayoría de los pacientes sobreviven aproximadamente entre 2 y 4 años (Hardiman et al, 2011). Lo indispensable al tratar a estos pacientes es mejorar su calidad de vida y aliviar el dolor en la manera que sea posible. Se debe promover la investigación para tener un mejor entendimiento fisiológico de la enfermedad. Futuros tratamientos deberían enfocarse en la prevención del daño neural.

Manejo y avances El tratamiento y manejo de la Esclerosis Lateral Amiotrófica ha cambiado de una manera significativa a través de los años. Existen varios estudios que han determinado que clínicas multidisciplinarias han mejorado la calidad de vida de los pacientes con ELA, e incluso, han llegado a prolongar los años de vida de sus pacientes. Ya que la mayor causa de muerte por el ELA es la insuficiencia respiratoria, existen varios métodos para monitorear y manejar la función respiratoria. El método más utilizado para evaluar la función respiratoria es a través de la medida de la Capacidad Vital Forzada (FVC). Un valor bajo de FVC está asociado con una sobrevivencia de poca duración. Es recomendado que se utilice la ventilación no-invasiva, lo cual ayuda a mejorar el tiempo de sobrevivencia ya que disminuye el declive de FVC y mejora la calidad de vida. Finalmente, muchos pacientes que sufren de la ELA padecen de disfagia, y no consumen la cantidad de calorías que su cuerpo requiere. Esta situación se maneja con el uso de la videofluoroscopia, que ayuda a evaluar qué tipo de consistencia que debe tener la comida de acuerdo a la condición del paciente. Eventualmente, los pacientes con ELA requieren alimentación entera a través del método conocido como la gastrostomía endoscópica

Bibliografía ALS Association (2019) SOD1 (copper zinc superoxide dismutase 1) and ALS http://www.alsa.org/research/focusareas/genetics/sod1.html Elman, AB (2018). Diagnosis of ALS and other forms of motor neuron disease.

UpToDate https://www.uptodate.com/contents /diagnosis-of-amyotrophic-lateralsclerosis-and-other-forms-of-motorneuron-disease Hardiman, O., van den Berg, L. and Kiernan, M. (2011). Clinical diagnosis and management of amyotrophic 19

lateral sclerosis. Nature Reviews Neurology, 7(11), pp.639-649.

Mateen, F. J., Carone, M., & Sorenson, E. J. (2010). Patients who survive 5 years or more with ALS in Olmsted County, 1925-2004. Journal of neurology, neurosurgery, and psychiatry, 81(10), 1144-6.

Mayo Clinic (2019) Symptoms and Causes.

Mayo Foundation for Medical Education and Research, www.mayoclinic.org/diseasesconditions/amyotrophic-lateralsclerosis/symptoms-causes/syc20354022?p=1.

Wijesekera, L. C., Mathers, S., Talman, P., et al (2009). Natural history and clinical features of the flail arm and flail leg ALS variants. Neurology, 72(12), 1087-94.

Zarei, S., Carr. K., Reiley, L., et al. (2015) A comprehensive review of amyotrophic lateral sclerosis. Surg Neurol Int., 6(171)

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Lake Maracaibo region of Venezuela where the prevalence of HD is about 700 per 100,000.

Everyone has the gene responsible for HD, but only those who inherit the expansion of the gene will develop it and can potentially pass it on to the next generation. Everyone who inherits the expanded HD gene will eventually develop the disease.

The clinical depression associated with Huntington's disease may increase the risk of suicide. Some research suggests that the greater risk of suicide occurs before a diagnosis is made and in the middle stages of the disease when a person has begun to lose independence.

Eventually, a person with Huntington's disease requires help with all activities of daily living and care. Late in the disease, he or she will likely be confined to a bed and unable to speak.

However, he or she is generally able to understand language and has an awareness of family and friends. Common causes of death include: pneumonia or other infections, injuries related to falls and complications related to the inability to swallow.

Huntington’s Disease By Cristian Betancourt, Amarilis Camacho, Zuleika De Jesús, Laura Fernández, Eduardo González, Benny Marín, Kristofer Medina, Félix Rodríguez, Mónica Román

Overview of the disease Huntington’s disease is a progressive neurodegenerative disease that causes uncontrolled movements, emotional problems, and loss of cognition with signs of dementia. It is also classified as an autosomal dominant disorder, from the inherited chromosome 4, which usually begins in mid-life. Adult-onset Huntington disease, the most common form, usually appears in a person's thirties or forties. Individuals with the adult-onset form of Huntington disease usually live about 15 to 20 years after signs and symptoms begin.

A less common form of Huntington disease known as the juvenile form begins in childhood or adolescence. It also involves movement problems and mental and emotional changes. Juvenile Huntington disease tends to progress more quickly than the adult-onset form; affected individuals usually live 10 to 15 years after signs and symptoms appear.

Huntington’s disease affects approximately one in every 10,000 people, and there are nearly 30,000 in the United States who have been recognized as symptomatic. More than 200,000 Americans are at-risk of inheriting the disease. There are a few isolated populations in Western Europe where HD is unusually common. A very high concentration of HD has also been found in the

Clinical Presentation Huntington’s disease has been characterized to cause movement, cognitive and psychiatric disorders. Signs and symptoms vary widely by patient due to its wide spectrum, number of the repeats and different onset. Movement disorders associated with the disease may include involuntary movements such as jerking and restriction on voluntary movements in which as the disease progresses patients’ capacity and independence is lost.

