Amyotrophic lateral sclerosis (ALS), which is also called motor neuron disease, Charcot's disease, or Lou Gehrig's disease, is an age-dependent fatal paralytic disorder caused by the degeneration of motor neurons in the motor cortex, brain stem, and spinal cord. About 10 percent of cases are familial (FALS) and the rest are sporadic (SALS).
Pathogenesis and Pathophysiology. ALS is a combined gray and white matter disease, affecting motor cells and motor fiber tracts. The hallmark of ALS is atrophy, degeneration, and loss of anterior horn neurons, followed by glial replacement. There is loss of pyramidal cells from the precentral cortex and large myelinated fibers of the anterior and lateral columns of the spinal cord, the brain stem, and the cerebrum. The posterior columns are usually spared in sporadic ALS. Lower brain stem nuclei are more often and more extensively involved than upper nuclei (.Fig 36.-1. ). Therefore, oculomotor nuclei loss is modest and rarely demonstrable clinically, whereas the hypoglossal nuclei are prominently degenerated. Previously, it was thought that Clarke's nucleus was unaffected, but it is now recognized that those neurons may also degenerate. In patients who have an extended disease course due to parenteral
Figure 36-1 Spinal cord section from J-M Charcot's original presentations on amyotrophic lateral sclerosis, showing the combined anterior horn cell degeneration (f) and the sclerosis of the lateral columns (a). c and p designate anterior and posterior horn regions as normal anatomical landmarks inserted as reference points by CharcifFrom Charcot J-M: Oeuvres Completes. Paris, Bureau du Progres Medical, 1873.)
nutrition and artificial ventilation, there may be late involvement of oculomotor and sacral nuclei.
Several cytoplasmic and ultrastructural abnormalities are associated with ALS. Spheroids with a strongly argentophilic fibrillary pattern develop in conjunction with cell soma atrophy, suggesting they may be complementary processes. Ultrastructurally, the spheroids are neurofilament bundles that may contain other cytoplasmic structures, such as mitochondria. Some investigators hypothesize that the reported increase in phosphorylated neurofilaments identified using monoclonal antibodies suggests premature or excessive neurofilament phosphorylation, which may be associated with impaired neurofilament transport. Other identified structures include Bunina bodies, tiny round eosinophilic structures that may be found in neuronal cytoplasm, and Lewy body-like eosinophilic inclusions found in both SALS and FALS. The latter are immunoreactive to neurofilaments, ubiquitin, and the gene encoding Cu/Zn superoxide dismutase (SOD1). [1
Genetic linkage has identified SOD1 at 21q22.1 as the cause in 20 percent of autosomal dominant familial cases (genetic nomenclature, ALS1). This has provided the first opportunity to study any type of ALS with a proven etiology. Because SALS is not associated with mutations in SOD1 but it is clinically indistinguishable from ALS1 and pathologically very similar, authorities assume there is a common pathway involved in the two diseases. Therefore, the ALS phenotype may result from a variety of disruptions in the events required for motor neuron maintenance. Consequently, much research on the pathogenesis of motor neuron disease has focused on SOD1, an endogenous free radical scavenger enzyme. It functions as a dismutase, converting superoxide to oxygen and hydrogen peroxide, and is thought to have peroxidase and sequestration properties. Superoxide is an unstable and highly active molecule that causes oxidation of cell constituents either directly or through toxic and stable derivatives. There is a 35 to 75 percent reduction in activity of mutant SOD1 in ALS1, but there is no reduction in SOD1 activity in non-chromosome 21 FALS. In most instances, loss of SOD1 enzyme activity appears to be due to enzymatic structural instability, resulting in a shortened half-life of the mutant SOD1 protein.
Exploration of mechanisms by which mutant SOD1 causes motor neuron degeneration have focused on exaggerated or disturbed functions of SOD1. Experiments with transgenic mice expressing different mutations suggest that it is unlikely that the disease phenotype is caused by a position effect of the mutant SOD1 gene. Rather, it is more likely that a toxic effect of mutant SOD1 leads to motor neuron death. Such a toxic mechanism may also underlie FALS in humans. y
Although SOD1 activity serves as an antioxidant defense, the effects of conversion of O 2 - to H2 O2 on the viability of cells may be double edged. Hydrogen peroxide and its derivatives are directly toxic to the cell and may signal apoptosis. Because SOD1 activity is reduced in ALS1, it is conceivable that increased superoxide free radical could be responsible for the disease. Although this hypothesis is supported by a number of in vitro studies, it is not fully defensible. First, not all mutations of the SOD1 gene cause a decrease in the steady state of cytosolic SOD1 activity. Second, transgenic mice overexpressing FALS-linked mutations in the SOD1 gene on normal mouse background develop disease similar to ALS in humans, whereas those overexpressing normal SOD1 remained phenotypically unaffected. Observations from overexpression transgenic mouse models and those from SOD1 "knockout" mice strongly refute a loss of function hypothesis while supporting a gain of toxic function hypothesis. Firm conclusions are not yet possible, but increased peroxidase activity of mutant SOD1 may play a critical role in the pathogenesis of ALS1. 
