A platform presentation given at the ENCALS Meeting 2025 (Turin, Italy, 3–6 June 2025; Centro Congressi Lingotto), in a plenary session on clinical characterisation, genetics and prognostic factors in ALS. The talk — “Examining the Cognitive Profile of Restricted Phenotypes in ALS: Insights from the National Registry of Ireland” — presented work carried out with the Academic Unit of Neurology at Trinity College Dublin (Robert McFarlane, Emmet Costello, Éanna Mac Domhnaill, Mark Heverin and Orla Hardiman), drawing on the National ALS Register of Ireland, during a research rotation at Trinity College Dublin.
Most people with ALS decline over a couple of years; a few do not — and the restricted phenotypes are the clearest example. Progressive bulbar palsy (PBP), flail arm syndrome (FAS) and flail leg syndrome (FLS) are forms of the disease that stay confined to one region for far longer and carry a markedly better prognosis. In other words, these patients already have what every ALS therapy is trying to deliver — a brake on progression. That is what makes them worth studying in their own right: whatever underlies their slower course is a clue to how the disease might be slowed in everyone else. The talk looked at who these patients are and whether their motor stability is matched by their cognition, using the National ALS Register of Ireland. In outline:
- A data-driven definition of “restricted” disease. King’s stage was estimated from the data available in the register, and phenotype-specific cut-offs for how long a patient stays in the earliest stage were set by a landmark-based threshold analysis of survival — so “restricted” is read off the clinical record rather than assigned by label alone, with the threshold tailored to each of PBP, FAS and FLS.
- What sets restricted patients apart. Compared with the rest of the cohort, restricted patients tended to be younger at onset, to progress more slowly on functional measures, and to have had a longer diagnostic delay — with the sex balance and the length of that delay differing across the three subtypes.
- Cognition. On cross-sectional ECAS scores, restricted patients looked cognitively better off than the rest of the cohort, with fewer of them falling in the impaired range; and when longitudinal ECAS scores were modelled with generalised additive mixed models (GAMMs), they not only started from a higher level but showed evidence of greater stability over time than the unrestricted phenotypes.
The picture, then, is of patients whose disease is held back on both the motor and the cognitive side — and the open question, the one that motivates the work, is what does the holding back.
The ENCALS Meeting is the annual conference of the European Network to Cure ALS; the 2025 edition brought roughly a thousand researchers and clinicians to Turin over four days for satellite meetings, plenaries, platform sessions and posters spanning ALS genetics, biomarkers, clinical trials and care.