The most common psychiatric disorder associated with Huntington's 21

disease is depression. It is classified as a brain injury and not as a reaction when diagnosed with the disease. Although depression is later seen with changes in, brain function and brain injury. Signs and symptoms may include lethargy and loss of energy, frequent thoughts of suicide or death, episodes of irritability, sadness or apathy, social section and insomnia.

Other common disorders usually observed are obsessive-compulsive disorder, mania, which can cause high mood, hyperactivity, impulsive behavior and increased self-esteem, and/or bipolar disorder.

The outbreak and evolution of Huntington's disease in youth may be slightly different from adults. Problems that often occur early in the course of the disease include behavioral changes such as: accelerated and significant decrease in educational achievement, loss of previously learned physical or academic skills.

Physical changes are observed including: changes in fine motor skills like handwriting, tremors or involuntary mild movements, convulsions, contracted and rigid muscles that affect gait, is especially seen young children.

longer huntingtin protein, mainly composed of a glutamine chain, which is later excessively processed into smaller fragments. These fragments accumulate into toxic clusters in striatal astrocytes, which results in hyper-excitable neurons due to damage of the potassium channel.

Neuronal dysfunctions lead to neuronal death, which triggers the usual neurodegenerative signs and symptoms of HD (“Huntington disease”). The increased fragmentation of glutamine chains leads to less synthesis of Gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter that is synthesized from glutamine (Constanzo). The neuronal death indirectly affects the inhibitory input - provided by GABA - of the striatum to the external globus pallidus, which in turn has an inhibitory input to the subthalamic nuclei (Constanzo). In HD, the subthalamic nuclei, which normally sends excitatory and inhibitory signals to the thalamus for motor control, is at a disbalance when the inhibitory pathway is damaged, causing prolonged periods of excitation that further damage neurons of the surrounding area.

Causes

As we have seen, Huntington’s Disease is a complicated illness and presents with a varied clinical picture. It is understood that the genetic trinucleotide repeat (CAG) is the cause of the pathology, but the molecular changes are rather unknown. Recent literature suggest that potassium channels on astrocytes are the primary cause of inflammation and motor deficit seen in these patients. The potassium channels are named KIR-4.1or inward rectifying potassium channels; which means that they permit influx of this ion in order to maintain resting membrane potential. In

Implication of Ion Channels

In Huntington’s disease, the Huntingtin gene (HTT) has an abnormal amount of CAG trinucleotide repeats, where individuals with more than 40 trinucleotide repeats almost always develop the disorder and people with 36-39 CAG repeats have the disease but may or may not present with signs and symptoms (“Huntington disease”).

The neuronal damage relating to HD mainly occurs in the basal ganglia; the deep nuclei of the telencephalon. The increased amount of CAG trinucleotide repeats leads to the production of a 22

astrocytes, these channels are used for regulation purposes; they diminish the excitatory signals in neurons. This same study demonstrated that knockout mice for the mentioned channel showed a significant neuronal inflammation, which can contribute with the pathologyâ&#x20AC;&#x2122;s clinical presentation.

Normally, high-affinity glutamate transporters are responsible for the maintenance of low levels of glutamate required for efficient excitatory amino acid (EAA) neurotransmission and for the prevention of excitotoxicity. GLAST (EAAT1) and GLT1 (EAAT2), the major glutamate transporter subtypes, are expressed by astroglial cells. Within the astroglia, glutamate is converted to the nontoxic amino acid glutamine. The glutamine is then passed back to the neuron for conversion into glutamate by glutaminase for neurotransmission. It has been demonstrated that the expression of both GLT1 and glutamine synthetase is decreased in mice used to study the condition, suggesting that a perturbation in astrocyte glutamate metabolism may contribute to the phenotype and neurodegeneration. Decreased EAAT expression, combined with a decreased activity of the transporter could in turn let the extracellular glutamate build-up and cause neuronal hyperexcitability and in the long-term cellular toxicity, possibly by acting on extrasynaptic NMDA receptors that have been particularly implicated in glutamate-associated toxicity.

should be discussed with patients as early as appropriate.

Currently, treatment for patients with HD is supportive. For patients that develop agitation and chorea, antipsychotics are prescribed to partially suppress those symptoms. Possible antipsychotics include Chlorpromazine, Haloperidol, Risperidone, Olanzapine, and Clozapine. Patients who take Clozapine should have their WBC counts monitored frequently because Clozapine carries the risk of agranulocytosis. The dosages of these medications may be increased until symptoms are controlled or adverse effects reach the threshold for what the patient deems tolerable. Tetrabenazine (a drug used to promote depletion of monoamines: serotonin, norepinephrine, and dopamine) is another option for treatment of chorea. As with the previously mentioned medications, dosages will be increased until symptoms are controlled or adverse effects are no longer tolerable. If depression is present (e.g. it is a side effect of tetrabenazine), antidepressants can be prescribed.

Therapeutic options currently being researched involve the attempted reduction of glutamatergic neurotransmission via the NMDA receptor as well as supporting mitochondrial energy production.

