Hereditary Spastic Paraplegia Type 4 (SPG4): A Clinico-Genetic Study in a Large Cohort of Patients with Spastic Paraplegia (P5.075)
Bibliographic record
Abstract
Objective: This study includes the evaluation of a comprehensive spectrum of clinical features and the mutational screening of the SPG4/SPAST gene in patients with hereditary spastic paraplegia (HSP). Background: HSP is a heterogeneous group of neurodegenerative disorders with the characteristics of slowly progressive spasticity and weakness of the lower limbs. Mutations in SPG4/SPAST represent the most frequent molecular etiology, but the worldwide incidence is unknown. Design/Methods: A cohort of 726 patients, 98 sporadic and 628 subjects belonging to 215 families, were recruited from Italian, Brazilian, and Japanese populations in a period from 2008 to 2015. Clinical and instrumental functional analyses consist of neurological assessment and neuroimaging. Mutational screening was carried out by PCR-direct sequencing and multiplex ligation dependent probe amplification. Haplotype studies were performed on three recurrent variants. Results: Our study highlights clinical and epidemiological differences among populations, especially regarding age at onset and disability degree, showing unique genotype-phenotype correlations. Genetic analysis revealed a total of 52 different pathogenic nucleotide changes in 284 HSP patients: 21 sporadic cases and 263 cases from 96 families. Among them, six nucleotide changes were novel and pathogenic. The analysis revealed a great portion of private mutations worldwide and confirmed the founder effect for one recurrent variant in the Italian population. Interestingly, mutations were detected in 21[percnt] of sporadic cases and in a range from 16[percnt] to 100[percnt] of families, depending on the number of affected in the family. Conclusions: This study represents the first worldwide SPG4/SPAST genetic screening on HSP patients. Epidemiological and clinical results broaden the spectrum of the clinical presentations of HSP associated with mutations in SPG4/SPAST. Finally, our findings provide evidence that the chance to detect SPG4/SPAST mutations varies proportionally to the number of affected in the family and is higher in sporadic cases than in families with only two affected.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 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".