An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria

https://www.cell.com/neuron/pdf/S0896-6273(12)00756-8.pdf

Synaptic Energy Use and Supply

We have performed a systematic review to summarize current knowledge concerning factors related to survival in ALS and to evaluate the implications of these data for clinical trials design. The median survival time from onset to death ranges from 20 to 48 months, but 10-20% of ALS patients have a survival longer than 10 years. Older age and bulbar onset are consistently reported to have a worse outcome. There are conflicting data on gender, diagnostic delay and El Escorial criteria. The rate of symptom progression was revealed to be an independent prognostic factor. Psychosocial factors, FTD, nutritional status, and respiratory function are also related to ALS outcome. The effect of enteral nutrition on survival is still unclear, while NIPPV has been found to improve survival. There are no well established biological markers of progression, although some are likely to emerge in the near future. These findings have relevant implications for the design of future trials. Randomization, besides the type of onset, should take into account age, respiratory status at entry, and a measure of disease progression pre-entry. Alternative trial designs can include the use of natural history controls, the so-called minimization method for treatment allocation, and the futility approach.

/pdf/prognostic-factors-in-als-a-critical-review-2qjr56a63n.pdf

Prognostic factors in ALS: A critical review

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disease of motor neurons, resulting in worsening weakness of voluntary muscles until death from respiratory failure occurs after about 3 years. Although great advances have been made in our understanding of the genetic causes of ALS, the contribution of environmental factors has been more difficult to assess. Large-scale studies of the clinical patterns of ALS, individual histories preceding the onset of ALS, and the rates of ALS in different populations and groups have led to improved patient care, but have not yet revealed a replicable, definitive environmental risk factor. In this Review, we outline what is currently known of the environmental and genetic epidemiology of ALS, describe the current state of the art with respect to the different types of ALS, and explore whether ALS should be considered a single disease or a syndrome. We examine the relationship between genetic and environmental risk factors, and propose a disease model in which ALS is considered to be the result of environmental risks and time acting on a pre-existing genetic load, followed by an automatic, self-perpetuating decline to death.

The epidemiology of ALS: a conspiracy of genes, environment and time

Increased expression of neurofilament subunit NF-L produces morphological alterations that resemble the pathology of human motor neuron disease

Clinical features and differential diagnosis of classical motor neurone disease. Spinal muscular atrophies. The post-polio motor neurone disease. ALS.PD comples on Guam. Natural history. Neurophysiology. The management of the early case. Coping with the disability of established disease. Respiratory function in motor neurone disease. Nutritional support in motor neurone disease. Terminal care. What part can lay MND/ALS associations play in research. Classical pathology. Molecular patholgy: ubiquitin. Neurofilamentous pathology. Epidemiology. Familial motor neurone disease. Gene expression in motor neurone disease. Environmental/gentic interaction. Excitatory amino acids. Metals and free radicals in motor neurone disease. Autoimmune aspects of amyotrophic lateral sclerosis. Trophic factors. Chemical toxins. Viruses and motor neurone disease - the viral hypothesis lives. Neuropeptides - occurrence in motor nerves and relevance to motor neurone disease. Cell culture of motor neurons. Trials in MND.

John L.R. Forsythe

Papers

Motor Neuron Disease