Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia

Jair Tenorio, Ignacio Álvarez, Leyre Riancho-Zarrabeitia, Gabriel Martos-Moreno, Giorgia Mandrile, Monserrat de la Flor Crespo, Mikhail Sukchev, Mostafa Sherif, Iza Kramer, María T. Darnaude-Ortiz, Pedro Arias, Gema Gordo, Irene Dapía, Julián Martinez-Villanueva, Rubén Gómez, José Manuel Iturzaeta, Ghada Otaify, Mayte García-Unzueta, Alessandro Rubinacci, José A. RianchoMona Aglan, Samia Temtamy, Mohamed Abdel Hamid, Jesús Argente, Víctor L. Ruiz-Pérez, Karen E. Heath, Pablo Lapunzina*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)601-610
Number of pages10
JournalAmerican Journal of Medical Genetics, Part A
Issue number3
Publication statusPublished - Mar 1 2017
Externally publishedYes


  • alkaline phosphatase
  • ALPL
  • bone mineralization
  • hypophosphatasia
  • odontohypophosphatasia
  • skeletal dysplasia

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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