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Multiple Sclerosis is an inflammatory disease of the central nervous system. Due to the major inflammation, demyelination and neurodegeneration involved in the progression of the disease, neurological dysfunction occurs, which can lead to severe physical and cognitive disabilities. Multiple Sclerosis can be a highly disabling disease yet the life-span of the patient is only shortened slightly, therefore it is greatly important to attempt to prevent its onset and progression in humans to help improve quality of life and also help decrease the huge impact MS has on the healthcare system. (Kenealy, et al., 2003) However despite years of studies and intense research there is still no direct cause known for the disease. It is thought to be a combination of genetic, environmental and immunological causes which makes it a very complex disorder. (Compston and Coles., 2002) Further complexities include the delayed diagnosis since the initial symptoms can appear silent. Also the numerous patterns/ types of MS and unpredictable morphological course are both factors which in turn lead to difficulty in the research of MS. (Weinshenker., 1994)
This paper will focus on the evidence which suggests a genetic susceptibility to MS as a neurological disorder, with reference to past research techniques. However, although many investigations in past research have brought knowledge of genetic predisposition to where it is today, the understanding of MS genetically still has a long way to go. Due to its complexity and also many limitations, which will be further discussed, the genetic factors of the disease can prove difficult to investigate, thus restricting the ability to trace back to the cause of onset in order to discover possible preventions and treatments. Nevertheless research is on-going and there are new ideas and applications constantly being tested in the hope to eventually trace back to discover a cause and find treatment and a cure for this debilitating disease. (Ebers., 1995)
There is thought to be different forms of Multiple Sclerosis. One subtype of MS is relapse-remitting MS (RR-MS) which is characterized by irregular relapses followed by variable periods of remission which can last years. A second subtype is the secondary-progressive MS (SP-MS) which can occur as a result of RR-MS and involves the loss of the remission period which previously existed; the primary-progressive MS is much less common. Progressive-relapsing is even less common and is characterized by the slow neurological decline but the patient however also experiences unexpected relapses too. The subtype of MS which a patient experiences is highly important in the prediction of outcome and in the therapeutic approach to take. The occurrence of neurological dysfunction is related to the site of pathology. (Reynolds, 2011) Beta-interferon (BetaseronÂ®) is currently used as a treatment for RR-MS. (Rudick et al., 2011) The complex biological response to the sub-cutaneous injection of interferon beta (IFNÎ²) means that its mechanism of action is still poorly understood however and progression and the possibility to build on this is therefore limited.
Jean-Martin Charcot, a French neurologist, first discovered MS recognizing it as a distinctive disease in 1868 and he termed the disease "sclérose en plaques". (Matthews, 1978) This name refers to the glial scarring which occurs mainly in the white matter of the brain and spinal cord (myelinated neurons) due to an autoimmune response against myelin proteins in particular. The myelin sheaths which surround the axons within the brain act as insulation and also accelerate conduction of nerve impulses (axon potentials) between nerve cells, and within the periphery as these axons communicate with effector organs such as muscles. (Matthews, 1978) Therefore the formation of plaques (scar tissue) affects the conduction of nerve impulses along axons and therefore impairs the normal functioning of the CNS. (Kenealy, et al., 2003)
The risk of developing MS is thought to be higher within relatives, suggesting a genetic disposition for the disease. (Dyment et al., 2004) Development in genetically susceptible individuals has aimed research to identify the particular genes that are susceptible to MS. However the burden of the high complexity of the disease remains, and success in discovering a distinct gene that is thought to create a central risk is yet to be achieved. (Haines., 2002) Particular sites on chromosomes, which may contribute to the risk factor, have however been identified but few of which have sufficient evidence supporting their role in susceptibility to MS. It is evident from multiple studies that although there is definitely a genetic component involved in MS, a simple model of inheritance is not apparent. Several loci are involved in the susceptibility risk and these loci may interact with each other each contributing only a small amount to the overall risk. (Haines., 1998)
Multiple Sclerosis is thought of as an autoimmune disease as it shows many characteristics which are common to other autoimmune disorders. Although the genetics of such are not fully understood, the Major histocompatibility complex (MHC) is a common genetic site in the majority of these disorders. This one major site has been confirmed to be related to MS susceptibility. (Keneathy etal., 2003) The linkage between MS and this particular site is thought to be directly related to the human leukocyte antigen (HLA) system which forms the MHC. The process of Class II MHC molecules, such as HLA, is thought to be disrupted in MS therefore resulting in myelin sheath damage. Differences within certain components of this have been shown to increase the risk of MS through functional candidate gene studies. The MHC site was discovered through half sibling studies, adoption studies and twin studies and is now widely accepted to have a positive genetic link to MS susceptibility, the details of which will be further discussed. (Haines., 1998)
There is strong evidence for both environmental and genetic causes of Multiple Sclerosis. (Ebers., 1995) The genetic factors have been researched through population studies, family-based studies, recurrence risk studies, segregation analysis and many more to try and reveal the true genetic cause of MS. (Keneathy, et al., 2003) However many genetic studies have limited sample sizes and lack consistency when repeated which is why MS is so misunderstood. Family-based studies look into familial aggregation which refers to evidence of a trait within family members that occurs more frequently than chance. A study by Ebers, et al (1995) investigated whether the increased risk of MS in monozygotic twins compared with first-degree relatives was solely due to genetic factors, and whether environmental factors played a substantial role due to increased environmental sharing. Their results stated that the occurrence of MS in non-biological first-degree relatives did not differ significantly from the occurrence of MS in the general population. This therefore suggests a genetic factor is of higher likelihood than any familial micro-environmental factor and therefore the study concluded that familial aggregation is genetically determined. Further studies which specifically looked at comparison between monozygotic (identical) and dizygotic (non-identical) twins confirmed the importance of both the genetic and the environmental factors of MS. Refsâ€¦ These types of study have consistently demonstrated that there are higher incidences of MS in monozygotic twins than in dizygotic twins. Therefore suggesting there must be genetic factors involved in determining the susceptibility of an individual to the disease. (Kalman and Lublin., 1999) Although it is evident genetic inheritance is a factor; this is not a simple Mendelian inheritance. The transmission path of MS is extremely complicated and genetic disposition is not sufficient alone for the development of MS.
