Think classical homocystinuria if the genetic test did not confirm Marfan syndrome: Late diagnosis and phenotypic variability in adult siblings with classical homocystinuria
Bibliographic record
Abstract
Classical homocystinuria is an inherited metabolic disease of homocysteine metabolism due to biallelic pathogenic variants in CBS . The biochemical hallmark is elevated homocysteine and methionine levels. The treatment consists of betaine supplementation and protein restricted diet. We report two adult siblings with late diagnosis of classical homocystinuria, a variable phenotype and good response to the treatment. Patient 1 is a 29-year-old female with a history of myopia, Marfanoid habitus with significant kyphoscoliosis, anxiety and a psychotic episode. Clinical exome sequencing identified compound heterozygous pathogenic variants in CBS (c.209+1G>A; c.992C>T (p.Ala331Val)). She had markedly elevated homocysteine (298 μmol/L) and methionine (1040 μmol/L) levels. Her brain magnetic resonance spectroscopy revealed a low n -acetyl-aspartic acid peak. She was started on betaine supplementation, and a protein-restricted diet (0.8 g/kg/day) leading to significant decrease in her homocysteine (37 μmol/L) and methionine (49 μmol/L) levels. Patient 2 is a 27-year-old female (younger sibling) with a history of anxiety, one generalized tonic-clonic seizure and a dural sinus thrombosis in neuroimaging. She had both familial CBS variants and markedly elevated homocysteine (152 μmol/L) and methionine (560 μmol/L) levels, which were improved significantly on betaine supplementation and the protein-restricted diet. Both siblings had average range intellectual abilities. Higher homocysteine levels may result in severe skeletal, and central nervous system phenotypes.
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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 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".