Recent studies have provided some insight for the possible causes of the familial type of amyotrophic lateral sclerosis (FALS). This disease occurs only in 10% of the known cases of ALS with the sporadic, non-hereditary form being predominant [7, 9]. ALS in general has an occurrence of 0.4 to 1.8 per 100,000 live births [1]. ALS has been called Lou Gehrig’s disease, Charcot’s disease and motor neuron disease in other literature [4]. ALS is a neurodegenerative disease of upper and lower motor neurons that can manifest in such a way that it can be misdiagnosed. Such areas include respiratory muscles with initial diagnosis of asthma, or even psychological problems that appear as a dementia [7]. The primary manifestations are not restricted to any certain area of the body. FALS is inherited autosomally as a dominant trait [9,12,13,17]. It exhibits heterogeneity and may not be present in a consecutive generation [1]. It is diagnosed usually near the age of fifty and ranges from 20-72 years [9,17]. Most patients are given a prognosis of 5 years of life after diagnosis [5]. It has also been proposed that the juvenile form may be recessive. There is a predominance of maternal transmission in later onset and paternal transmission in early onset [9].

The bulk of this paper will deal with the SOD1 gene mutations as the proposed cause for some types of FALS. Many other hypothesis have been developed and will be briefly addressed at this point. Autoimmune disease and mutations in the glutamate receptor are other proposed causes.

Autoimmune disease has been studied as a possible agent for the cause of FALS [6]. Supportive evidence includes the deficiency of IgG1 or IgG3 or both in 16/25 observed patients; subclass deficiency could be occurring in some patients who were not included in the group of 16. In the clinical setting total IgG is most often measured and this may obscure an underlying subclass deficiency [15].

Mutations in the glutamate receptors have also been studied. Glutamate is known to be a powerful neurotoxin [6]. The GluR5 gene, located on chromosome 21, codes for the glutamine receptor N--Methyl D-Aspartate (NMDA) which is also located near the locus for the familial form of ALS. This includes it as a possible causative agent for ALS, as well [3,5,6]. Clear delineation’s between motor neuron disease, Parkinson’s disease and dementia are hard to make [7]. The definition of ALS includes degeneration of upper and lower motor neurons. Sometimes dementia may be the result of ALS and this may be misdiagnosed.

FALS is considered an autosomal dominantly inherited trait. Due to the rare occurrence, few twin studies have been made; however, there has been a set of identical twins found in which one was diagnosed with ALS and the other was not [12]. There can be a problem in reviewing FALS due to under-reporting and incomplete family histories. Family studies are as extensive as possible and even involve reviewing death certificates. More in depth studies have involved the investigation of gene defects. Interfamilial and intrafamilial heterogeneity have been studied [1].

The SOD1 gene of chromosome 21 has been proposed as the causative agent for several cases of FALS [ 3, 4,11]. The SOD gene encodes the peptide superoxide dismutase [11]. FALS has been linked to the long arm of chromosome 21 with the SOD gene at or near the same locus [5,10]. In all of the mutations analyzed, one chromosome was normal and one had the mutation [16].

The activity of SOD in the body is to convert the superoxide radical into hydrogen peroxide [16]. Decreased activity of the enzyme may lead to increased levels of free radicals and eventual neurodegeneration [4, 10]. Free radicals other than superoxide may also be produced indirectly [10]. The polymerase chain reaction (PCR) and single-stand conformational polymorphism (SSCP) have been utilized to help isolate mutations causing ALS. The analysis leads to visualization of sequence variations [16]. The SOD1 mutations are not usually related directly to the catalytic site, but disrupt the 3D structure of the enzyme. This could reduce the stability and the activity of the enzyme [4,5,11]. Any of the twelve different amino acids in the SOD enzyme can be changed; however, one missense mutation—the replacement of Alanine with Valine at position 4--was found to be common [4,11]. The activity of several mutations have been measured. this results in 40% decreased activity [4]. Of the exons studied, no changes were found in exon 3, but mutations were found in exons 1,2,4, and 5 (single base pair changes) [4,16]. For their identification PCR and SSCP were analyzed.

Restriction enzymes have been used to find restrictions sites that can be altered by various mutations of SOD. The fragments that were found in the mutated genes were compared to fragments formed from the same procedure with a normal patient control. Different fragments were found in 70 ALS patients vs 73 normal controls [16]. Other restriction enzymes were used as well and led to the conclusion that the changes were not normal allelic variations.

In some mutations the SOD activity may even be increased. The amino acids isoleucine 113 and leucine 106 are thought to form intrachain hydrogen bonds. This could increase the thermos/ability of SOD and increase the activity and i/2 life [16].

The alanine to valine mutation would disrupt the subunit fold and the dimer contact; this does not effect the active site of the enzyme, but does effect the stability and ½ life [2,4]. Other specific mutations have been studied and similar findings were also found that did not effect the active site, but did alter the stability of the enzyme [4]. It was also stated, that the dominance of the disorder may indicate that both subunits of the dimer are effected. SOD enzymes are found all over the body. Mitochondrial SOD (MnSOD) and extracellular fluids (EcSOD) may partially compensate for the defective SOD in some form of ALS which could indicate the occurrence in later years of life [4]. It is also believed that the other SOD forms may be causative agents for the sporadic form of ALS and this hypothesis should be further pursued [4,16]. Research has found that MnSOD is up-regulated in some patients, which would support this theory [4].

Nitric oxide is produced by interneurons that surround motor nuclei. Interneurons may indirectly contribute to the neurodegeneration found in ALS. Superoxide is known to act with nitrous oxide at a 3X faster rate than with SOD. The result is a more powerful oxidant peroxynitrite (ONOO)[3]. The peroxynitrite can then react with SOD forming an intermediate that nitrates tyrosine residues [2]. Peroxynitrite can also lead to the generation of hydroxy radicals, which are more toxic than superoxide radicals [16]. Furthermore, the assumed decrease in SOD activity in ALS patients leads to increased superoxide levels almost by 50%, which further up-regulates the above mechanisms. The importance of these actions is that nitration of proteins can slowly injure cells including motor neurons. Motor neurons are at a disadvantage because they cannot regenerate once they have been harmed. These findings further support the SOD mutation theory for the causative agent for some FALS.

There are patients with FALS that do not have mutations in the SOD gene. The problems associated with these patients may have arisen from some kind of trauma or inflammation near motor neurons. The trauma could lead to peroxynitrite formation which could cause neurodegeneration [2]. Death usually occurs for ALS patients by their fifth year after diagnosis. Sometimes, prolongation can be made by intubation and artificial respiration; however, quality of life is not improved and the progressive nature of the disease is not halted [14]. Survival time may be decreased if protein levels in CSF are elevated. Reports indicate that levels > 0.45 g/L occurs in 32% of cases and > 75 g/L in 12% of the cases. This correlates with a decreased mean survival time. This proves to be a significant measurement that clinicians should be aware of when counseling patients.

If SOD is the causative agent for some FALS, treatment with compounds that reduce levels of free radicals would be beneficial [10,18]. This could apply to the sporadic form as well, but more investigation is necessary; The sporadic form may be caused by similar mechanisms. Hopefully clinical trials of SOD or other compounds that can penetrate the CNS and reduce levels of free radicals can be applied. Such treatments are currently being tried for Parkinsonism and may be helpful for patients with ALS [16].

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