Current concepts on amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a progressive degenerative disease of the upper (motor cortex) and lower motor neurons (anterior horns). ALS occurs in sporadic (90% of all cases) and familial forms. There is general agreement that the death of the motor neurons results from a cascade of toxic events triggered by a variety of factors not well identified. It is very likely that ALS may be caused by a variety of primary insults, all of which culminate in the final degeneration of motor neurons. There are currently five major mechanisms to explain the pathogenesis of ALS: the excitotoxins (cellular damage based in glutamate's toxic actions), oxidative stress, calcium channel autoantibodies, the relation of the disease with several neurotrophic factors and the anomalies in neurofilaments and cytoskelet. The relation of these mechanisms with initial triggers is suspected. Evidence suggests that environmental factors (unusual virus infections, heavy metals) may be important triggers. The discovery of Cu/Zn superoxide dismutase (SOD1) mutation in 20-30% of patients with familial ALS is a very important event in ALS research,because mechanisms about how mutant SOD1 leads to motor neuron degeneration have begun to be elucidated and will greatly assist to understand the process of damage in sporadic ALS. A consensus has developed that a key strategy for increasing benefit is the treatment of ALS patients with a combination of drugs that are effective individually to achieve additive or synergistic benefits. The approval of Riluzole (antiglutamate agent) as the first drug to treat ALS and the experimental work with several neurotrophic factors that slows the progression of the disease, brought the treatment of ALS into a new era, with several ethic questions about the appropriate selection of candidates to each therapy.