Leyre Riancho-Zarrabeitia1, Mayte García-Unzueta2, Jair A Tenorio3, Juan A Gómez-Gerique4, Víctor L Ruiz Pérez5, Karen E Heath6, Pablo Lapunzina7, José A Riancho8. 1. Dept. of Rheumatology, Hospital Universitario Marqués Valdecilla, IDIVAL, Santander, Spain. Electronic address: leyre1987@hotmail.com. 2. Dept. of Clinical Biochemistry, Hospital Universitario Marqués Valdecilla, IDIVAL, Santander, Spain. Electronic address: garciaunzueta@yahoo.es. 3. Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autónoma de Madrid, Spain; CIBERER, ISCIII, Madrid, Spain. Electronic address: jairantonio.tenorio@salud.madrid.org. 4. Dept. of Clinical Biochemistry, Hospital Universitario Marqués Valdecilla, IDIVAL, Santander, Spain. Electronic address: jgomez@humv.es. 5. Instituto de Investigaciones Biomédicas "Alberto Sols", IdiPAZ, UAM-CIBERER - ISCIII, Madrid, Spain. Electronic address: vlruiz@iib.uam.es. 6. Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autónoma de Madrid, Spain; Skeletal Dysplasia Multidisciplinary Unit, Hospital Universitario La Paz, Madrid, Spain. Electronic address: kheath71@yahoo.com. 7. Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autónoma de Madrid, Spain; Skeletal Dysplasia Multidisciplinary Unit, Hospital Universitario La Paz, Madrid, Spain. Electronic address: pablo.lapunzina@salud.madrid.org. 8. Dept. of Internal Medicine, Hospital Universitario Marqués Valdecilla, IDIVAL, University of Cantabria, RETICEF, Santander, Spain. Electronic address: rianchoj@unican.es.
Abstract
BACKGROUND: Low serum levels of alkaline phosphatase (ALP) are a hallmark of hypophosphatasia. However, the clinical significance and the underlying genetics of low ALP in unselected populations are unclear. METHODS: In order to clarify this issue, we performed a clinical, biochemical and genetic study of 42 individuals (age range 20-77yr) with unexplained low ALP levels. RESULTS: Nine had mild hyperphosphatemia and three had mild hypercalcemia. ALP levels were inversely correlated with serum calcium (r=-0.38, p=0.012), pyridoxal phosphate (PLP; r=-0.51, p=0.001) and urine phosphoethanolamine (PEA; r=-0.49, p=0.001). Although many subjects experienced minor complaints, such as mild musculoskeletal pain, none had major health problems. Mutations in ALPL were found in 21 subjects (50%), including six novel mutations. All but one, were heterozygous mutations. Missense mutations were the most common (present in 18 subjects; 86%) and the majority were predicted to have a damaging effect on protein activity. The presence of a mutated allele was associated with tooth loss (48% versus 12%; p=0.04), slightly lower levels of serum ALP (p=0.002), higher levels of PLP (p<0.0001) and PEA (p<0.0001), as well as mildly increased serum phosphate (p=0.03). Ten individuals (24%) had PLP levels above the reference range; all carried a mutated allele. CONCLUSION: One-half of adult individuals with unexplained low serum ALP carried an ALPL mutation. Although the associated clinical manifestations are usually mild, in approximately 50% of the cases, enzyme activity is low enough to cause substrate accumulation and may predispose to defects in calcified tissues.
BACKGROUND: Low serum levels of alkaline phosphatase (ALP) are a hallmark of hypophosphatasia. However, the clinical significance and the underlying genetics of low ALP in unselected populations are unclear. METHODS: In order to clarify this issue, we performed a clinical, biochemical and genetic study of 42 individuals (age range 20-77yr) with unexplained low ALP levels. RESULTS: Nine had mild hyperphosphatemia and three had mild hypercalcemia. ALP levels were inversely correlated with serum calcium (r=-0.38, p=0.012), pyridoxal phosphate (PLP; r=-0.51, p=0.001) and urine phosphoethanolamine (PEA; r=-0.49, p=0.001). Although many subjects experienced minor complaints, such as mild musculoskeletal pain, none had major health problems. Mutations in ALPL were found in 21 subjects (50%), including six novel mutations. All but one, were heterozygous mutations. Missense mutations were the most common (present in 18 subjects; 86%) and the majority were predicted to have a damaging effect on protein activity. The presence of a mutated allele was associated with tooth loss (48% versus 12%; p=0.04), slightly lower levels of serum ALP (p=0.002), higher levels of PLP (p<0.0001) and PEA (p<0.0001), as well as mildly increased serum phosphate (p=0.03). Ten individuals (24%) had PLP levels above the reference range; all carried a mutated allele. CONCLUSION: One-half of adult individuals with unexplained low serum ALP carried an ALPL mutation. Although the associated clinical manifestations are usually mild, in approximately 50% of the cases, enzyme activity is low enough to cause substrate accumulation and may predispose to defects in calcified tissues.
Authors: L López-Delgado; L Riancho-Zarrabeitia; M T García-Unzueta; J A Tenorio; M García-Hoyos; P Lapunzina; C Valero; J A Riancho Journal: Osteoporos Int Date: 2018-06-12 Impact factor: 4.507
Authors: T Schmidt; H Mussawy; T Rolvien; T Hawellek; J Hubert; W Rüther; M Amling; F Barvencik Journal: Osteoporos Int Date: 2017-05-25 Impact factor: 4.507
Authors: Raquel Sanabria-de la Torre; Luis Martínez-Heredia; Sheila González-Salvatierra; Francisco Andújar-Vera; Iván Iglesias-Baena; Juan Miguel Villa-Suárez; Victoria Contreras-Bolívar; Mario Corbacho-Soto; Gonzalo Martínez-Navajas; Pedro J Real; Cristina García-Fontana; Manuel Muñoz-Torres; Beatriz García-Fontana Journal: Front Endocrinol (Lausanne) Date: 2022-04-14 Impact factor: 6.055