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Neurodegenerative Diseases: Systems, Causes and Treatments

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  • Simon Mendy

Compare the symptoms, causes and available or future treatments for Motor Neuron Disease, Spinal Muscular Atrophy and Myasthenia Gravis.

Neurodegenerative diseases are hereditary (inherited) and sporadic (acquired during a person’s life) conditions caused by progressive nervous system dysfunction (http://ec.europa.eu/health/major_chronic_diseases/diseases/brain_neurological/index_en.htm). Motor neuron disease and Spinal Muscular Atrophy (shrink) are neurodegenerative conditions that arise due to motor neurons dysfunction and Myasthenia Gravis is an autoimmune neurodegenerative disorder. Motor neuron disease is caused by damage to motor neurons; Spinal muscular atrophy is due to deterioration of the motor neurons connecting the brain and spinal cord; Myasthenia gravis is an autoimmune condition that arises due to the damage or blocking of muscle receptors by antibodies accidently produced by the immune system. All three disorders result in weakness, making there diagnosis very hard, because weakness is a very common symptom of many conditions. However, possibilities are ruled out depending on the age of the person affected. If someone exhibiting muscle weakness is 1 year old, it is more likely that the person has SMA than the MG or MND, because SMA generally affects children ranging from less than six months to around the age of three, whereas MND is common in teenagers and young adults, and MG normally affects middle aged adults.

Motor neurone disease is a unique condition of unknown aetiology that occurs when motor neurons (specialist nerve cells in the brain and spinal cord that relay signals from the brain to the muscles) become damaged and ultimately stop working (http://www.nhs.uk/conditions/Motor-neurone-disease/Pages/Introduction.aspx). This causes the muscles that the damage nerves supply to gradually lose strength, usually with wasting of muscles. It is unclear exactly what causes motor neurons to stop working, but, there is not thought to be a link with factors like lifestyle, race and diet. In a small number of cases (about 5%), there is a family history of either motor neuron disease or a related condition known as frontotemporal dementia. However, there is no single test to diagnose MND and diagnosis is solely based on the opinion of a neurologist, on the basis of the symptoms observed and a physical examination. In some cases a specialised test is needed to rule out other possible conditions.

Symptoms of motor neurone disease begin gradually over a period of weeks and months, generally only on one side of the body at the beginning, and gradually get worse with time. Symptoms normally include having clumsy fingers or weaker grip (early signs of weakness). Other symptoms include: wasting of muscles, muscle cramps, hardships with swallowing and communication, excess saliva (difficulties swallowing saliva), and coughing after swallowing. After sometime, a person with motor neuron disease may find themselves unable to move. In a small number of cases (10-15%), motor neuron disease is associated with a type of dementia called frontotemporal dementia that can affect behaviour and personality.

The main types of motor neuron disease are: amyotrophic lateral sclerosis (ALS) (accounts for 60-70% of all cases), progressive bulbar palsy (PBP), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS) (http://www.patient.co.uk/health/Motor-Neurone-Disease).

Spinal muscular atrophy (SMA) is an autosomal (a chromosome that is not allosome) recessive genetic disease that causes muscle weakness and progressive loss of movement (http://www.fsma.org/FSMACommunity/understandingsma/WhatCausesSMA/). Around 1 out of every 40 people are genetic carriers of the disease (they carry the mutated gene but do not actually have SMA) (http://www.fsma.org/FSMACommunity/understandingsma/WhatCausesSMA/). Gene mutation is a permanent alteration in the DNA sequence that makes up a gene (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/genemutation). Gene mutation occurs in two different ways: they are either inherited from parents (known as hereditary mutation) or they are acquired at some time during a person’s life (known as acquired mutation). Hereditary mutations happen when mutations are present in both the egg and sperm cells. A person that has inherited this type of mutation has it present in virtually every cell in their body, throughout their lifetime. Acquired mutations occur in individual cells at some time during a person’s lifetime. These changes can occur due to environmental factors like ultraviolet (UV) light from the sun, chemicals, and radiation, or if a mistake is made whilst DNA copies itself during cell division (mitosis and meiosis). Acquired mutations are only inherited if they occur in sex cells. According to the National Genome Institute, almost all diseases have some kind of genetic factor. These disorders can be cause by multiple gene mutations, a mutation in a single gene, combined gene mutation and environmental factors, or by chromosome damage or mutation. Gene mutation has been identified as the cause of numerous disorders including spinal muscular atrophy (SMA), haemophilia, Tay-Sachs, sickle cell, anaemia, cystic fibrosis and some cancers (http://biology.about.com/od/basicgenetics/ss/gene-mutation.htm).