Conclusions Huntington's disease is an autosomal dominant disorder that causes a progressive degeneration of nerve cells in the brain. Huntington's disease has a impacts a person's functional abilities and usually results in movement, cognitive and psychiatric disorders. Most people with Huntington's disease develop signs and symptoms in their 30s or 40s. However, the disease may emerge earlier or

Treatment Huntington Disease is ultimately fatal. As of yet, there are no disease-modifying therapies available, though research is being conducted into creating such treatments. As such, end-of-life-care

23

later in life. This disease usually causes movement, cognitive and psychiatric disorders with a wide spectrum of signs and symptoms. Some examples are involuntary jerking, difficulty in learning new information and social withdrawal. A preliminary diagnosis of Huntington's disease is based primarily on your answers to questions, a general physical exam, a review of your family medical history, and neurological and psychiatric examinations. Medications are available to help manage the symptoms of Huntington's disease, but treatments cannot prevent the physical, mental and behavioral decline associated with the condition.

disease. Communicative & integrative biology, 7(4), 694-703.

References Constanzo, L. S. (2018). Neurophysiology.

In Physiology(6th ed., pp. 33,110).

Philadelphia, PA: Elsevier. ISBN: 9780323478816 Gonzalez-Usigli, Hector A. â&#x20AC;&#x153;Huntington Disease Neurologic Disorders.â&#x20AC;? Merck Manuals Professional Edition, Merck Manuals, www.merckmanuals.com/en-pr/professional/neurologicdisorders/movement-and-cerebellardisorders/huntington-disease Huntington's disease. (2018, May 16).

Retrieved March 23, 2019, from https://www.mayoclinic.org/diseases -conditions/huntingtonsdisease/symptoms-causes/syc20356117 Huntington disease - Genetics Home Reference - NIH. (2019, March).

Retrieved from https://ghr.nlm.nih.gov/condition/hu ntington-disease Proft, J., & Weiss, N. (2014). Rectifying rectifier channels in Huntington

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Causes and Clinical Presentations

Alzheimer’s disease

There is current debate on the exact cause of Alzheimer’s, but scientists concur that it stems from a combination of genetic, lifestyle, and environmental factors. The main problem for patients that develop the disease is an accumulation of proteins known as amyloid plaques and tau tangles that lead to neuronal damage. The proteins’ toxic effects targets cell-to-cell communication between neurons, which disrupt the brain’s ability to remember, plan familiar tasks and modulate behavior [2]. There are current studies that have shown evidence that the disruption of ion channels, specifically those of calcium, may have an implication on the development of Alzheimer’s [12].

By Bryan Padua, Cristian Mantilla, Gabriel Nieves, Giovanni Ramírez, Johanna Irizarry, Laura Maza y Lionel Pagán

Introduction Alzheimer’s disease (AD) is a progressive and neurodegenerative disease, which starts with mild memory issues but eventually leads to a gradual decline in behavior and cognitive skills [2]. It is the leading cause of dementia in the US [12], the fourth cause of death in Puerto Rico and the sixth in the US [11].

The characteristic feature of AD is the Amyloid β peptide (Aβ). Senile plaques or amyloid plaques are composed of mainly of Aβ proteins [14]. These deposits are localized around neurons and principally in the temporoparietal cortices, frontal cortices, cingulate gyrus and hippocampus [12]. Another distinctive aspect of AD are the neurofibrillary tangles (NFT) within the neuron. These are intra-axonal structural anomalies that are composed of the hyperphosphorylated microtubule associated (MAP) protein [12].

Investigations of Aβ toxicity suggests they contribute to form ion channels. In 1992, Hardy and Higgins found that Aβ peptides disrupt calcium homeostasis in neurons and increase intracellular calcium [12]. A year later, it was investigated that Aβ peptides might function like Ca 2+ ion channels [3].

Therefore, both investigations suggests that Aβ peptides might be toxic to neurons contributing to the formation of ion channels and altering homeostasis.

Symptoms The early signs of Alzheimer’s disease are forgetting recent events and conversations. A person with Alzheimer’s disease may be aware of having difficulty with remembering things and organizing thoughts. Other family members or friends will notice how the symptoms worsen. As the disease progresses, a person with Alzheimer will develop severe memory impairment and lose the ability to perform everyday tasks.

Brain changes associated with the disease tend to worsen these symptoms affecting the ability to function. Thinking and reasoning are difficult for people with Alzheimer’s disease. They tend to repeat phrases various times without remembering they already said it. They forget conversations, events, names of family, friends and everyday objects.

Often get lost in familiar places, misplace possessions, and have trouble to express their thoughts. Patients with Alzheimer’s 25

disease have difficulty in thinking, concentrating, multitasking and managing finances. The disease affects reasonable decisions in everyday situations such as burning food on the stove or wearing appropriate clothes for the weather.

As Alzheimer’s disease progresses, organizing, planning, and performing tasks become difficult. In advanced stages of the disease, they forget how to perform basic tasks such as bathing and dressing.

Changes that occur at the brain cell level can occur and affect personality and behavior, affecting emotions, which lead to depression, mood swings, irritability, and aggressiveness. Change in sleeping patterns, loss of inhibitions, and delusions can occur. As Alzheimer’s progresses to the latest stages, the brain changes begin to affect physical functions such as swallowing, balance, bowel movements, bladder control, malnutrition, and dehydration [2].

is not enough. Memantine is then used because it blocks the receptor similar to how magnesium does it. Generally, it was found that memantine is more useful in moderate to severe AD than in mild AD. Overall memantine is well tolerated with the only side effects being dizziness, headaches, somnolence and hypertension and even these are only found in rare cases [8].

