**2. Overview of genetics of ALS**

The inheritance of FALS in many families is atypical with one proband and one or two first/second degree relatives who also have the disease (Valdmanis & Rouleau 2008). The first big breakthrough in the genetics of FALS came in 1993 with the discovery of

Genetics of Familial Amyotrophic Lateral Sclerosis 519

The three most common genetic causes of FALS, together accounting for approximately 30%

The first genetic cause of familial ALS was identified by Rosen and colleagues (Rosen et al 1993) when, following analysis of FALS pedigrees demonstrating linkage to chromosome 21, mutations were identified in the *SOD1* gene. Since then, over 150 mutations have been described throughout the 5 exons encoding the gene consisting predominantly of missense mutations, although nonsense mutations, insertions and deletions have also been described (Lill et al 2011). The frequency of *SOD1* mutations is widely reported to be 20% of FALS cases, though this varies across European and North American populations, from 12% in Germany to 23.5% in USA (Andersen 2006). Whilst the majority of mutations are inherited in an autosomal dominant manner, in Scandinavia the p.D90A mutation is polymorphic, (0.5-5% of Scandinavian populations), with the disease manifesting only in individuals who are homozygous (Andersen et al 1995). However, this inheritance pattern is not attributable to the specific amino acid substitution, as p.D90A has been shown to be inherited as an autosomal dominant mutation in other populations. Mutations in *SOD1* have also been identified in sporadic ALS, albeit at lower frequencies, suggesting that some mutations have reduced penetrance. This has been shown in a family where the p.I113T mutation shows

Clinically, *SOD1* mutations are not associated with a distinctive phenotype. Individuals with *SOD1*-related ALS predominantly manifest with limb onset ALS, with symptoms more likely to start in the lower limbs (rather than upper limbs). However, bulbar onset is seen in approximately 7% of *SOD1*-related cases (ALSoD database: http:alsod.iop.kcl.ac.uk). Whilst duration of disease varies widely among *SOD1* mutations, even within members of the same family with the same mutation, the p.A4V mutation has been shown to be associated with a rapid disease progression and only 1-2 years survival (Andersen 2006). In contrast to the indistinguishable clinical phenotype, *SOD1*-related ALS cases appear to have a characteristic pathology distinguished by SOD1 positive, but TDP-43 negative, protein

The mature SOD1 protein is a homodimer of 153 amino acid subunits. This free radical scavenging protein converts the superoxide anion to hydrogen peroxide; this in turn is converted to water and oxygen by glutathione peroxidise or catalase. Mutations in *SOD1* cause a toxic gain of function in the resulting mutant protein, though the mechanism(s) by which this brings about selective neurodegeneration of the motor neurones appears to be a complex interplay between multiple interacting pathomechanisms. The main hypotheses involve either an altered redox function or misfolding of the protein leading to aggregation (Rakhit & Chakrabartty 2006). Interestingly, not only have SOD1 positive aggregations been seen in SALS spinal cord, recent work has also shown that a conformation specific antibody raised against mutant SOD1 binds oxidised, but not normal, wild-type SOD1 in a subset of

Identification of *SOD1* led to the generation of many cellular and animal models which mirror aspects of the disease process and enable mechanistic insights and therapeutic approaches to be investigated. Current pathogenic mechanisms associated with mutant

SALS cases thereby linking both *SOD1*-ALS and SALS (Bosco et al 2010).

**3.1 Most common genetic causes of autosomal dominant, adult onset ALS** 

of cases are mutation of the *SOD1*, *TARDBP* and fused in sarcoma (*FUS*) genes.

**3.1.1 ALS1: Cu-Zn superoxide dismutase 1 (***SOD1***)** 

age-related penetrance (Lopate et al 2010).

inclusions (Mackenzie et al 2007).

**3. Genetic causes of FALS** 

pathological mutations in the Cu-Zn superoxide dismutase (*SOD1*) gene in ALS patients (Rosen et al 1993). Since then there has been an explosion of research into the mechanism(s) by which *SOD1* mutations cause ALS, however the answer remains elusive. There are now 16 genes associated with Mendelian forms of ALS (Table 1) which have mostly been identified using linkage analysis of rare families with large pedigrees affected by the disease (Lill et al 2011). More recently, studies to identify the proteins found in the ubiquitinated inclusions that are a common neuropathological feature of both ALS and FTD, have identified trans-activation response element (TAR) DNA binding protein of 43kDa (TDP-43) as the major component (Arai et al 2006; Neumann et al 2006). Mutations in the gene encoding TDP-43, *TARDBP*, were subsequently found as a genetic cause of ALS (Sreedharan et al 2008). The genetics of FALS has moved forward rapidly in recent years, providing invaluable insight into disease pathogenesis and allowing the development of animal models to further study the disease and efficacy of therapeutic compounds.


Table 1. Summary of the Genetic Causes of Familial ALS