The term SMA is used mainly for the most common form spinal muscular atrophy, which is caused by a genetic problem where one copy of the genetic error (mutation in autosomes) is inherited from each parent. SMA is classified into four different categories, from Type I - IV. The classification of SMA depends on the age at which symptoms of the disease arise and the severity of the symptoms. Symptoms of SMA normally include problems with breathing, eating, moving and swallowing; floppy arms and legs (In children with either Type I or II SMA); twitching of the muscles in the arms, legs or tongue. Type I SMA is the most severe, it develops in babies under six months old. Type II is less severe that Type I SMA, it affects babies between the ages 6 to 18 months. Type III and Type IV are the mildest types of SMA. Type III normally affects children around 3 years old. Type IV affects adults. In the most severe cases of SMA (Types I and II), fatal respiratory problems usually develop during childhood. In mild cases such as Types III and IV SMA, life expectancy is normally unaffected (http://www.nhs.uk/conditions/Spinal-muscular-atrophy/Pages/Introduction.aspx).

Spinal muscular atrophy is caused by the deletion of the survival motor neuron gene 1 (SMN1) (http://www.fsma.org/FSMACommunity/understandingsma/WhatCausesSMA/). In healthy people SMN1 produces a protein known as the survival motor neuron (SMN) protein. In a person with mutated genes, the supply of this protein is absent or is significantly decreased. This results in the deterioration of the nerve cells (motor neurons) connecting the brain and spinal cord to the body’s muscles, therefore causing muscle weakness and gradual loss of movement, because the SMN protein is critical to the survival and health of motor neurons. Spinal muscular atrophy affects 1 in 6000 to 1 in 10000 people.

Myasthenia gravis is a unique long-term autoimmune condition which affects the nerves and muscles, resulting in the muscles becoming weak. An autoimmune condition is caused by the immune system mistakenly attacking and destroying healthy body tissue. Ordinarily, the immune systems white blood cells protect the body from harmful substances, known as antigens. For examples: viruses, bacteria, toxins, etc. antibodies are produced as a counter measure by the immune system that destroy the antigens. In people with autoimmune disorder, the immune system has difficulty distinguishing between antigens and healthy body tissue. Due to this an immune system response that kills healthy body tissue is produced. The cause of the immune system no longer being able to distinguish between antigens and healthy body tissue is unknown at present. A theory suggests that drugs or microorganisms (like bacteria or viruses) may trigger some of these changes. In myasthenia gravis, the immune system accidentally produces antibodies (proteins) that damage or block muscle receptor cells. This stops muscles contracting because the antibodies prevent messages being past from the nerve endings to the muscles. However, it is not understood why the immune system of some people produce antibodies that attack the muscle receptor cells.

Symptoms of myasthenia gravis generally include impaired eye movement and weakness of muscles that are voluntarily controlled, therefore affecting functions such as facial expressions, eye and eye lid movement, chewing, talking and swallowing, and weakness of neck and limbs. However since weakness is a common symptom in many different diseases and conditions, diagnosis of myasthenia gravis is normally delayed or missed. Myasthenia gravis is diagnosed through Blood tests, Genetic tests and Electromyogram. In the U.S about 20 in 100,000 people are diagnosed with myasthenia gravis.