The second type of medication used is cholinesterase inhibitors that work on the enzyme acetylcholinesterase.

Acetylcholine is a major transmitter at neuromuscular junctions, autonomic ganglia, and at many sites in the central nervous system [10]. Research has shown that people with Alzheimer's disease have a reduced amount of acetylcholine, and is thought that the loss of this neurotransmitter interferes with memory [5]. Acetylcholine is generally not used as an administered drug because it is broken down very rapidly by acetylcholinesterases [10]. Therefore, acetylcholinesterase inhibitors are used to reduce the breakdown of the neurotransmitter in the synaptic cleft after signal transmission. The cholinesterase inhibitors include: donepezil, galantamine, and rivastigmine [7]. Patients taking this medication may find improvement with memory, behavioral symptoms, and daily life functions. Side effects may include: diarrhoea, nausea, insomnia, fatigue and loss of appetite [7].

Treatments Pharmacological treatments for Alzheimer’s disease (AD) have two categories. The first one is an N-methyl Daspartate (NMDA) antagonist called memantine. The idea behind this treatment is that in the Central Nervous System glutamate is an excitatory neurotransmitter that is important in the learning process. Normally it stimulates the ionotropic receptor NMDA and causes an influx of calcium ions. In Alzheimer’s patients, the neurons that release glutamate demonstrate hyperactivity causing the NMDA receptors to be activated more frequently. All of this leads to an increase inflow of calcium that causes excitotoxicity, eventually this result in neuronal injury or death [8].

Normally magnesium blocks the NMDA receptor channel but in these patients, it

Results Aβ plaque fragment accumulation in Alzheimer’s was found to be characterized by perturbed neuronal Ca2+ homeostasis. The latter peptide can oligomerize and insert into the neuronal plasma membrane as a cation-selective 26

ion channel. This abnormal insertion disrupts normal homeostasis. When Arispe(1993) created a planar bilayer of palmitoyloleolylphosphatidylethanolamin e and phosphatidylserine, he saw that after measuring with a voltage patchclamp the number of newly inserted Ca2+ channels rose as higher and higher concentrations of Aβ1–40 where applied to the synthetic membrane. The ionophore channel activity could be modulated and blocked with Zn2+ when applied to the intracellular face of the membrane. Aβ1–42 was shown to cause morphologically proven cellular degeneration more readily than the other isoforms and that this effect was concentration dependent. This was also dependent on the presence of Ca2+. As predicted, micromolar amounts of Zn2+ afforded protection from peptide induced cell damage in the study [4]. Finally, they also reported that at small physiologic Aβ1–42 concentrations, these plaques cause neuronal cell death in mouse neuroblastoma cells.

enable only a thermodynamically controlled influx of calcium channels as opposed to biologically regulated, eventually causing neurotoxicity [3].

Although the experiments designed used synthetic membranes as the medium and current evidence is still insufficient to attribute ion channels as the cause, the hypothesis has been further supported by the fact that clinical trials targeting the fibrillization process have failed to show promise [9]. This new hypothesis has received support from the scientific community since it provides a new perspective on the molecular events during the progression of the disease; explain the lack of success with prior clinical trials, and the possibility of developing effective therapies.

References Abramov, Andrey Y.; Canevari, Laura; Duchen, Michael R. (2004-12-06).

"Calcium signals induced by amyloid β peptide and their consequences in neurons and astrocytes in culture".

Biochimica et Biophysica Acta (BBA) Molecular Cell Research. 8th European Symposium on Calcium. 1742 (1–3): 81–87.

Alzheimer's disease - Symptoms and causes. (2019). Retrieved from https://www.mayoclinic.org/diseases -conditions/alzheimersdisease/symptoms-causes/syc20350447 Arispe, N; Rojas, E; Pollard, H B (1993-0115). "Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum".

Proceedings of the National Academy of Sciences of the United States of America. 90 (2): 567–571.

Conclusion To date, the scientific community is actively researching in attempt to establish the cause of Alzheimer's disease.

The amyloid hypothesis attributes the disease to calcium homeostasis. The original hypothesis postulated the aggregation of beta amyloid insoluble fibers to cause a disruption of calcium homeostasis which signals the cells of the CNS to undergo apoptosis [1,6]; however a recent hypothesis (the ion channel hypothesis) postulated that Alzheimer’s Disease is due to a soluble form of betaamyloid forming ion channel in the cell membranes of neurons. These oligomers of beta amyloid introduce unregulated calcium channels in the neurons, that 27

Bhatia R, Lin H, et al. 2000. Fresh and globular amyloid beta protein (1-42) induces rapid cellular degeneration: evidence for AbetaP channelmediated cellular toxicity. Faseb J, 14(9):1233–43.

Dementia.org [Internet]. Australia: Dementia Q&A; 2006- [Updated 2018]. Available from: https://www.dementia.org.au/files/h elpsheets/HelpsheetDementiaQandA01CholinesteraseInhibitors_english.pdf Ekinci, Fatma J; Linsley, Maria-Dawn; Shea, Thomas B (2000-03-29). "βAmyloid-induced calcium influx induces apoptosis in culture by oxidative stress rather than tau phosphorylation". Molecular Brain Research. 76 (2): 389–395.

