Orrell 2010
Several genes are linked to classical ALS, in particular SOD1 (copper/zinc superoxide dismutase), TARDBP (TAR DNA-binding protein 43) and FUS (fused in sarcoma/translated in liposarcoma), together with genes linked to other motor neuron disorders.
There is the consideration whether, for example, ALS/MND associated with SOD1 mutations is a specific disorder, which may respond to specific treatment.
In clinical practice, it is assumed that all ALS/MND patients will respond similarly to potential treatment, but it is important that in future, patients with specific genetic mutations are identified and analysed as subgroups. It may be that some gene-directed therapies will be targeted on specific genetic conditions.
Benatar and others 2009
Approximately 5% to 7% of ALS/MND patients report a family history of a similarly affected relative. Superoxide dismutase-1 gene mutations are the cause in about 20% of familial cases. In those with non-familial (sporadic) ALS/MND the cause is unknown.
There was no statistical evidence for a different response to treatment in patients with familial ALS/MND compared to those with sporadic ALS/MND.
Future RCTs should document whether patients with familial ALS/MND are included and the presence or absence of a mutation in the superoxide dismutase-1 gene amongst those with familial ALS/MND.
Chio and others 2009
Most studies have not found any differences in outcome between patients with sporadic and those with familial. However, it is now generally accepted that different mutations of Cu/Zn superoxide dismutase (SOD1) have different effects on the age of onset of symptoms and on the rate of progression of the disease.
For example, A4V mutation is associated with an extremely rapid decline, with a mean survival of 12 months, whereas E21G, G37R, D90A G93C, and I113T mutations determine a more benign course, with a median survival >80 months). In most instances, clinically mild mutations are characterized by a prevalent lower motor neuron disease, with few or no pyramidal signs. Furthermore, some mutations, such as I113T, are characterized by large intrafamilial variations both in age of onset and in clinical phenotype, indicating the presence of modifying factors that may either be genetic or environmental in nature. A systematic analysis of the different phenotypes of SOD1 mutations is still lacking.
