title: Gene Expression and Variation in Multiple Sclerosis
Creators: name: Szvetko, Attila Laszlo
Publisher: name: Griffith University
Year: 2009
Subjects: subject: Multiple Sclerosis
subject: MS
subject: gene expression
subject: neurological diseases
subject: central nervous system
subject: CNS
subject: relapsing-remitting multiple sclerosis
subject: RRMS
subject: secondary-progressive multiple sclerosis
subject: SPMS
subject: primary-progressive multiple sclerosis
subject: PPMS

description: Neurological diseases are complex and difficult diseases to study. Although new approaches and therapies have been developed for other disorders such as Alzheimer’s, Epilepsy, and Parkinson’s disease, Multiple Sclerosis (MS) still remains seemingly inexorable. MS is the archetypal complex disease; it is a paradigm of debilitating neuropathology. Discounting trauma, MS is the most common chronic neurological condition resulting in disability affecting young adults. In its typical form it primarily affects the brain, spinal cord, and optic nerves and is characterised by lesions in the central nervous system (CNS) separated in space and time. Chronic inflammatory cells have been shown to be involved and axons and myelin are ultimately damaged. The changes observed in the MS brain are not uniformly distributed with foci of inflammation termed lesions or plaques being spread throughout the CNS. Inflammatory demyelination of the CNS leads to aberrant conduction of nerve signals resulting in anomalous impulse trafficking. This aberration results in a diverse array of neurological signs and clinical features. The MS plaque evolves with time; in the early stages there is local breakdown of the blood-brain barrier (BBB), then inflammation and oedema, loss of myelin, and finally the deposition of the CNS equivalent of scar tissue; gliosis. The resulting shrunken area of sclerosis may or may not be associated with clinical deficits depending on the localisation and extent of the lesion. The CNS shows some potential for remyelination, and patients often experience remissions characterised by return of normal function. ii The underlying pathological sequence corresponds to the clinical patterns seen in sufferers, with characteristic phases of relapses and remissions. Several clinical courses of the disease are recognised and serve to distinguish different stages of the disease. Approximately 80% of patients present with the relapsingremitting form of the disease (RRMS). This phase sees the patient suffering paroxysmal symptomatic episodes with near-complete remissions. Residual disability may accumulate with time and this leads to the next stage, the secondary-progressive form (SPMS). The SPMS course is similar to the RRMS phase but for the steady accumulation of neurological deficits and disability. The third and most severe phenotype of the disease is the primary-progressive form (PPMS). The PPMS course is characterised by progressive disability, although not necessarily uniformly increasing with time, and does not generally involve remissions. The natural history of MS is highly variable and patients show variable expressivity with some progressing through all stages swiftly while others do not. Amalgamating numerous lines of evidence, the foremost hypothesis is that MS is the result of an environmental trigger in genetically susceptible individuals. The role of immune mechanisms in MS is most strongly supported by the presence of chronic inflammatory cells, and findings that genes in the major histocompatibility complex (MHC) are specifically involved. The MHC findings in conjunction with twin concordance studies lend strong support to the notion that MS involves a significant genetic component. MS is more common in temperate regions than the tropics and this geographical variation is thought to suggest an environmental factor (e.g. virus) may trigger the condition in susceptible individuals. Epidemiological studies have taught us that MS risk can be transferred from location to location if the sufferer relocates, however the risk appears to be correlated with where the first 15 or so years of life were spent. Not discounting other possible causes or multiple triggers, these two lines of evidence together suggest that if an environmental factor does in fact trigger the disease, it is most likely to be active in the first few decades of life...