Table 1

Molecular clues to the core historical clinical observations in ALS, and the current gaps in knowledge

Core clinical observationMolecular cluesKey knowledge gap
Combined UMN and LMN degenerationUbiquitinated neuronal inclusions found in cortical and anterior horn neuronal cell bodies34Variable clinical expression of UMN versus LMN pathology, including extremes (PMA, PLS)54
Variable site of symptom onsetHigher proportion of bulbar-onset disease linked to C9orf72 G4C2 expansions; and under-represented in SOD1 mutation-associated ALS72Many examples, including:
Isolated bulbar variants;73
Reduced bulbar-onset with younger age;74
Lack of upper-limb onset in PLS (personal observation—MRT)
Variable age at symptom onsetFUS mutations linked to ALS with basophilic inclusions occur in young adults75The apparent fall in incidence of ALS in those aged above age 85 years 76
Familial casesC9orf72 G4C2 expansions plus SOD1, TDP-43, and FUS mutations account for two-thirds of those with a family history of ALS or FTD77Only 10% of all ALS cases carry one of these gene mutations77
Variable rate of disease progressionSOD1 ‘A4V’ (dominant, rapid) versus ‘D90A’ (typically recessive, slow) mutations78Typically relatively stable rates of disease progression in individual patients with ALS (familial and apparently sporadic)12 79
Cognitive involvementC9orf72 G4C2 expansions strongly associated with ALS-FTD;
Under-represented in SOD1 mutations37
Carriers of C9orf72 G4C2 expansions within the same pedigree may develop pure FTD instead of ALS80
  • ALS, amyotrophic lateral sclerosis; FTD, frontotemporal dementia; LMN, lower motor neuronal; PLS primary lateral sclerosis; PMA, progressive muscular atrophy; UMN, upper motor neuronal.