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 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 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 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 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".