Hansen, R. A., Gartlehner, G., Webb, A. P., Morgan, L. C., Moore, C. G., & Jonas, D. E. (2008). Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer's disease: a systematic review and meta-analysis. Clinical interventions in aging, 3(2), 211-25.

InformedHealth.org [Internet]. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-. Alzheimer's disease: Does memantine help? 2011 Jul 5 [Updated 2017 Jun 29]. Available from: https://www.ncbi.nlm.nih.gov/books /NBK279356/ Jang, Hyunbum; Connelly, Laura; Arce, Fernando Teran; Ramachandran, Srinivasan; Lal, Ratnesh; Kagan, Bruce L.; Nussinov, Ruth (2013-05-22).

"Alzheimer's disease: which type of amyloid-preventing drug agents to employ?" Physical Chemistry Chemical Physics. 15 (23): 8868–77.

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Acetylcholinesterase inhibitors in Alzheimer's disease. British journal of clinical pharmacology, 48(4), 471-80.

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División para la Prevención y el Control de Enfermedades Crónicas.

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2009;5:237-47.

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Proceedings of the National Academy of Sciences of the United States of America, 82(24), 8729-32.

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Causes

Myotonia Congenita: Thomsen’s and Becker’s Disease

Thomsen and Becker’s Disease are two forms of Myotonia Congenita; which differ in their inheritance pattern.

Thomsen’s Disease is inherited in an autosomal dominant pattern, which implies that one copy of the affected gene is sufficient to cause the disorder. On the other hand, Becker’s Disease is autosomal recessive; entailing that both copies of the altered gene are necessary for the manifestation of the phenotype.

The mutation is located in CLCN-1 gene, which is a gene that belongs to the family of CLC, that encode for the making of chloride channels called CLC-1. ClC-1 channels are membrane spanning channels made of two protein subunits that create separate pore for chloride ion flow. These channels are abundant in skeletal muscles; therefore, the clinical manifestations of the disease are associated with the use of skeletal muscle and movement.

Symptoms

By R. Avilés, L Calimano, V. Chaloka, P. Díaz, L Miranda, A. Rodríguez, A. Rosario, L. Vilá

Introduction Myotonia is defined as an inability to relax skeletal muscles after voluntary contraction. In other words, the muscles take an unusually long time to relax. An example of a patient with myotonia can be seen when a clenched fist remains several seconds in that position before relaxing. Myotonia Congenita or Thomsen and Becker’s disease are manifested due to a chloride channel mutation. These types of channels transport negatively charged chlorine ions in or out of the cell; thereby affecting the cells ability to generate and transmit electrical signals.

A major determinant of muscle resting membrane potential is the high permeability of chloride. Mutated chloride channels lead to increased resistance, which lead to an increased time constant and results in muscles fibers taking a longer than normal time to repolarize after an action potential. As a result, the resting membrane potential is determined more by the K+ concentration. This leads to a higher sensitivity of the cell for extracellular K+ concentration. In other words, a depolarizing stimulus that normally leads to a single action potential will now result to multiple action potentials.

The following symptoms may be indicative of an individual having Thomsen and Becker’s Disease:

Clinical Setting Autosomal Dominant: usually appears in infancy or early childhood.

Autosomal Recessive: tend to appear later in childhood and symptoms are more severe. 

  

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Myotonia, which is stiffness or cramps of striated muscles; especially facial, thenar, tongue, and extrinsic eye muscles Percussion of muscles elicits a myotonic contraction Hypertrophic muscles Muscle weakness





“Warm-Up” Effect: stiffness, which is alleviated by brief exercise or repeated contraction of the muscle.

Abnormal cardiac conduction, early cataracts or endocrine dysfunction.



Laboratory Setting

Genomic Testing: normally used if single-gene testing fails to confirm a diagnosis. Genomic Testing includes exome sequencing, genome sequencing and mitochondrial sequencing.

Diagnostics

High concentration of serum creatine kinase  Electromyography (EMG) with needle electrodes showing spontaneous electrical activity (Myotonic Bursts) The proper diagnostic of Thomsen and Becker’s Disease should be through genetic testing. Genetic Testing is a medical test that identifies abnormal changes in chromosomes, genes or proteins. Therefore, this type of test can confirm if the etiology of the manifested symptoms are based on a genetic nature; and can also determine the chances of an affected individual passing the disorder to his or her offspring.

The first step on the diagnosis of Myotonia Congenita is to establish a proband, which is the person that serves as the starting point for the genetic study.

This person is identified as the individual with the possibility of having the altered pathogenic gene; in this case, a CLCN1 gene mutation. Since there is a pathogenic difference between autosomal dominant Myotonia Congenita and autosomal recessive, their diagnostics rely deeply on family history.

There are three types of genetic testing: single-gene testing, multigene panel and genomic testing.  Single-gene testing: sequence analysis of CLCN1; followed by deletion/duplication analysis if no pathogenic variant is found.  Multigene Panel testing: testing of multiple genes, including CLCN1, that have similar clinical manifestations. 

After carefully assessing the clinical and laboratory manifestations of a patient suspected of Myotonia Congenita, the next step would be to make a diagnostic.

