Familial ALS (FALS) is a rare form of the disease. However, it is of elementary importance for research into the causes of ALS and the basic understanding of ALS including the non hereditary disease. Due to the inherited character of FALS certain genetic methods can be used (genetic coupling analyses), which enable identification of ALS genes. With the elucidation of ALS associated genes, neurologists in close collaboration with geneticists and basic scientists are able to obtain initial information about the causes (aetiology) and mechanisms (pathogenesis) of the nerve cell degeneration in ALS.
Fig. 1a
Spatial structure of the superoxide
dismutase molecule (SOD1).
Up to now, two genes have been causally associated with FALS. The first ALS gene to be demonstrated was superoxide dismutase (SOD1) in 1993. About 10% of cases of FALS are associated with mutations in the SOD1 gene (Fig. 1a). The SOD1 protein is used in the normal central nervous system (CNS) for detoxification of cellular free radicals and accounts for about 1% of the total protein in the CNS. Reduced detoxification of free radicals is linked with the ageing process of neuronal tissue. The original hypothesis of a loss of function of SOD1 as the cause of ALS has not, however, been confirmed and is apparently of subordinate importance. Rather, the SOD1 protein is converted to a toxic protein by the mutations (toxic gain of function), which leads to damage of motor nerve cells. The mechanism of the neuron damage is still unknown. The various ways of nerve cell damage by the SOD1 mutations are still being argued (Fig. 1b).
Fig. 1b
Mechanisms of neuron degeneration by SOD1 mutation.
Due to the structural alteration of the mutated SOD1 the central copper and zinc atoms are presented more strongly on the surface of the molecule. Chemical reactions activated by copper/zinc can therefore be catalysed in an uncontrolled manner (copper/zinc mediated toxicity). The mutated SOD1 molecules also have a tendency to form aggregates and lead to a harmful accumulation of the SOD1 protein in the motor neurons. The mutated SOD1 has altered properties, which lead to a paradoxical increase in the production of free radicals, e.g. peroxynitrites. In 2001 the ALS2 (alsin) gene was identified, which is responsible for ALS in families in North Africa and Kuwait. The ALS2 gene has a probable role in certain transport functions inside nerve cells (axonal transport). The causal significance of this gene for FALS in Europe and its possible role as risk gene for non hereditary ALS are still completely unclarified. Basic science research into the ALS2 gene is of interest for understanding the causes of typical ALS also. Classification of individual mutations in the ALS2 gene to the clinical symptoms has shown that certain mutations lead to a very benign form of ALS with degeneration of the 1st motoneuron exclusively, which is known in Europe by the clinical name of primary lateral sclerosis (PLS (Fig. 2)).
Fig. 2
Diagram of the ALS2 gene, which is copied in a regular and in a shortened form (short and long spliced form of the ALS2). Arrows mark the known mutations indicating the clinical phenotype. PLS – primary lateral sclerosis. For FALS 8 gene sites on different chromosomes have so far been identified by genetic coupling analyses (table).
| Gene site |
Mode |
Product |
Onset |
Phenotype |
Frequency |
Reference |
| 2lq |
AD |
SOD1 |
adult |
variable |
10% of FALS |
Rosen et al. 1993 |
| 2q |
AR |
ALS2 |
juvenil |
slow >1MN |
North Africa, Kuwait |
Hadano et al. 2001 |
| 15q |
AR |
? |
adult |
slow, not bulbar |
most common AR ALS |
Hentati et al. 1998 |
| 9q34 |
AD |
? |
juvenil |
variable |
very rare |
Channce et al. 1998 |
| 9q21 |
AD |
? |
adult |
ALS FTD |
rare |
Hosler et al. 2000 |
| 18q12 |
AD |
? |
adult |
typical |
rare |
Hand et al. 2002 |
| 16q12 |
AD |
? |
adult |
typical |
probably frequent |
Ruddy et al. 2003 |
| 20p |
AD |
? |
adult |
typical |
unknown |
Sapp et al. 2003 |
Known gene sites of familial ALS. AD – autosomal dominant; AR – autosomal recessive; MN – motoneuron; FTD – frontotemporal dementia; SOD1 – Superoxide dismutase 1.
2 gene products have so far been characterised at the 8 ALS gene sites (SOD1, ALS2). The responsible genes at the remaining 6 gene locations are still unknown. The molecular genetic elucidation of these 6 gene sites will be an important step in understanding the causes of ALS. Possible pathogenetic common ground between the SOD1 associated neuron degeneration and disease processes due to hitherto unknown genes are of the greatest interest. Future elucidation of a joint final pathway of mutations in different genes is the first step in developing pathogenesis based therapeutic strategies.