Molecular clues to the core historical clinical observations in ALS, and the current gaps in knowledge
| Core clinical observation | Molecular clues | Key knowledge gap |
|---|---|---|
| Combined UMN and LMN degeneration | Ubiquitinated neuronal inclusions found in cortical and anterior horn neuronal cell bodies34 | Variable clinical expression of UMN versus LMN pathology, including extremes (PMA, PLS)54 |
| Variable site of symptom onset | Higher proportion of bulbar-onset disease linked to C9orf72 G4C2 expansions; and under-represented in SOD1 mutation-associated ALS72 | Many 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 onset | FUS mutations linked to ALS with basophilic inclusions occur in young adults75 | The apparent fall in incidence of ALS in those aged above age 85 years 76 |
| Familial cases | C9orf72 G4C2 expansions plus SOD1, TDP-43, and FUS mutations account for two-thirds of those with a family history of ALS or FTD77 | Only 10% of all ALS cases carry one of these gene mutations77 |
| Variable rate of disease progression | SOD1 ‘A4V’ (dominant, rapid) versus ‘D90A’ (typically recessive, slow) mutations78 | Typically relatively stable rates of disease progression in individual patients with ALS (familial and apparently sporadic)12 79 |
| Cognitive involvement | C9orf72 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.