Differential diagnosis is important in the diagnosis of Myotonia Congenita, due to the fact that there are other type of disorders that present with the same clinical symptoms, especially myotonia. In order to distinguish Thomsen and Becker’s Disease from other type of disorders, the following parameters should be assessed: factors that elicit or ease myotonia, the presence or absence of extramuscular manifestations and electrodiagnostic testing.

The following disorders should be considered in the process of differential diagnosis:  Paramyotonia Congenita: As in Myotonia Congenita, this type of disorder also presents with “episodes of generalized stiffness in early childhood”. Nevertheless, patients with Paramyotonia Congenita display extreme cold sensitivity, not present in patients with Myotonia congenita.

And, Myotonia Congenita patients display the “warm-up” effect while exercise in patients with Paramyotonia Congenita aggravate the stiffness.  Potassium-aggravated Myotonia: like in Myotonia Congenita, this type of disease presents with episodes of 30



muscle stiffness. Yet, these patients’ symptoms worse with potassium ingestion, which is not present in patients with Myotonia Congenita. Also, these types of patients do not demonstrate the “warm-up” effect. Finally, Myotonia Congenita patients do not report pain during myotonia episodes, while patients with Potassium-aggravated Myotonia do.

Myotonic Dystrophy Type 1 and Myotonic Dystrophy Type 2: both type of diseases present myotonia.

But, these type of disorders present extramuscular manifestations; while Myotonia Congenita does not.

reported to also be beneficial in some cases.

Both type of Myotonia Congenita are unusual in the population. Some studies state that Autosomal Dominant (Thomsen’s Disease) occur with a frequency of 1:23,000; while other report an incidence of .3 per 100,000 people in the general population. On the other hand, some studies reported that Autosomal Recessive (Becker’s Disease) occur with a frequency of 1;50,000, while other state a .6 per 100,000 people in the general population. Nevertheless, all statistics demonstrated a low incidence of this disorder.

It has also been stated that the autosomal recessive form is more common than the autosomal dominant form; while, both type of Myotonia Congenita are thought to affect males and females in equal numbers.

Finally, northern Scandinavia has been reported with the country with the highest prevalence of Myotonia Congenita with a frequency of 1:10,000; while the rest of the world has a prevalence of 1:100,000.

Lifestyle activity changes may be enough for patients with mild manifestation of Myotonia Congenita’s symptoms. Exercise has been reported as a lifestyle change that alleviates Thomsen and Becker’s Disease symptoms; since some clinical manifestations are alleviated with exercise, referred to as the “warm up” effect.

Another treatment for this disease is the pharmaceutical approach with Sodium Channel Blockers. These types of drugs inhibit the inward sodium current; therefore, reducing the rate of rise of phase 0 of the action potential. Mexiletine has been reported as the best treatment option, while at the same time having potential side effects that include nausea, dizziness, ataxia and tremors. Phenytoin and Carbamazepine are other Sodium Channel Blockers reported to have beneficial effects. On the other hand, Quinine (an antimalarial drug), Dantrolene (muscle relaxant drug) and Acetazolamide (diuretic) have been

In conclusion, it is important to recall that myotonia congenita is an inherited myopathy. Which causes certain problems with the tone and tonicity of skeletal muscle. Also it is an important fact to understand that this disease does not atrophy the muscle; instead it enlarges it increasing muscle strength.

Leaving on us with the question, what prognosis does these type of patients have? The disease has its onset in childhood, nonetheless patients with this disease can have a long and productive life. Some may encounter muscle stiffness which it is relieved by exercise, or light movements after resting, but very interestingly some patients excel in sports 31

especially the ones where strength is more important that agility.

As we have seen this disease characterizes itself by mutations in the gene for a chloride channel used in the event of muscle contraction. Which can be classified in two types of myotonia congenita. Such as Becker, which is autosomal recessive and is the most common of both and Thomsen, which is autosomal dominant and is usually very rare and it is considered a relatively mild form of the disease.

References Myotonia Congenita (Thomsen Disease and Becker Type). (2017, December 06). Retrieved from https://www.mda.org/disease/myoto nia-congenita Myotonia Congenita Information Page. (n.d.). Retrieved from https://www.ninds.nih.gov/Disorders /All-Disorders/Myotonia-CongenitaInformation-Page Dunø, M. (2015, August 06). Myotonia Congenita. Retrieved from https://www.ncbi.nlm.nih.gov/books /NBK1355/

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cannot cross the blood brain barrier.

Some experimental treatments for PD involve implantation of a human fetal substantia nigra or electrical stimulation of the basal nucleus, both stimulation According to the Parkinson’s Foundation, around 10 million people around the world are living with Parkinson’s disease. Approximately 60,000 Americans are diagnosed with PD each year. Studies show that in Puerto Rico around 25,000 people are currently living with PD. It has been reported that men are 1.5x more likely to suffer from this condition when compared to women.

Being diagnosed with PD may present a financial stress; PD patients spend nearly $2,500 on medications per year and PD related surgeries may cost up to $100,000 per patient.

Parkinson’s Disease By Valeria Rullán Varela, Claudia Cruz Bosch, Alejandro Santiago Nazario, Marlian Montesinos-Cartagena, Esteban Santiago Ramos, Carlos González Baerga, Eduardo Sánchez Pérez, Gabriel Seda Pombrol

Introduction Described by an English doctor who suffered from it as “paralysis agitans” in 1817, the illness today carries his second name, James Parkinson.

