Amyotrophic lateral sclerosis (ALS), is classically considered as a degeneration of the upper and lower motor neuron. However, clinical imaging and neuropathologic data show involvement of the non-motor neuro-axis, with up to 50% of ALS patients develop cognitive and behavioral impairment, and 13% of cases with concomitant behavioral variant frontotemporal dementia (bv-FTD). These observations, together with discovery of expansions in the gene C9orf72 as the major genetic cause of both ALS and FTD, and a polygenic association between ALS and neuropsychiatric disorders, require re-characterization of ALS as a neurodegenerative rather than a neuromuscular disorder.

There are many clinical classification systems for ALS, but all are based on the motor aspects of the syndrome. An additional system classifies the extra- motor (cognitive/behavioural) domains. However, within each classification system, a range of subphenotypes and clinical trajectories can be demonstrated.

In the familial forms of the disease many known ALS-associated genes are incompletely penetrant, and with rare exceptions, genotype does not necessarily predict phenotype. For these reasons, the best way to describe ALS is as a clinically and genetically heterogeneous neurodegenerative syndrome of motor and extra-motor systems with multiple underlying pathophysiological mechanisms and different clinical sub-phenotypes.

From a therapeutic perspective, the challenge is to define mechanisms of disease amenable to drug targeting, and to define subcohorts of patients that are likely to respond to these new targeted therapeutics. We urgently need to characterize all aspects of ALS that contribute to disease heterogeneity, and to identify how best to incorporate advances in our understanding of the entire disease spectrum into more efficient and effective clinical trials.