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Can we identify individuals with an ALPL variant in adults with persistent hypophosphatasaemia?

ABSTRACT: BACKGROUND:Hypophosphatasia (HPP) is an inborn error of metabolism characterized by low levels of serum alkaline phosphatase (ALP). Scarce evidence exists about features that should signal the potential association between hypophosphatasaemia and HPP in adults. The aim of this study is to estimate the prevalence of ALPL variants in subjects with persistent hypophosphatasaemia and determine the associated clinical and laboratory features. For this cross-sectional study, laboratory records of 386,353 subjects were screened by measurement of ALP activity. A total of 85 (0.18%) subjects with persistent hypophosphatasaemia (?2 serum alkaline phosphatase-ALP-measurements ?35?IU/L and none >?45?IU/L) were included (secondary causes previously discarded). ALPL genetic testing and a systematized questionnaire to retrieve demographic, clinical and laboratory data were performed. Descriptive analysis and logistic regression models were employed to identify the clinical and laboratory characteristics associated with ALPL variants. RESULTS:Forty subjects (47%) had a variant(s) in ALPL. With regard to clinical characteristics, the presence of an ALPL variant was significantly associated only with musculoskeletal pain (OR: 7.6; 95% IC: 1.9-30.9). Nevertheless, a trend to present more dental abnormalities (OR: 3.6; 95% IC: 0.9-13.4) was observed. Metatarsal stress fractures were also more frequent (4 vs 0; p?

SUBMITTER: Tornero C

PROVIDER: S-EPMC7026995 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Can we identify individuals with an ALPL variant in adults with persistent hypophosphatasaemia?

Tornero C C Navarro-Compán V V Tenorio J A JA García-Carazo S S Buño A A Monjo I I Plasencia-Rodriguez C C Iturzaeta J M JM Lapunzina P P Heath K E KE Balsa A A Aguado P P

Orphanet journal of rare diseases 20200217 1

<h4>Background</h4>Hypophosphatasia (HPP) is an inborn error of metabolism characterized by low levels of serum alkaline phosphatase (ALP). Scarce evidence exists about features that should signal the potential association between hypophosphatasaemia and HPP in adults. The aim of this study is to estimate the prevalence of ALPL variants in subjects with persistent hypophosphatasaemia and determine the associated clinical and laboratory features. For this cross-sectional study, laboratory records ...[more]

PMID: 32066479

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Project description:BackgroundHypophosphatasia (HPP) is a rare and underdiagnosed condition characterized by deficient bone and teeth mineralization. The aim of this study was first, to evaluate the diagnostic utility of employing alkaline phosphatase (ALP) threshold levels to identify adults with variants in ALPL among individuals with persistently low ALP levels and second, to determine the value of also including its substrates (serum pyridoxal-5'-phosphate-PLP-and urinary phosphoetanolamine-PEA) for this purpose in order to create a biochemical algorithm that could facilitate the diagnostic work-up of HPP.ResultsThe study population comprised 77 subjects with persistent hypophosphatasaemia. They were divided into two groups according to the presence (+GT) or absence (-GT) of pathogenic ALPL variants: 40 +GT and 37 -GT. Diagnostic utility measures were calculated for different ALP thresholds and Receiver Operating Characteristic (ROC) curves were employed to determine PLP and PEA optimal cut-off levels to predict the presence of variants. The optimal threshold for ALP was 25 IU/L; for PLP, 180 nmol/L and for PEA, 30 µmol/g creatinine. Biochemical predictive models were assessed using binary logistic regression analysis and bootstrapping machine learning technique and results were then validated. For ALP < 25 UI/L (model 1), the area under curve (AUC) and the 95% confidence intervals (CI) was 0.68 (95% CI 0.63-0.72) and it improved to 0.87 (95% CI 0.8-0.9), when PEA or PLP threshold levels were added (models 2 and 3), reaching 0.94 (0.91-0.97) when both substrates were included (model 4). The internal validation showed that the addition of serum PLP threshold levels to the model just including ALP improved significantly sensitivity (S) and negative predictive value (NPV) - 100%, respectively- with an accuracy (AC) of 93% in comparison to the inclusion of urinary PEA (S: 71%; NPV 75% and AC: 79%) and similar diagnostic utility measures as those observed in model 3 were detected when both substrates were added.ConclusionsIn this study, we propose a biochemical predictive model based on the threshold levels of the main biochemical markers of HPP (ALP < 25 IU/L and PLP > 180 nmol/L) that when combined, seem to be very useful to identify individuals with ALPL variants.