Presently there is no known cure for MND, SMA, OR MG, however there are treatments that can be initiated with aims to ease symptoms to help the person feel more comfortable and have a better quality of life, and compensate for the gradual loss of bodily functions like mobility, communication, breathing and swallowing. For example, for MND, muscle relaxants can help reduce muscle stiffness; medicines such as phenytoin can treat muscle cramps; a breathing mask can help reduce shortness of breath. Right now, the only available treatment for MND that affects the progression of the disease is Riluzole, however it doesn’t stop the progression of motor neuron disease, but only slows it down by a few months (http://www.nhs.uk/conditions/Motor-neurone-disease/Pages/Introduction.aspx). With SMA, depending on the severity, treatment could involve: exercise, to prevent joint stiffness and improve range of movement and flexibility; assistive equipment such as motorised wheelchairs and walking frames if someone with SMA has difficulty moving; nutrition advice and feeding tubes; bracing and surgery to treat scoliosis (curvature of the spine) (http://www.nhs.uk/Conditions/Spinal-muscular-atrophy/Pages/Treatment.aspx). For patients with MG, medication such as pyridostigmine and neostigmine (less common), can prevent the breakdown of acetylcholine, an important chemical that assists the muscles in contracting (http://www.nhs.uk/Conditions/Myasthenia-gravis/Pages/Treatment.aspx). If pyridostigmine is ineffective, steroid tablets can be used to lessen the symptoms. Doctors also often prescribe azathioprine, methotrexate or mycophenolate, to suppress the immune system. Muscle strength can be improved by controlling the production of abnormal antibodies through the use immunosuppressants. In some cases of MG, surgery to remove the thymus gland (a thymectomy) may be recommended. The thymus gland is part of the immune system and is found underneath the breast bone, it is sometimes abnormal in people with MG. In numerous cases, treatment of MG substantially improves muscle weakness allowing a person with the condition to lead a comparatively normal life. Some people may experience permanent or temporally periods where symptoms stop and treatment is no longer needed. Permanent remissions occur in about a third of the people who have a thymectomy (http://www.nhs.uk/Conditions/Myasthenia-gravis/Pages/Treatment.aspx).

Currently, the hope of many is that stem cells of extraneural or neural origin might be modified in vitro (i.e. transforming skin cells into induced pluripotent stem cell (iPS)) (http://www.eurostemcell.org/factsheet/motor-neurone-disease-how-could-stem-cells-help) to differentiate into motor neurons that would migrate to sites of motor neuron loss and restore the motor pathways lost in MND by forming functional connections (Boulis, 2011). The most promising cells so far that can be used for stem treatment of MND are spinal cord stem cells, which are able to produce both motor neurons and a cell call glia. Many of the proteins known as growth factors that contribute to motor neurons development are secreted by glia. There is also a possibility that non-neuronal cells such as glia can be used to prevent further damage to motor neurons and encourage repair through the production of the working version of the protein SOD1, which in some types of MND doesn’t function properly (http://www.eurostemcell.org/factsheet/motor-neurone-disease-how-could-stem-cells-help). Stem cell therapy also has to the potential to be used as a possible cure for SMA, MG and other neurological conditions.

Gene therapy uses genes to prevent or treat a disease by introducing genetic material in cells to compensate for abnormal genes or to make a beneficial protein (MacKenzie, 2010). Gene therapy was found to be well suited as a future treatment for SMA by the Kaspar group: who described a self-complementary (sc) AAV9 vector that crosses the blood-brain barriers after systemic administration; because of scAAV9’s remarkable efficiency in central nervous system (CNS) gene transfer, after intravenous delivery in mice and other larger animals. Using this as a base, the Kaspar group along with Arthur burgees, detail the most successful rescue reported yet in a mouse model of severe SMA. This was achieved by injecting scAAV9 that is carrying SMN1, into the facial vein of mice pups on their day of birth (MacKenzie, 2010). The approach of injecting scAAV9 into mice pups, resulted in the transduction of 40% of motor neurons, and an extension of the lifespan of the mice from 2 weeks to more than 250 days, combined with almost normalised neuromuscular electrophysiology and normal motor function (MacKenzie, 2010).

