Epidemiological, Clinical and Genetic Study of Hypophosphatasia in A Spanish Population: Identification of Two Novel Mutations in The Alpl Gene

Cristina García-Fontana,Gonzalo Martínez-Navajas,Juan M Villa-Suárez,Sheila González-Salvatierra,Pedro J Real,José M Gómez Vida,Manuel Muñoz-Torres,Beatriz García-Fontana,Tomás De Haro,Francisco Andújar-Vera

doi:10.1038/s41598-019-46004-2

Abstract

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.

Highlights

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
Low levels of serum total alkaline phosphatase (ALP), in conjunction with the accumulation of natural substrates from tissue-nonspecific alkaline phosphatase protein (TNSALP) and with the clinical and radiographic findings are the hallmark for the diagnosis of HPP
We found that patients with a positive genetic test showed significantly lower levels of ALP and higher levels of PLP (Fig. 2)

Summary

Introduction

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. Low levels of serum total alkaline phosphatase (ALP), in conjunction with the accumulation of natural substrates from TNSALP and with the clinical and radiographic findings are the hallmark for the diagnosis of HPP This disorder has been categorized in seven clinical forms including perinatal, infantile, childhood, adult, odonto-HPP, pseudo-HPP and benign prenatal HPP. The clinical manifestation of HPP in adults include loss of mineralization leading to recurrent metatarsal stress fractures, femoral pseudofractures (usually showing a delayed consolidation), history of rickets in childhood, musculoskeletal and joint pain[6] This hypomineralization is caused by PPi accumulation in the extracellular matrix, which inhibits the formation of hydroxyapatite crystals[10]. The increase of endogenous levels of PPi produce calcium pyrophosphate dihydrate crystal deposits in articular cartilage causing PPi arthropathy (including pseudogout), chondrocalcinosis and enthesopathy[12,13,14] leading to musculoskeletal pain in HPP adult patients[6]

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