Biochemical phenotype of hypophosphatasia in asymptomatic individuals carrying <i>ALPL</i> variants
Bibliographic record
Abstract
Hypophosphatasia (HPP) is the rare metabolic disorder caused by variants in the ALPL gene, resulting in deficient activity of tissue-nonspecific alkaline phosphatase (ALP). This leads to accumulation of substrates contributing to impaired bone mineralization. Hypophosphatasia manifests with a broad clinical spectrum; however, an increasing number of individuals with ALPL variants have been identified presenting the hallmark biochemical feature of HPP of low serum ALP activity, with or without elevated serum pyridoxal-5-phosphate (PLP) or urine phosphoethanolamine (PEA), while remaining asymptomatic. These ALPL carriers may represent a distinct subgroup within the HPP continuum, prompting the need for clearer classification. Using data from the Global ALPL Gene Variant Database, we identified 43 subjects who fulfilled the following criteria: low ALP (adjusted for age/sex), at least one ALPL variant, and no overt or reported HPP-related symptoms. Their median age was 29 yr (range 0-64); 23 were female. Serum ALP activity was reduced in all cases, with 76% of subjects showing levels less than 50% below the lower limit of normal. In 19 of 43 individuals, PLP or PEA was also elevated. Thirty distinct genotypes were observed; 79% of subjects were heterozygous, while 21% harbored homozygous or compound heterozygous variants. The identified variants were largely missense (77%), mostly affecting regions without a specific domain (38%). Five variants showed a dominant-negative effect in vitro, yet produced no clinical manifestations. Some identified genotypes were also linked to adult, childhood, or odontohypophosphatasia phenotypes, underscoring significant genotype-phenotype variability. These findings refine our understanding of the HPP spectrum, identifying a cohort of asymptomatic ALPL carriers with biochemical phenotype of HPP. Recognizing this group is important for improving diagnostic criteria and preventing overdiagnosis and unnecessary treatment. Longitudinal studies are needed to clarify follow-up strategies and determine whether these individuals develop clinical manifestations later in life or remain asymptomatic.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.003 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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".