als pathogenesis

However, longer survival is not rare. Upstream targets include genetic mechanisms such as SOD1. Armon C. Occurrence of amyotrophic lateral sclerosis among Gulf War veterans. There are also p62-positive neuronal cytoplasmic inclusions, composed of dipeptide repeat (DPR) proteins formed by translation from the abnormally expanded repeat in C9orf72. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Radiotherapy reduces sialorrhea in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis genetics with Mendelian inheritance. PLoS Genet. Van Laere K, Vanhee A, Verschueren J, et al. 2006 Dec 22. On the other hand, the abundance of potential mechanisms has led to many attempts at treatments which usually fail in clinical trials.51 The potential reasons for failure are many, and include the wrong target, inappropriate pharmacodynamics, route of administration, outcome measures, publication bias and the probability that there may be different pathogenic mechanisms at play in different patients.

[Full Text]. Brooks BR, Miller RG, Swash M, Munsat TL. ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration. J Neurol Neurosurg Psychiatry. 2002. Neuroepidemiology. 2009 May 12. There is much discussion of how best to approach this from a clinical point of view, and there are a range of theories.57 At one extreme, the identification of a gene may be helpful for decision making in families with clear multi-generation autosomal-dominant inheritance, such as some families with SOD1 mutations. 123(3):409-17. Amyotroph Lateral Scler. 108 (1):260-5. As the number of motor units innervating a muscle decreases further, reinnervation can no longer keep up with denervation, permanent weakness develops and progresses, and the affected muscles gradually atrophy. In PMA, as in ALS, the factors present at diagnosis that predicted shorter survival were greater number of body regions affected, lower FVC, and lower ALSFRS-R score. 2012. More convincing evidence for racial differences has come from an epidemiologic study in Cuba. [66] In their analysis of an extended North American clinical series, DeJesus-Hernandez et al found the C9orf72 expansion in 23.5% of patients with ALS cases and 11.7% of patients with familial frontotemporal dementia. Neuroepidemiology. 323(5918):1205-8. There is no evidence of infectivity of ALS, although conjugal cases occur rarely. [Medline]. Armon C. Amyotrophic lateral sclerosis and soccer: a different epidemiological approach strengthen the previous findings. [Full Text]. Patients with other forms of familial ALS may be referred to centers with a research interest in familial ALS. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. [Medline]. Four per cent of patients had variants in more than one gene. [Medline]. 280(52):42826-30. Using statistical modelling, a six step process has been identified as underlying ALS pathogenesis, with conceptual similarities to cancer pathogenesis.1 The findings at the late stage of disease probably do not represent, and may mask, factors earlier in the disease, which predates onset of any symptoms and signs. Proc Natl Acad Sci U S A. Neuroepidemiology. A pathway analysis of results from two ALS genome-wide association studies (GWAS) supported shared genetic pathways with Alzheimer's disease and Parkinson's disease.29 A range of neurodegenerative diseases, beyond ALS and FTD, are more frequent than expected in individuals with large C9orf72 hexanucleotide repeat expansions.30 It remains probable that ALS is the final end point of a number of different pathogenic pathways, converging at the clinical presentation. [Medline]. 2012 Aug 23. [Medline]. [Medline]. 2009 Feb. 39(2):137-43. Pasinelli P, Brown RH.

2009 Apr. An alternative trigger for disease onset might be appearance of a misfolded intracellular protein that induces other proteins to misfold, with cell-to-cell transmission of the misfolded protein within the motor network. [Medline].

1994 Apr. Andersen PM, Al-Chalabi A. 1996 May 25. 167-206.

[Medline]. Almeida V, de Carvalho M, Scotto M, Pinto S, Pinto A, Ohana B, et al. Ann Neurol. [Full Text]. Ravits J, Paul P, Jorg C. Focality of upper and lower motor neuron degeneration at the clinical onset of ALS. Many specific heritable gene mutations have been described in familial ALS (see Table 1, below). J Neurol. The disorder is named for its underlying pathophysiology, with “amyotrophy” referring to the atrophy of muscle fibers, which are denervated as their corresponding anterior horn cells degenerate. [Medline]. Laaksovirta H, Peuralinna T, Schymick JC, Scholz SW, Lai SL, Myllykangas L. Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Borenstein AR, Mortimer JA, Schellenberg GD, Galasko D. The ALS/PDC syndrome of Guam and the cycad hypothesis. [124] Exclusion of injuries occurring within 3 years of diagnosis is necessary to have some assurance that the injury occurred before biologic onset of the disease, which likely precedes clinical onset by several years. 1994 Oct. 44(10):1872-7. Al-Sarraj S, King A, Troakes C, Smith B, Maekawa S, Bodi I, et al. Neurobiol Aging. Physical activity, including sports and repeated traumatic events, was not found to be a risk factor for ALS and could be protective.26 Repeated head trauma was associated with risk of ALS,20 and intriguingly TDP-43-positive inclusions have been identified in the frontotemporal brain and spinal cord of people with chronic traumatic encephalopathy.27 There are studies suggesting associations with football, smoking, heavy metals, pesticides and chemicals, occupation, military service, electric shock, geography and cyanotoxins, but the evidence is not clear, and proof of causation not available.2,28, There are a wide range of potential pathogenic mechanisms, reflecting the range and fashion of mechanisms of neurodegeneration. Neurology.

Age at onset in sod1-mediated amyotrophic lateral sclerosis shows familiality. 2012 Mar. Majounie E, Renton AE, Mok K, et al. Armon C. Smoking may be considered an established risk factor for sporadic ALS. [Medline]. Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. [Medline]. Science. This in turn lends credibility to the concept of a focal trigger for ALS onset that generates the production of 1 or more agents of spread.

2008 Apr. Menke RA, Korner S, Filippini N, et al. 65(4):378-85. [Medline]. 2003 Nov 11. [Medline]. Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial. 79(19):1970-4. The identification of C9orf72 hexanucleotide repeats as the most frequent genetic background to ALS, and the association with frontotemporal dementia, gives the potential of a genetic background against which to study other risk factors, triggers and pathogenic mechanisms, and to develop potential therapies.

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[81]. [Medline]. A key question remains as to why the motor neurons are selectively involved. [20, 21] Loss of ability to integrate motor function (apraxia), a premotor function, is seen at times. 62(1):42-52. 2004 May 25. [Medline]. It is a rapidly progressive degeneration of upper and lower motor neurons, which results in weakness and wasting of muscle in the arms, leg, trunk and bulbar region. 169(1-2):13-21. Braak H, Brettschneider J, Ludolph AC, et al.

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