Hypophosphatasia (HPP) is a rare genetic disease characterized by a decrease in the activity of tissue non-specific alkaline phosphatase (TNSALP). TNSALP is encoded by the ALPL gene, which is abundantly expressed in the skeleton, liver, kidney, and developing teeth. HPP exhibits high clinical variability largely due to the high allelic heterogeneity of the ALPL gene. HPP is characterized by multisystemic complications, although the most common clinical manifestations are those that occur in the skeleton, muscles, and teeth. These complications are mainly due to the accumulation of inorganic pyrophosphate (PPi) and pyridoxal-5′-phosphate (PLP). It has been observed that the prevalence of mild forms of the disease is more than 40 times the prevalence of severe forms. Patients with HPP present at least one mutation in the ALPL gene. However, it is known that there are other causes that lead to decreased alkaline phosphatase (ALP) levels without mutations in the ALPL gene. Although the phenotype can be correlated with the genotype in HPP, the prediction of the phenotype from the genotype cannot be made with complete certainty. The availability of a specific enzyme replacement therapy for HPP undoubtedly represents an advance in therapeutic strategy, especially in severe forms of the disease in pediatric patients.

Hypophosphatasia (HPP) is a genetic disease caused by one or several mutations in ALPL gene encoding the tissue-nonspecific alkaline phosphatase affecting the mineralization process. Due to its low prevalence and lack of recognition, this metabolic disorder is generally confused with other more frequent bone disorders. An assessment of serum total alkaline phosphatase (ALP) levels was performed in 78,590 subjects. Pyridoxal-5′-phosphate (PLP) concentrations were determined and ALPL gene was sequenced in patients potentially affected by HPP. Functional validation of the novel mutations found was performed using a cell-based assay. Our results showed persistently low serum ALP levels in 0.12% of subjects. Among the studied subjects, 40% presented with HPP-related symptoms. Nine of them (~28%) had a history of fractures, 5 (~16%) subjects showed chondrocalcinosis and 4 (~13%) subjects presented with dental abnormalities. Eleven subjects showed increased PLP concentrations. Seven of them showed ALPL gene mutations (2 of the mutations corresponded to novel genetic variants). In summary, we identified two novel ALPL gene mutations associated with adult HPP. Using this protocol, almost half of the studied patients were diagnosed with HPP. Based on these results, the estimated prevalence of mild HPP in Spain could be up to double than previously reported.

Undercarboxylated osteocalcin (ucoc) could be a biomarker of glucose disturbances and cardiovascular risk. our study aimed to determine the association between serum levels of ucoc and cardiovascular risk in metabolic syndrome (MetS) patients and to analyse its potential role as estimator of type 2 diabetes (T2D) risk in this population. This cross-sectional study included 235 patients with MetS, 53.2% women, aged 55-75 years. Circulating ucOC levels were measured by ELISA. Cardiovascular risk was determined as Z-score of the diagnostic criteria for MetS (CV-ZS). Linear regression model was performed to analyse the association between circulating ucoc and cV-ZS. A receiver operating curve (ROC) was performed to analyse the usefulness of ucOC as T2D risk estimator. Patients above the CV-ZS median showed significant lower ucOC levels. We found an inverse association between ucOC levels and CV-ZS in MetS patients without T2D. Patients with ucOC levels below the 25 th percentile showed worse cardiometabolic profile and higher cardiovascular and T2D risk. The area under the curve performed better when ucOC levels were included along with the classic T2D risk factors. The measurement of circulating ucOC could be a useful tool to identify increased cardiovascular and T2D risk in MetS patients without T2D. Current lifestyle is causing a remarkable increase in overweight up to epidemic numbers globally 1. In Spain, over 60% of the adult population is overweight or obese 2. According to this trend, an increase of 16% in the number of cases is estimated by 2030 associated with a 58% increase in direct healthcare costs 3. A large body of evidence has shown that all-cause mortality, and especially cardiovascular-related mortality, is associated with an increased central adiposity and overweight 4. Visceral obesity in conjunction with other disorders, such as dyslipidaemia, hypertension and fasting hyperglycaemia lead to the metabolic syndrome (MetS), conferring thus a larger risk of developing cardiovascular disease (CVD) 5. An association between osteoporosis, CVD and cardiovascular-related mortality has been reported 6,7. The common risk factors involved in bone fragility and CVD could partially explain this association. Therefore, the