This preliminary data obtained in the gene therapy rescue of SMA in the mouse model, reported by the Kaspar group and Arthur Burghes (a pioneer of SMA), suggests that the same approach could be used in primates. The authors investigated systemic injection of scAAV9-GFP in a cynomolgus monkey (1 day of age). After four weeks, the magnitude of GFP in spinal motor neurons recorded was similar to that shown by the mice (MacKenzie, 2010), boding well for possible application to humans. This news, along with recent encouraging reports of AAV gene therapy of retinal disease, supports the further rehabilitation of gene therapy as a credible therapeutic alternative for neurological diseases, including MG, SMA and MND.

The stage seems set: with seemingly untreatable disorders of unknown pathogenesis; an unknown presymptomatic way of diagnosis; and, the small possibility of a cure through gene therapy and stem cell therapy, which are by far the best hopes, not only for MND, SMA and MG, but also for other neurological diseases. However, gene therapy and stem cell therapy are subject to a lot of public disagreement. For gene therapy this is due to fact that, gene therapy targeted at germ cells (egg and sperm cells), (known as germline gene therapy) could be pass on to next generations. Whilst it spares a family and their future generations from a specific genetic disorder, there’s a possibility it could affect the development of a fetus in unexpected ways or have yet unknown long-term side effects (http://ghr.nlm.nih.gov/handbook/therapy/ethics). Because the people who are going to be affected are not yet born, they are unable to choose whether to have the treatment, resulting in big debates one whether germline gene therapy should be used. Other ethical concerns involve negative impacts on what society thinks is “normal”, and discrimination toward those with the “undesirable traits” that arise from using gene therapy as a form “modification” for unwanted traits or to make “genetic improvements”. The idea of stem cell therapy is also controversial. Whilst it can used for the treatment of many diseases including neurological ones, there are ethical problems involving how it is obtained. For example, stem cells obtained from the embryo, because the embryo is viewed as a potential person. Due to this, taking stem cells from an embryo is considered to be murder, however, it’s argued that, an early embryo that hasn’t be implanted into the uterus doesn’t have properties we associate with being a person, and therefore can and should be used for the benefit of patients (who are persons).

Bibliography:

  1. http://ec.europa.eu/health/major_chronic_diseases/diseases/brain_neurological/index_en.htm (20/07/2014)
  2. http://www.nhs.uk/conditions/Motor-neurone-disease/Pages/Introduction.aspx (20/07/2014)
  3. http://www.patient.co.uk/health/Motor-Neurone-Disease (20/07/2014)
  4. http://www.fsma.org/FSMACommunity/understandingsma/WhatCausesSMA/ (04/07/2014)
  5. http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/genemutation (20/06/2014)
  6. http://biology.about.com/od/basicgenetics/ss/gene-mutation.htm (21/06/2014)
  7. http://www.nhs.uk/conditions/Spinal-muscular-atrophy/Pages/Introduction.aspx (20/07/2014)
  8. http://www.nhs.uk/Conditions/Spinal-muscular-atrophy/Pages/Treatment.aspx (04/07/2014)
  9. http://www.nhs.uk/Conditions/Myasthenia-gravis/Pages/Treatment.aspx (21/07/2014)
  10. http://www.eurostemcell.org/factsheet/motor-neurone-disease-how-could-stem-cells-help (05/07/2014)
  11. Nicholas M. Boulis. (2011). Gene Therapy for Motor Neuron Disease.Gene Vector Design and Application to Treat Nervous System Disorders. 33 (3), p41-49
  12. Alex MacKenzie. (2010). A severe inherited neuromuscular disease is corrected in mice by intravenous gene delivery.Gene therapy for spinal muscular atrophy. 28 (3), 235-237
  13. http://ghr.nlm.nih.gov/handbook/therapy/genetherapy, (27/06/2014)
  14. http://ghr.nlm.nih.gov/handbook/therapy/ethics, (28/06/2014)
  15. http://ghr.nlm.nih.gov/handbook/therapy/procedures, (27/06/2014)

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