Genetic Etiology of Early-Onset Parkinsonism in Norway (P5.371)
Bibliographic record
Abstract
Objective: To investigate the genetic etiology of early-onset (AAO < 45 Years) parkinsonism. Background: Age is a major risk factor for developing Parkinson’s disease (PD), and about 4[percnt] of patients develop early-onset disease. Mutations in PRKN, PINK1, and DJ-1 cause a mild and slowly progressive disease, whereas mutations in ATP13A2, PLA2G6, FBXO7, DNAJC6 and SYNJ1 causes early/juvenile-onset atypical parkinsonism with additional clinical signs. Interestingly, proteins of aforementioned genes are important for mitochondrial maintenance and lysosomal degradation. Methods: We studied 103 early-onset parkinsonism [Mean AAO = 39.3 ± 5.0 years] patients from Norway. Exon-dosage analyses, whole-exome sequencing and genome-wide genotyping was performed. Analysis of the data, under a recessive model, was done by: i) Describing variability in previously described genes, ii) genetic components of nominated cellular pathways, and iii) mapping novel genes within shared runs of homozygosity (ROH). Results: Seven patients were found carrying homozygous or compound-heterozygous variability in PINK1 or PRKN. Compound-heterozygous variants in GBA were seen in three patients with additional cognitive impairment and a patient with oculogyric crisis and dystonic features carried a variant in GLUT1. Furthermore, variability in TIMM44, LAMP2, OPA1, EP300 and ITPR1, all important for mitochondrial maintenance and lysosomal degradation was found and additional genes/variability in 250 nominated ROH is currently being evaluated. Conclusions: We have described ~7[percnt] of patients through mutations in PINK1 and PRKN, and a further ~4[percnt] of patients, with additional clinical signs, in previously described genes. Additionally, we have found variability in five genes involved in mitochondrial maintenance and lysosomal degradation. There is a significant genetic component in the etiology of early-onset parkinsonism, distinguishing multiple disorders which present parkinsonism in early stages. An accurate and early diagnosis of such disorders is challenging, albeit important, for effective treatments and identification of the genetic causation will undoubtedly aid in finding beneficial therapeutic interventions.
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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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".