Microarray based gene expression profiling of large numbers of genes has been used by different researchers to further investigate MS and its animal model; Experimental Allergic Encephalomyelitis (EAE). (Comabella et al 2007) EAE is a complex disorder which involves a variety of immunological and pathological mechanisms which lead to the same pathological features of Multiple Sclerosis therefore it is an ideal animal model for the disease. (Constantinescu., 2011) Many of the drugs currently available for helping the treatment MS have been discovered through use of EAE studies, therefore it is hopeful that EAE could eventually help develop a cure for MS. This technique allows for the understanding of the more complex molecular basis for the disease and also can help direct research to possible treatment targets through the identification of biomarkers. (Comabella et al., 2007) However due to the many procedures involved in this type of study there is a high chance of potential errors arising (Whitney et al 2003) and therefore further investigation is still required in order to improve the reliability of such studies.
Another "breakthrough" was in 2008 when an Italian vascular surgeon, Paolo Zamboni, suggested that MS involved the constriction of the veins within the brain and was related to process with he called Chronic Cerebrospinal Venous Insufficiency (CCSVI). However, although he reported a 73% improvement in patients suffering from MS with this CCSVI disease process, other studies have found dissimilar results () and his work has been criticised due to the lack of blind testing and lack of controls. Therefore many rejections have been made to the theory that CCSVI originates from MS.
More recently research has again started to focus on the possibility relating vitamin-D deficiency as a risk for Multiple Sclerosis. (Kelly., 2012) This relationship between vitamin-d deficiency and Multiple Sclerosis was proposed a long time ago initially. () However, further immunological, genetic and epidemiological studies are necessary to exactly clarify how vitamin-d reduces the risk of MS. It is thought that high vitamin-d intake at the time of the first demyelinating events can cause a lower risk of onset and progression of MS. (Kelly., 2012) Although the evidence within this area is increasing and this could be a possible area for future breakthrough, a lot of research is still required before vitamin-d could start to be administered as a suitable treatment for MS.
Another technique which has been proposed as a possible treatment for the recovery of MS is the transplantation of olfactory ensheathing cells (OEC) into the transected spinal cord. In the rat, OEC have been shown to have the potential to support the renewal of damaged axons in spinal cord injury and also even to form myelin sheaths around demyelinated axons. (Li et al., 1997) If a similar cell based therapy could be identified in the human this could lead to a future breakthrough for both spinal cord injury and also repairing the sites of demyelination which occur in MS. However the human olfactory system is not as developed as that of the rat and therefore the ability to identify these cells is not as straight-forward and further issues include whether human OEC can be grown in tissue culture like that of the rodent. A study by Barnett et al (Barnett et al., 2000) however has indicated that OEC form the human olfactory bulb can be grown in tissue culture and then transplanted into areas of demyelination in the rat to induce the formation of new myelin sheaths. This is a step forward as before studies focussed on rodent OEC into rodent models and did were not comparable to human CNS diseases as they lacked the knowledge indicating that human OEC had remyelinating properties. (Franklin et al., 1996; Imaizumi et al., 1998) However in Barnett et al's (2000) study, not all cells expressed the ability to repair demyelinating foci suggesting that human OEC may adopt a variety of morphologies and appropriate cells would need to be selected prior to transplantation in order for successful results. Further problems which exist with the results from this study include the issue that the human OEC were obtained using invasive neurosurgery for an unrelated tumour removal. It would therefore be necessary to determine whether OECs could be obtained from the glial cells that exist outside the cranium in the olfactory epithelium as this less invasive location could lead to a more realistic treatment possibility for CNS diseases such as Multiple Sclerosis. However clinical application is drawing closer due to the discovery that human OECs are a possible candidate cell for transplantation based treatment of demyelinating diseases.
One of the problems in Multiple Sclerosis research is the lack of results when experiments are replicated. Although a huge amount of research studies have been carried out, the inability to replicate these using a different sample set means they are not considered highly accurate or reliable. A lot of problems exist such as the use of rodent models previously discussed, and the inability to compare these results and techniques with potential human treatments for Multiple Sclerosis. Successful treatment plans and the possibility of a cure for MS are under continuous research but due to the difficulties and restrictions in knowledge so far, the majority of research has proved continuously unsuccessful.
Matthews, B., 1978. Multiple Sclerosis the Facts. Oxford: Oxford University Press.