An observational study of pleiotropy and penetrance of amyotrophic lateral sclerosis associated with CAG-repeat expansion of ATXN2
Bibliographic record
Abstract
Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) are both associated with a CAG-repeat expansion in ATXN2 and with TDP-43-positive neuronal cytoplasmic inclusions. The two disorders have been viewed as distinct entities, where an intermediate length expansion of 31-33 CAG-repeats is associated with sporadic ALS and a full length expansion of ≥34 CAG-repeats is associated with SCA2. We report the clinical phenotype of ATXN2-positive patients and their relatives, identified in three specialist ALS clinics, which force a reconsideration of this dichotomy. We also report the frequency of ATXN2 expansions in two large cohorts of ALS patients and in a population-matched cohort of controls. We report ten cases of familial ALS in which disease is associated with either an intermediate or a full-length ATXN2 CAG-repeat expansion. Pedigrees and patients feature additional phenotypes including parkinsonism, dementia and essential tremor (ET). We conclude that CAG-repeat expansions in ATXN2 exhibit pleiotropy and are associated with a disease spectrum that includes ALS, SCA2, and parkinsonism; to recognise this complexity we propose the new term 'ATXN2-related neurodegeneration'. We also observed sporadic ALS associated with full-length expansions. We conclude that ATXN2 CAG-repeat expansions, irrespective of length, should be considered a risk factor for ALS. Interrupted CAG-repeats were associated with an ALS phenotype in our data but we also identified ALS cases with uninterrupted expansions. Our findings have relevance for researchers, patients and families linked to CAG-repeat expansions in ATXN2.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".