Project description:ImportanceRegaining the ability to walk safely is a high priority for adults with vestibular loss. Thus, practitioners need comprehensive knowledge of vestibulopathic gait to design, provide, and/or interpret outcomes of interventions. To date, few studies have characterized the effects of vestibular loss on gait.ObjectivesTo investigate the use of an instrumented 2-minute walk test in adults with vestibular loss, to further characterize vestibulopathic gait, and to assess whether those with chronic vestibular loss have enduring gait deficits.Design, setting, and participantsThis cross-sectional study, conducted between April 3, 2018, and June 27, 2019, recruited adults 20 to 79 years of age from an academic, tertiary, hospital-based, ambulatory care setting who were healthy or had confirmed unilateral or bilateral vestibular hypofunction. Of the 43 adults who were screened from convenience and referred samples, 2 declined, and 7 were excluded because of health conditions.ExposuresThe main exposure was the instrumented 2-minute walk test, which was conducted with participants using wearable inertial measurement units while they walked a 10-m path at their self-selected speed and turned 180° in their self-selected direction at either end.Main outcomes and measuresThe primary measures were spatiotemporal gait metrics (eg, stride length [SL] and peak whole-body turning velocity). Multivariate analysis of variance was used to assess between-group differences. Validity was assessed using the area under the curve from receiver operator characteristic analyses.ResultsData from 17 healthy adults (mean [SD] age, 39.27 [11.20] years; 13 [76%] female) and 13 adults with vestibular loss (mean [SD] age, 60.50 [10.81] years; 6 [46%] female) were analyzed. Very large between-group differences were found for SL (left) (estimated marginal mean [SE] for healthy vs vestibular groups, 1.47 [0.04] m vs 1.31 [0.04] m; Cohen d, 1.35; 95% CI, 0.18-2.52), SL (right) (estimated marginal mean [SE] for healthy vs vestibular groups, 1.46 [0.04] m vs 1.29 [0.04] m; Cohen d, 1.44; 95% CI, 0.25-2.62), and peak turn velocity (estimated marginal mean [SE] for healthy vs vestibular groups, 240.17 [12.78]°/s vs 189.74 [14.70]°/s; Cohen d, 1.23; 95% CI, 0.07-2.40). The area under the curve was 0.79 (95% CI, 0.62-0.95) for SL (left), 0.81 (95% CI, 0.64-0.97) for SL (right), and 0.86 (95% CI, 0.72-0.99) for peak turn velocity.Conclusions and relevanceIn this cross-sectional study, instrumented gait analysis had good discriminative validity and revealed persistent deficits in gait stability in those with chronic vestibular loss. The findings of this study suggest that these clinically and functionally meaningful deficits could be targets for vestibular rehabilitation.

Project description:Loss-of-function mutations in ALPL result in hypophosphatasia (HPP), an inborn error of metabolism that causes defective skeletal and dental mineralization. ALPL encodes tissue-nonspecific alkaline phosphatase, an enzyme expressed in bone, teeth, liver, and kidney that hydrolyzes the mineralization inhibitor inorganic pyrophosphate. As Alpl-null mice die before weaning, we aimed to generate mouse models of late-onset HPP with extended life spans by engineering a floxed Alpl allele, allowing for conditional gene ablation (conditional knockout [cKO]) when crossed with Cre recombinase transgenic mice. The authors hypothesized that targeted deletion of Alpl in osteoblasts and selected dental cells ( Col1a1-cKO) or deletion in chondrocytes, osteoblasts, and craniofacial mesenchyme ( Prx1-cKO) would phenocopy skeletal and dental manifestations of late-onset HPP. Col1a1-cKO and Prx1-cKO mice were viable and fertile, and they did not manifest the epileptic seizures characteristic of the Alpl-/- model of severe infantile HPP. Both cKO models featured normal postnatal body weight but significant reduction as compared with wild type mice by 8 to 12 wk. Plasma alkaline phosphatase for both cKO models at 24 wk was reduced by approximately 75% as compared with controls. Radiography revealed profound skeletal defects in cKO mice, including rachitic changes, hypomineralized long bones, deformations, and signs of fractures. Microcomputed tomography confirmed quantitative differences in cortical and trabecular bone, including decreased cortical thickness and mineral density. Col1a1-cKO mice exhibited classic signs of HPP dentoalveolar disease, including short molar roots with thin dentin, lack of acellular cementum, and osteoid accumulation in alveolar bone. Prx1-cKO mice exhibited the same array of periodontal defects but featured less affected molar dentin. Both cKO models exhibited reduced alveolar bone height and 4-fold increased numbers of osteoclast-like cells versus wild type at 24 wk, consistent with HPP-associated periodontal disease. These novel models of late-onset HPP can inform on long-term skeletal and dental manifestations and will provide essential tools to further studies of etiopathologies and therapeutic interventions.

Dataset Information

Can we identify individuals with an ALPL variant in adults with persistent hypophosphatasaemia?

Publications

Can we identify individuals with an ALPL variant in adults with persistent hypophosphatasaemia?

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