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Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia
Author(s) -
Tenorio Jair,
Álvarez Ignacio,
RianchoZarrabeitia Leyre,
MartosMoreno Gabriel Á.,
Mandrile Giorgia,
de la Flor Crespo Monserrat,
Sukchev Mikhail,
Sherif Mostafa,
Kramer Iza,
DarnaudeOrtiz María T.,
Arias Pedro,
Gordo Gema,
Dapía Irene,
MartinezVillanueva Julián,
Gómez Rubén,
Iturzaeta José Manuel,
Otaify Ghada,
GarcíaUnzueta Mayte,
Rubinacci Alessandro,
Riancho José A.,
Aglan Mona,
Temtamy Samia,
Hamid Mohamed Abdel,
Argente Jesús,
RuizPérez Víctor L.,
Heath Karen E.,
Lapunzina Pablo
Publication year - 2017
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.37991
Subject(s) - hypophosphatasia , proband , medicine , missense mutation , pediatrics , alkaline phosphatase , enzyme replacement therapy , fabry disease , dysplasia , disease , pathology , genetics , mutation , gene , biology , enzyme , biochemistry
Hypophosphatasia (HPP) is a rare autosomal dominant or recessive metabolic disorder caused by mutations in the tissue nonspecific alkaline phosphatase gene ( ALPL ). To date, over 300 different mutations in ALPL have been identified. Disease severity is widely variable with severe forms usually manifesting during perinatal and/or infantile periods while mild forms are sometimes only diagnosed in adulthood or remain undiagnosed. Common clinical features of HPP are defects in bone and tooth mineralization along with the biochemical hallmark of decreased serum alkaline phosphatase activity. The incidence of severe HPP is approximately 1 in 300,000 in Europe and 1 in 100,000 in Canada. We present the clinical and molecular findings of 83 probands and 28 family members, referred for genetic analysis due to a clinical and biochemical suspicion of HPP. Patient referrals included those with isolated low alkaline phosphatase levels and without any additional clinical features, to those with a severe skeletal dysplasia. Thirty‐six (43.3%) probands were found to have pathogenic ALPL mutations. Eleven previously unreported mutations were identified, thus adding to the ever increasing list of ALPL mutations. Seven of these eleven were inherited in an autosomal dominant manner while the remaining four were observed in the homozygous state. Thus, this study includes a large number of well‐characterized patients with hypophosphatasemia which has permitted us to study the genotype:phenotype correlation. Accurate diagnosis of patients with a clinical suspicion of HPP is crucial as not only is the disease life‐threatening but the patients may be offered bone targeted enzymatic replacement therapy. © 2017 Wiley Periodicals, Inc.