Reply: Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers
Bibliographic record
Abstract
Sir, Thank you for the opportunity to reply to the correspondence concerning our recent publication in Brain , ‘Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers’ (Mencacci et al. , 2014). We read with great interest these letters and we thank the authors for their insights. Guella et al. (2014) report the screening of GCH1 in 528 Canadian cases with Parkinson’s disease and atypical parkinsonism and 290 matched controls. They identified two variants, the known pathogenic p.K224R (×2) and the novel variant p.A99D (likely pathogenic according to in silico prediction tools and interspecies conservation) in three unrelated cases with Parkinsons’s disease and the two benign variants p.P23L and p.P69L in one single control individual. The mutational frequency, excluding the aforementioned benign variants, was 0.56% (3/528) in cases versus 0% (0/290) in controls, consistent with the frequency we observed in our study (0.75% in cases versus 0.1% in controls). This result is relevant as it represents the first independent confirmation that rare deleterious GCH1 variants are enriched in patients with Parkinson’s disease compared to control subjects. Furthermore, they describe the post-mortem findings of one of the mutated patients, who presented at the age of 82 with DOPA-responsive asymmetric rest tremor. This showed a combination of brainstem Lewy body pathology together with the presence of tau-immunoreactive neurofibrillary tangles. To date, the only available brain pathology analysis of a GCH1 -associated neurodegenerative parkinsonism case showed severe nigral neurodegeneration and Lewy bodies in surviving nigral cells and in the locus coeruleus (Gibb et al. , 1991; Segawa et al. , 2004). Further studies are needed to establish if the tauopathy described by Guella et al. …
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".