Progressive loss of motor neurons from the anterior horn of the SPINAL CORD and, in the later stages of the disease, from the motor nuclei of the CRANIAL NERVES and CEREBRAL CORTEX. Degeneration of the spinal CORTICOSPINAL TRACTS (lateral sclerosis) and associated muscle wasting (amyotrophy) account for its name. In the USA the condition is also associated with the name of Lou Gehrig, a sports personality, and in the UK with the well-known figure of Stephen Hawking, astrophysicist and best-selling author.
The disease usually presents in middle age with limb weakness and FASCICULATION—fleeting contractions of isolated muscle bundles, visible in one muscle after another. A paradoxical increase in the strength of tendon reflexes coupled with weakness and wasting of the same limb is a distinctive feature. The paradox is accounted for by the loss of spinal (lower motor) neurons being accompanied by loss of inhibitory input from cortical (upper motor) neurons. As the disease progresses, gradual involvement of cranial nerve nuclei (that is, progressive BULBAR palsy) leads to increasing difficulty with swallowing and speech, but eye movement, sphincter control and intellect are usually preserved.
The cause of ALS remains unknown.
Evidence for the involvement of a virus, dietary toxins or autoimmune processes is weak. About 10% of cases are familial, showing AUTOSOMAL DOMINANT inheritance, and of these about one-fifth carry one of many identified mutations affecting the gene (SOD1) that encodes the enzyme copper/zinc SUPEROXIDE DISMUTASE. This enzyme is thought to confer protection against oxidative damage by free radicals, but the harmful effects of the mutant gene product are also likely to result from a gain in function that causes it to act as an oxidant in its own right. The role of OXIDATIVE STRESS in sporadic (non-familial) ALS has not been clearly established. Other possible contributory factors include endogenous EXCITOTOXINS, especially the amino acid neuro-transmitter GLUTAMATE. Excessive extracellular concentrations of this compound in the spinal cord are thought to result in harmful trans-membrane inward currents of calcium ions (Ca2+); certain glutamate antagonists (for instance, riluzole) have accordingly been approved for the long-term treatment of ALS but their efficacy and the rationale for their use have been questioned. Therapeutic trials with intrathecal injections of ciliary neurotrophic factor, a NEUROTROPHIN, have met with limited success. Supportive treatment of advanced ALS with artificial feeding, assisted breathing, synthesized phonation and computerized communication has reached a high degree of sophistication but may not be unreservedly welcomed by those involved.
L.JACOB HERBERG
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