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Eur J Intern Med. 2016 Apr;29:40-5. doi: 10.1016/j.ejim.2015.12.019. Epub 2016 Jan 11.

Clinical, biochemical and genetic spectrum of low alkaline phosphatase levels in adults.

Author information

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.

KEYWORDS:

ALPL; Alkaline phosphatase; Hypophosphatasia; Mutation analysis; Phosphoethanolamine; Pyridoxal phosphate

PMID:
26783040
DOI:
10.1016/j.ejim.2015.12.019
[Indexed for MEDLINE]

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