**3. Familial ALS**

The only forms of MND in which a clear cause has been established are the genetic variants. 20% of all familial cases are the dominantly inherited adult onset form of MND, which is clinically indistinguishable from the sporadic form of MND. These are due to a point mutation in the cytosolic Cu, Zn superoxide dismutase 1, (SOD1) gene on long arm of chromosome 21 (21q22.1). (Siddique & Deng, 1996). Mutations in other genes, alsin and the heavy subunit of neurofilament (NEFH) can also result in motor neurone degeneration in humans. Two other genes that have been investigated are the other isoforms of SOD. MnSOD (SOD2) maps to chromosome 6q25 and is primarily located in mitochondria and extracellular SOD (SOD3) maps to chromosome 4p15.2. Neither of these genes have yet to be linked to FALS. (Hand & Rouleau, 2002). There is however genetic heterogeneous and other causal genes remain to be found to explain the vast majority of FALS cases. (Siddique et al., 1989).

The initial study to establish a causal link between the SOD1 gene and familial MND (FALS) identified a total of 11 missense mutations in two exons studied in 13 autosomal dominant MND families. (Rosen et al., 1993). This led to an explosion of SOD1 gene screening in MND pedigrees. To date 112 different mutations in the SOD1 have been found which can lead to changes throughout the protein. There have been 99 substitutions, 5 polymorphisms, 3 insertions, 4 deletions and 1 compound mutation types identified. Mutations have been identified in all five exons of the gene. These include 20 on exon 1, 13 on exon 2, 8 on exon 3, 39 on exon 4 and 29 on exon 5 (Figure 1). There have also been 2 non-exon mutations identified on intron 4 and intron 1 and 14 'apparently' sporadic cases described with 6 different SOD1 mutations. (Shaw et al., 1998).

**Figure 1.** Number of SOD1 mutations identified for each exon

weakness due to myelin alteration. At this point, there was a striking loss of motor units. There was also decrease in evoked motor potentials (an indirect measure of the number of motor units), prior to the onset of symptoms. The onset of disease in transgenic G93A mice involves a sharp decline of muscle strength and a transient explosive increase in vacuoles derived from degenerating mitochondria, but little motor neurone death. These did not die until the terminal stage. (Kong & Xu, 1998). The decline exhibited kinetics consistent with both a constant and exponentially decreasing risk of neuronal death. An escalating risk forced by cumulative

It is possible that the high metabolic activity in motor neurones, combined with the toxic oxidative properties of the mutant SOD1, causes massive mitochondrial vacuolation in motor neurones, resulting in degeneration, earlier than other neurones, triggering the onset of weakness. The involvement of mitochondrial degeneration in the early stages is consistent with a direct effect of toxicity, mediated by properties gained by the mutant enzyme in

Until recently, it has not been possible to address this in humans, as pre-symptomatic diagnosis was not possible. Now, with the ability to identify Cu, Zn superoxide dismutase 1, (SOD1) mutation carriers, a group of human pre-symptomatic subjects can be studied to determine whether there was gradual lifelong pre-symptomatic loss of motor neurones or whether sudden catastrophic loss of motor neurones occurs just prior to the onset of clinical symptoms.

The only forms of MND in which a clear cause has been established are the genetic variants. 20% of all familial cases are the dominantly inherited adult onset form of MND, which is clinically indistinguishable from the sporadic form of MND. These are due to a point mutation in the cytosolic Cu, Zn superoxide dismutase 1, (SOD1) gene on long arm of chromosome 21 (21q22.1). (Siddique & Deng, 1996). Mutations in other genes, alsin and the heavy subunit of neurofilament (NEFH) can also result in motor neurone degeneration in humans. Two other genes that have been investigated are the other isoforms of SOD. MnSOD (SOD2) maps to chromosome 6q25 and is primarily located in mitochondria and extracellular SOD (SOD3) maps to chromosome 4p15.2. Neither of these genes have yet to be linked to FALS. (Hand & Rouleau, 2002). There is however genetic heterogeneous and other causal genes remain to be

The initial study to establish a causal link between the SOD1 gene and familial MND (FALS) identified a total of 11 missense mutations in two exons studied in 13 autosomal dominant MND families. (Rosen et al., 1993). This led to an explosion of SOD1 gene screening in MND pedigrees. To date 112 different mutations in the SOD1 have been found which can lead to changes throughout the protein. There have been 99 substitutions, 5 polymorphisms, 3 insertions, 4 deletions and 1 compound mutation types identified. Mutations have been identified in all five exons of the gene. These include 20 on exon 1, 13 on exon 2, 8 on exon 3, 39 on exon 4 and 29 on exon 5 (Figure 1). There have also been 2 non-exon mutations identified

found to explain the vast majority of FALS cases. (Siddique et al., 1989).

damage was not responsible for cell death. (Azzouz et al., 1997).

catalysing redox reactions. (Beckman et al., 1993).

186 Current Advances in Amyotrophic Lateral Sclerosis

**3. Familial ALS**

Most are autosomal dominant in inheritance, but there is one confirmed autosomal recessive mutation, the D90A mutation in exon 4. This is unique in that it exists in dominant families in a heterozygous state, but in a number of pedigrees, specifically those of Scandinavian ancestry, homozygous mutations are required for disease. (Andersen et al., 1997).

Mutations in the heavy polypeptide 200kDa subunit of neurofilaments (NEFH) have been identified in sporadic MND cases, (Figlewicz et al., 1994) and in one FALS case. (Al-Chalabi et al., 1999). Accumulation of neurofilaments in cell bodies and axons of motor neurons is a pathological hallmark of early stages of many neurodegenerative diseases. These mutations lie in the region of the protein involved in cross-linking and thus may disrupt normal aggre‐ gation of filaments. Thus far, 1 insertion and 5 deletion mutations have been identified on exon 4. Analysis of the NEFH locus on chromosome 22 however has failed to detect linkage in MND families. (Vechio et al., 1996). Genome search on a large pedigree with autosomal dominant juvenile onset MND found strong evidence for linkage to chromosome 9q34 (ALS4). The average age of onset is 17 years, with slow progression of disease. (Chance et al., 1998). There is also an autosomal recessive, juvenile onset MND, with linkage to a locus on chromosome 15 (ALS5). (Hentati et al., 1998).

The other 90% of all MND patients have the sporadic form. There is no recognisable phenotypic difference between FALS and sporadic MND. The male: female ratio is 1:1 in FALS and 1.7:1 in sporadic MND. (De Belleroche et al., 1995). This decreases with increasing age of onset and approaches 1:1 after the age of 70. (Haverkamp et al., 1995). The site of onset is variable. Survival does not seem to be affected by age or gender, but rather the site of symptom onset. Generally, bulbar onset disease has a worse prognosis, and upper limb onset is more favour‐ able. (Mulder et al., 1986).

It has be postulated that sporadic MND may be the final development of a chain of events that may be set in motion at one or more places in the central nervous system by endogenous and exogenous causes, or both. The aetiology of MND however remains unknown and is probably multifactorial. (Eisen 1995). There is no evidence to support the cause of sporadic MND being due to accumulation of heavy metals in the environment, (Needleman, 1997), deficiencies or excess of essential trace metals, (Mena et al., 1967) or exposure to environmental poisons and industrial solvents. (Leigh, 1997). There is also no evidence to support the cause of sporadic MND being due excessive physical activity or antecedent trauma.