Parkinson’s disease (PD) is considered the second most common neurodegenerative disease in the United States—the most common being Alzheimer’s disease. PD affects the person’s special orientation, attention, memory, language, mood, and sleep cycles (Marras). For this reason, this presentation aims to understand Parkinson as a disease and an illness that affects the patient’s quality of life. PD is a neurodegenerative disease in which a patient suffers a variety of motor and physiological difficulties due to a deficit in the dopamine levels secreted by substantia nigra (component of the basal nuclei). Two important structures involved with posture and fine motor movement are the telencephalic basal nuclei (inhibitory) and the cerebellum (excitatory). If either of these neuronal centers is dysfunctional then problems with posture and fine movement, like those three and Parkinson’s disease, will ensure. Most cases are reported to be idiopathic; however, 10% of cases are of genetic origin (LRRK2 gene). Medications for PD are in the form of dopamine precursors because dopamine itself

Causes The causes for Parkinson’s disease are not yet fully understood. Research has hinted at the possibility that genetics may play a role in predisposing individuals to the illness (Kilarski et al. 2012). However, other studies have suggested that this is not always the case, as in patients diagnosed with Parkinson’s above the age of 65 (Wang et al. 2008). Research is still trying to uncover the risk factors that may bring about Parkinson. Some of the possible risk factors are pesticide exposure (Ascherio et al. 2006, Dick et al.

2007), family history of Parkinson’s or melanoma (Gao et al. 2009) and medical history of severe head injury (Bower et al, 2003).

Clinical Presentation A person with Parkinson’s disease experiences tremors (shaking). Tremors usually begin with the hands and fingers.

The patient’s hand may shake when at 33

rest, and he/she may display pill-rolling tremor. Bradykinesia, or slowed movement, is also common among persons with Parkinson’s disease. The patient’s steps may become shorter, while dragging the feet when trying to walk.

The patient displays a shuffling gate, and muscle stiffness can occur in any part of the body, limiting the person’s range of motion. Posture may become stooped, and the person may display balance problems. Dyskinesia are involuntary and erratic writhing movements of the face, arms, legs and trunk, and they are another symptom of Parkinson’s disease.

Non-motor symptoms often present before the diagnosis, contributing to disability, impaired quality of life and shortened life expectancy. Some of these non-motor symptoms include depression, anxiety, apathy, and irritability. A person with Parkinson’s disease may display cognitive changes, such as: problems with memory, attention, language and planning.

Parkinson’s disease can be characterized or defined in stages. In stage one; the person has mild symptoms that do not interfere with daily activities.

However, he/she may experience tremors on one side of the body, as well as changes in posture, walking and facial expression. In stage two, tremors and rigidity affect both sides of the body.

During stage three, symptoms significantly impair daily activities such as dressing, and eating. Loss of balance and bradykinesia are the hallmarks of this stage, and the person is more prone to falls. At stage four, symptoms are severe, and the patient is unable to live alone.

During stage five, stiffness in the legs may make it impossible to stand or walk. This is the most advanced and debilitating stage and the patient may require a wheelchair, or is bedridden. Usually,

he/she may also display hallucinations and delusions.

Treatment Treatments for Parkinson’s disease have been formulated through the years to control symptoms and to relatively delay the progressiveness of the disease. For example, the combination of Carbidopa and Levodopa has been extensively used today to treat Parkinson’s disease symptoms. Since dopamine cannot cross the blood-brainbarrier, L-dopa is administered in combination with Carbidopa (a decarboxylase inhibitor) to decrease the extent to which Levodopa is degraded in the peripheral system. Dopamine agonists like Rasagiline and Selegiline have also been used, but its high number of side effects have drawn medical professionals to use other medications.

MAO-B inhibitors have also been used to treat these symptoms because they help to lower the degradation rate of L-dopa when administered. Surgical procedures also are an alternative; for example, deep brain stimulation (DBS) has proven to work in patients to improve their muscle rigidity and tremors in extremities.

Ongoing Research An area of active research in the treatment of Parkinson’s disease is looking to better understand the mechanisms underlying DBS. In addition, scientists are working on targeting new regions of the brain to treat mote symptoms associated with the disease. As an example, they are stimulating the pedunculopontine nucleus of the brain to treat problems with balance and walking (Mazzone, P; 2018). On the other hand, work is being done in a more individualized approach to DBS. The socalled “smart” DBS monitors the 34

neurological activity of the patient and delivers the stimulation only when necessary (Smith, KA, et. al; 2016).

Another field of research in the treatment of Parkinson’s disease centers in the protein alpha synuclein. The aggregation of this protein is found in Lewis bodies, which are characteristic in Parkinson’s. However, the mechanisms by which this protein causes neurotoxicity is still not known (Rocha, EM, et. al. 2018).

Nevertheless, work is being conducted in creating antibodies against alpha synuclein, compounds that modulate the aggregation of it and compounds that facilitate its autophagia (Oertel, W; 2017).

