Adult Alexander Disease With Autosomal Dominant Transmission
Bibliographic record
Abstract
BACKGROUND: Infantile and juvenile forms of Alexander disease are well characterized and are caused by de novo mutations in the glial fibrillary acid protein (GFAP) gene. In contrast, the adult form of the disease has been rarely described, and the etiology of this variant remains unknown. OBJECTIVE: To characterize the clinical phenotype and identify the gene causing an autosomal dominant form of adult Alexander disease. METHODS: We identified a large kindred segregating clinical features compatible with adult Alexander disease in an autosomal dominant fashion. A neurological examination was performed on all affected members of this family. Most of these patients also underwent magnetic resonance imaging of the brain and a polysomnographic study. The diagnosis was confirmed pathologically in 2 individuals. We screened all coding regions of the GFAP gene in affected individuals by means of direct sequencing and single-stranded conformational polymorphisms analysis. RESULTS: We found a novel D78E mutation in GFAP in all affected individuals. This mutation was not detected in more than 100 control subjects. Clinical and radiological features of affected individuals were clearly different from those of patients with the infantile and juvenile forms of the disease. The most consistent finding was the presence of bulbar signs. In addition, sleep disturbance (mainly sleep apnea), symptoms of dysautonomia, and dysmorphism were found in all affected individuals. In younger patients, magnetic resonance imaging showed T2 signal abnormalities in the medulla compatible with an area of demyelination. In contrast, in older patients, we found marked atrophy of the medulla without signal abnormalities. None of the affected individuals exhibit signs of demyelination of the cerebral white matter. CONCLUSIONS: The present study is the first demonstration of a mutation in GFAP that causes an autosomal dominant form of Alexander disease and establishes the existence of the adult variant. Clinical evaluation in individuals carrying mutation in the GFAP gene allowed a better definition of this heterogeneous clinical syndrome and will help increase its recognition in neurological practice.
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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 | 0.000 | 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) | 0.003 | 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".