title: Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia.
abstract: 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.
authors.affiliation: Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autónoma de Madrid, Madrid, Spain.|CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.
authors.forename: Jair
authors.initials: J
authors.lastname: Tenorio
authors.affiliation: Medical Division, Alexion Pharmaceuticals, Madrid, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Álvarez
authors.affiliation: Department of Rheumatology, Hospital Universitario Marqués Valdecilla, IDIVAL, Santander, Spain.
authors.forename: Leyre
authors.initials: L
authors.lastname: Riancho-Zarrabeitia
authors.affiliation: Department of Endocrinology, Hospital Universitario Niño Jesús, IIS La Princesa, Madrid, Spain.|Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain.|CIBEROBN, Centro de Investigación Biomédica en Red sobre Fisiopatología de la obesidad y nutrición, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Gabriel Á
authors.initials: GÁ
authors.lastname: Martos-Moreno
authors.affiliation: Department of Medical Genetics, San Luigi University Hospital, Orbassano, Italy.|Department Clinical and Biological Sciences, University of Torino, Torino, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Mandrile
authors.affiliation: Department of Pediatrics, Hospital de la Moraleja, Madrid, Spain.
authors.forename: Monserrat
authors.initials: M
authors.lastname: de la Flor Crespo
authors.affiliation: Diagnostic Specialist, Alexion Pharmaceuticals, Moscow, Russia.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Sukchev
authors.affiliation: Medical Division, Alexion Pharma Middle East, Dubai Media City, United Arab Emirates.
authors.forename: Mostafa
authors.initials: M
authors.lastname: Sherif
authors.affiliation: Department of Pediatrics, Privat Hospitalet Denmark, Charlottenlund, Denmark.
authors.forename: Iza
authors.initials: I
authors.lastname: Kramer
authors.affiliation: Department of Genetics, Hospital Universitario de Móstoles, Madrid, Spain.
authors.forename: María T
authors.initials: MT
authors.lastname: Darnaude-Ortiz
authors.affiliation: Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autónoma de Madrid, Madrid, Spain.|CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Arias
authors.affiliation: Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autónoma de Madrid, Madrid, Spain.|CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Gordo
authors.affiliation: Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autónoma de Madrid, Madrid, Spain.|CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Dapía
authors.affiliation: Department of Endocrinology, Hospital Universitario Niño Jesús, IIS La Princesa, Madrid, Spain.
authors.forename: Julián
authors.initials: J
authors.lastname: Martinez-Villanueva
authors.affiliation: Department of Biochemistry, Hospital Universitario La Paz, IdiPaz, Madrid, Spain.
authors.forename: Rubén
authors.initials: R
authors.lastname: Gómez
authors.affiliation: Department of Biochemistry, Hospital Universitario La Paz, IdiPaz, Madrid, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Iturzaeta
authors.affiliation: Division of Human Genetics and Genome Research, Department of Clinical Genetics, National Research Centre, Cairo, Egypt.|Centre of Excellence for Human Genetics, National Research Centre, Cairo, Egypt.
authors.forename: Ghada
authors.initials: G
authors.lastname: Otaify
authors.affiliation: Department of Clinical Biochemistry, Hospital Universitario Marqués Valdecilla, IDIVAL, Santander, Spain.
authors.forename: Mayte
authors.initials: M
authors.lastname: García-Unzueta
authors.affiliation: Bone Metabolism Unit, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rubinacci
authors.affiliation: Department of Internal Medicine, Hospital Universitario Marqués Valdecilla, IDIVAL, University of Cantabria, RETICEF, Santander, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Riancho
authors.affiliation: Division of Human Genetics and Genome Research, Department of Clinical Genetics, National Research Centre, Cairo, Egypt.|Centre of Excellence for Human Genetics, National Research Centre, Cairo, Egypt.
authors.forename: Mona
authors.initials: M
authors.lastname: Aglan
authors.affiliation: Division of Human Genetics and Genome Research, Department of Clinical Genetics, National Research Centre, Cairo, Egypt.|Centre of Excellence for Human Genetics, National Research Centre, Cairo, Egypt.
authors.forename: Samia
authors.initials: S
authors.lastname: Temtamy
authors.affiliation: Centre of Excellence for Human Genetics, National Research Centre, Cairo, Egypt.|Division of Human Genetics and Genome Research, Department of Medical Molecular Genetics, National Research Centre, El Cairo, Egypt.
authors.forename: Mohamed Abdel
authors.initials: MA
authors.lastname: Hamid
authors.affiliation: Department of Endocrinology, Hospital Universitario Niño Jesús, IIS La Princesa, Madrid, Spain.|Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain.|CIBEROBN, Centro de Investigación Biomédica en Red sobre Fisiopatología de la obesidad y nutrición, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Argente
authors.affiliation: CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.|Skeletal Dysplasia Multidisciplinary Unit (UMDE), Hospital Universitario La Paz, Madrid, Spain.|Instituto de Investigaciones Biológicas (IB), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Víctor L
authors.initials: VL
authors.lastname: Ruiz-Pérez
authors.affiliation: Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autónoma de Madrid, Madrid, Spain.|CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.|Skeletal Dysplasia Multidisciplinary Unit (UMDE), Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Heath
authors.affiliation: Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autónoma de Madrid, Madrid, Spain.|CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.|Skeletal Dysplasia Multidisciplinary Unit (UMDE), Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapunzina
mesh_terms: D000293:Adolescent; D000328:Adult; D000469:Alkaline Phosphatase / Q000235:genetics*; D000483:Alleles; D019943:Amino Acid Substitution; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D056726:Genetic Association Studies; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007014:Hypophosphatasia / Q000175:diagnosis* / Q000235:genetics*; D040582:Inheritance Patterns; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: C548267:ALPL protein, human; D000469:Alkaline Phosphatase
keywords: ALPL; TNSALP; alkaline phosphatase; bone mineralization; hypophosphatasia; odontohypophosphatasia; skeletal dysplasia