Preliminary studies on protein structure using antibodies against SOD1 suggest that a common conformational change occurs in the mutants A4V, G37R, and H46R coded by exon 3 that may affect the lower rim of its electrostatic guidance channel. Crystallographic structural mapping predicts that ALS1 mutations lead to structural changes in SOD1 that may distort the lower rim of this channel, allowing the catalytic site to become shallower and more exposed. As a result, molecules normally excluded may gain access to the catalytic reactive site (rim hypothesis). y Beckman and colleagues have proposed that cell injury occurs when the mutant SOD1 reacts with peroxynitrite (ONOO- ) formed from superoxide and nitric oxide with resultant nitration of tyrosine residues of critical cytosolic proteins. [3 The access of peroxynitrite would be in keeping with the model of promiscuous accessibility to the copper site.
Finally, mutant SOD1 may exhibit metal-mediated cytotoxicities by disrupting the intracellular homeostasis of copper and zinc. It is well known that copper and zinc are potential neurotoxins, and sudden en masse release of zinc from SOD1 aggregates in motor neurons may lead to cell death. [2
Different SOD1 mutations of ALS1 do not seem to influence age of onset, but they do influence the progression of the disease, with the A4V mutation duration averaging 1.2 years, the E100G mutation 4.7 years, and the H46R and G37R mutations averaging 18 to 20 years. [2
In genetic research, the risk to relatives of an affected person as compared to the general population can be calculated with greater estimates corresponding to larger genetic control of trait variation. The estimated risk to siblings of ALS patients suggests that there is a significant genetic contribution. ALS1 represents a large genetic effect in a small ALS population (2.5 percent of ALS cases). Conversely, SALS may result from a genetic predisposition due to multiple small effects in larger ALS populations. Thus, newer techniques of identifying these effects, such as transmission disequilibrium testing, are being applied to SALS. Genes for glutamate transporters, calcium homeostasis, apoptosis, or intracellular protein cargo transport are reasonable candidates for evaluation. y
Rare recessive ALS (RFALS), which produces three different phenotypes classified according to type and timing of motor neuron involvement, has been identified in highly consanguineous families. RFALS type 3 (genetic nomenclature ALS2) has been linked to chromosome 2q33, and RFALS type 1 (genetic nomenclature ALS4) has been linked to another site that has not yet been published; several other families remain unlinked. y
FALS with dementia, a disinhibition dementia-parkin
sonism-amyotrophy complex has been linked to a region on chromosome 17q21-22  (see Chapter.33 ).
A number of abnormalities in metabolism of the excitatory neurotransmitter glutamate have been identified in ALS, including alterations in tissue glutamate levels, transporter proteins, postsynaptic receptors, and indications of possible toxic agonists. Whether these are primary or secondary events and how they relate to the genesis of ALS is unclear but under intense investigation. [5
Epidemiology and Risk Factors. Broadly, there are three types of ALS usually considered in epidemiological studies: SALS, FALS, and a variant of ALS, sometimes called Guamanian ALS, found in the Western Pacific, that is characterized by the co-occurrence of parkinsonism or dementia, or both, in some patients. Sporadic ALS has a worldwide incidence of 1 to 2 in 100,000 persons, with fairly uniform distribution worldwide and equal representation among racial groups. The occurrence of ALS before the age of 40 years is uncommon. The incidence is greatest between the ages of 50 and 70 years, and it seems to decline thereafter. The male-to-female ratio is about 1.3:1. Clusters of the disease have been identified, particularly in the Kii peninsula of Japan and the Mariana Islands. The only indisputable risk factor other than age and gender is genetic susceptibility, with familial cases occurring in about 10 percent of most case series. Many isolated potential etiologies have been proposed for sporadic ALS, with the only consistent associations thus far being long-term exposure to heavy metals, particularly lead, and a family history of parkinsonism and dementia.^
Clinical and Associated Disorders. ALS is a syndrome of upper and lower motor neuron dysfunction at several levels of the neuraxis without involvement of other neurological systems. There is no definitive test that can diagnose ALS. In 1994 the El Escorial criteria were developed to standardize its diagnosis ( „TabJeJS-l ). M
_TABLE 36-1 -- SUMMARY OF EL ESCORIAL CRITERIA FOR THE DIAGNOSIS OFAMYOTROPHIC LATERAL SCLEROSIS (ALS)_
The diagnosis of ALS requires the presence of signs of lower motor neuron (LMN) degeneration by clinical, electrophysiological, or neuropathological examination and signs of upper motor neuron (UMN) degeneration by clinical examination, and the progressive spread of these signs within a region or to other regions, together with the absence of eleetrophysiological or neuroimaging evidenee of other disease processes that might explain these signs.
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