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. 2023 Aug 1:14:1205977.
doi: 10.3389/fendo.2023.1205977. eCollection 2023.

Clinical and molecular description of the first Italian cohort of 33 subjects with hypophosphatasia

Luigia Cinque  1 , Flavia Pugliese  2 , Antonio Stefano Salcuni  3 , Domenico Trombetta  4 , Claudia Battista  2 , Tommaso Biagini  5 , Bartolomeo Augello  1 , Grazia Nardella  1 , Francesco Conti  6 , Sabrina Corbetta  7   8 , Rita Fischetto  9 , Thomas Foiadelli  10 , Agostino Gaudio  11 , Cosimo Giannini  12 , Enrico Grosso  13 , Gregorio Guabello  14 , Stefania Massuras  13 , Andrea Palermo  15 , Luisa Politano  16 , Francesca Pigliaru  17 , Rosaria Maddalena Ruggeri  18 , Emanuela Scarano  19 , Piera Vicchio  20 , Salvatore Cannavò  18 , Mauro Celli  21 , Francesco Petrizzelli  5 , Mario Mastroianno  22 , Marco Castori  1 , Alfredo Scillitani  2 , Vito Guarnieri  1
Affiliations

Clinical and molecular description of the first Italian cohort of 33 subjects with hypophosphatasia

Luigia Cinque et al. Front Endocrinol (Lausanne). .

Abstract

Introduction: Hypophosphatasia (HPP) is a rare genetic disease caused by inactivating variants of the ALPL gene. Few data are available on the clinical presentation in Italy and/or on Italian HPP surveys.

Methods: There were 30 suspected HPP patients recruited from different Italian tertiary cares. Biological samples and related clinical, biochemical, and anamnestic data were collected and the ALPL gene sequenced. Search for large genomic deletions at the ALPL locus (1p36) was done. Phylogenetic conservation and modeling were applied to infer the effect of the variants on the protein structure.

Results: There were 21 ALPL variants and one large genomic deletion found in 20 out of 30 patients. Unexpectedly, NGS-driven differential diagnosis allowed uncovering three hidden additional HPP cases, for a total of 33 HPP subjects. Eight out of 24 coding variants were novel and classified as "pathogenic", "likely pathogenic", and "variants of uncertain significance". Bioinformatic analysis confirmed that all the variants strongly destabilize the homodimer structure. There were 10 cases with low ALP and high VitB6 that resulted negative to genetic testing, whereas two positive cases have an unexpected normal ALP value. No association was evident with other biochemical/clinical parameters.

Discussion: We present the survey of HPP Italian patients with the highest ALPL mutation rate so far reported and confirm the complexity of a prompt recognition of the syndrome, mostly for HPP in adults. Low ALP and high VitB6 values are mandatory for the genetic screening, this latter remaining the gold standard not only to confirm the clinical diagnosis but also to make differential diagnosis, to identify carriers, to avoid likely dangerous therapy in unrecognized cases.

Keywords: ALPL; alkaline phosphatase; dominant negative effect; genetics; hypophosphatasia; vitamin B6.

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Conflict of interest statement

LC was the recipient of a fellowship by Alexion, AstraZeneca Rare Disease. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Boxplot chart showing the deletion of the exon 2.
Figure 2
Figure 2
Family trees of some of the families under study.
Figure 3
Figure 3
Boxplot showing the correlation between the presence of the ALPL mutation and the percentage deviation of the ALP value to the minimum range.
Figure 4
Figure 4
Phylogenetic multialignment showing the conservation level of the aminoadic sequence surrounding the novel changes, in different orthologous. Residues mutated are in red and show a high conservation up to Fishes.
Figure 5
Figure 5
3D structure of ALPL dimer obtained through molecular modeling. Mutations were mapped on the wild-type structure and highlighted in red.
See this image and copyright information in PMC

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