Immunotherapy is on trial phase I and II and one of the challenges it is facing is the number of antibodies that can cross the blood brain barrier (BBB). Currently, there are already two compounds that can modulate the aggregation of the protein in vitro. The advantage of this technique is that, in contrast to immunotherapy, these compounds can cross the BBB readily. As for the compounds that increase alpha synuclein autophagia, they are still in the pre-clinic stage.

the parkin gene on chromosome 6, αsynuclein gene, and LKRR2 gene are all potential triggers of early Parkinsonism onset. Most researchers are focused on studying alfa synuclein which is found deposited in the Lewy Bodies in patients with the disease. Additionally, current treatments are intended towards the maximization of the effects of the limited availability of endogenous and exogenous dopamine. Some studies have mentioned that doing aerobic exercise and ingesting caffeinated drinks would diminish the risk of Parkinson’s disease, but this is not fully understood.

References Ascherio, A. , Chen, H. , Weisskopf, M. G., O'Reilly, E. , McCullough, M. L., Calle, E. E., Schwarzschild, M. A. and Thun, M. J. (2006), Pesticide exposure and risk for Parkinson's disease. Ann Neurol., 60: 197-203. doi:10.1002/ana.20904 Comprendiendo la Enfermedad de Parkinson. (2016, March 22).

Retrieved March 26, 2019, from https://www.cienciapr.org/es/blogs/ conocimiento-tusalud/comprendiendo-la-enfermedadde-parkinson Dick FD, De Palma G, Ahmadi A, et alEnvironmental risk factors for Parkinson’s disease and parkinsonism: the Geoparkinson study. Occupational and Environmental Medicine 2007;64:666-672.

Goedert, M. and Compston, A. (2017).

Parkinson's disease — the story of an eponym. Nature Reviews Neurology, 14(1), pp.57-62. https://parkinson.org/Understanding -Parkinsons/What-isParkinsons/Stages-of-Parkinsons

Conclusion In conclusion, Parkinson’s disease is an age-related neurodegenerative disease. Its cardinal features of are loss or impairment of voluntary control (akinesia), slowness of movements (bradykinesia), muscular rigidity, and loss of automaticity of movement, which reflects a loss of the basal ganglia’s role in procedural motor skills. As stated previously, the pathological hallmark of Parkinson’s disease is the progressive loss of dopaminergic neurons in substancia nigra, but current research suggests a genetic etiology. A mutation in 35

https://www.mayoclinic.org/diseases -conditions/parkinsonsdisease/symptomscauses/syc20376055 https://www.physiopedia.com/Parkinson%27s_Disease__Clinical_Presentation J. H. Bower, D. M. Maraganore, et al.(2003) Head trauma preceding PD. Neurology May 2003, 60 (10) 16101615; DOI:10.1212/01.WNL.0000068008.78 394.2C Kandel, E. and Mack, S. (2016). Principles of Neural Science. 5th ed. McGraw Hill Medical, pp. 982-998 Kilarski, L. L., et al. (2012), Systematic Review and UK‐Based Study of PARK2 (parkin), PINK1, PARK7 (DJ‐1) and LRRK2 in early‐onset Parkinson's disease. Mov. Disord., 27: 1522-1529. doi:10.1002/mds.25132 Marras, C., Troster, A. I., Kulisevsky, J. & Stebbins, G. T. The tools of the trade: a state of the art “How to Assess Cognition” in the patient with Parkinson’s dis- ease. Mov. Disord. 29, 584–596 (2014).

Mazzone, P., Vitale, F., Capozzo, A., Viselli, F., & Scarnati, E. (2018). Deep Brain Stimulation of the Pedunculopontine Tegmental Nucleus Improves Static Balance in Parkinson’s disease.

Neromodulation, 967-976. doi:10.1016/b978-0-12-8053539.00079-6 Oertel W. H. (2017). Recent advances in treating Parkinson's disease.

F1000Research, 6, 260. doi:10.12688/f1000research.10100.1 Retrieved in March 20, 2019: https://www.michaeljfox.org/underst anding-parkinsons/living-withpd/topic.php?deep-brain-stimulation Rocha, E. M., Miranda, B. D., & Sanders, L. H. (2018). Alpha-synuclein: Pathology,

mitochondrial dysfunction and neuroinflammation in Parkinson’s disease. Neurobiology of Disease, 109, 249-257. doi:10.1016/j.nbd.2017.04.004 Smith, K. A., Pahwa, R., Lyons, K. E., & Nazzaro, J. M. (2016). Deep brain stimulation for Parkinsons disease: Current status and future outlook.

Neurodegenerative Disease Management, 6(4), 299-317. doi:10.2217/nmt-2016-0012 Statistics. (2019, February 07). Retrieved from https://parkinson.org/Understanding Parkinsons/Statistics Treatment. (2019). Retrieved from https://www.mayoclinic.org/diseases -conditionhhs/parkinsonsdisease/diagnosis-treatment/drc20376062 https://www.nia.nih.gov/health/park insons-disease Wang, Y. et al.(2008). Risk of Parkinson disease in carriers of parkin mutations: estimation using the kincohort method. Archives of neurology, 65(4), 467-74.

X. Gao, K. C. Simon, J. Han, M. A. Schwarzschild, A. Ascherio. Family history of melanoma and Parkinson disease risk. Neurology Oct 2009, 73 (16) 1286-1291; DOI:10.1212/WNL.0b013e3181bd13a 1

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