title: Clinical, biochemical and genetic spectrum of low alkaline phosphatase levels in adults.
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.
  
  
  CONCLUSIONS
  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.affiliation: Dept. of Rheumatology, Hospital Universitario Marqués Valdecilla, IDIVAL, Santander, Spain. Electronic address: leyre1987@hotmail.com.
authors.forename: Leyre
authors.initials: L
authors.lastname: Riancho-Zarrabeitia
authors.affiliation: Dept. of Clinical Biochemistry, Hospital Universitario Marqués Valdecilla, IDIVAL, Santander, Spain. Electronic address: garciaunzueta@yahoo.es.
authors.forename: Mayte
authors.initials: M
authors.lastname: García-Unzueta
authors.affiliation: 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.
authors.forename: Jair A
authors.initials: JA
authors.lastname: Tenorio
authors.affiliation: Dept. of Clinical Biochemistry, Hospital Universitario Marqués Valdecilla, IDIVAL, Santander, Spain. Electronic address: jgomez@humv.es.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Gómez-Gerique
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", IdiPAZ, UAM-CIBERER - ISCIII, Madrid, Spain. Electronic address: vlruiz@iib.uam.es.
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, Spain; Skeletal Dysplasia Multidisciplinary Unit, Hospital Universitario La Paz, Madrid, Spain. Electronic address: kheath71@yahoo.com.
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, Spain; Skeletal Dysplasia Multidisciplinary Unit, Hospital Universitario La Paz, Madrid, Spain. Electronic address: pablo.lapunzina@salud.madrid.org.
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapunzina
authors.affiliation: Dept. of Internal Medicine, Hospital Universitario Marqués Valdecilla, IDIVAL, University of Cantabria, RETICEF, Santander, Spain. Electronic address: rianchoj@unican.es.
authors.forename: José A
authors.initials: JA
authors.lastname: Riancho
mesh_terms: D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase / Q000097:blood / Q000235:genetics*; D002118:Calcium / Q000097:blood*; D004983:Ethanolamines / Q000652:urine*; D005260:Female; D006579:Heterozygote; D006801:Humans; D007014:Hypophosphatasia / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D011732:Pyridoxal Phosphate / Q000097:blood*; D055815:Young Adult
chemical_list: D004983:Ethanolamines; D011732:Pyridoxal Phosphate; C005448:phosphorylethanolamine; C548267:ALPL protein, human; D000469:Alkaline Phosphatase; D002118:Calcium
keywords: ALPL; Alkaline phosphatase; Hypophosphatasia; Mutation analysis; Phosphoethanolamine; Pyridoxal phosphate