In:
Journal of Bone and Mineral Research, Wiley, Vol. 32, No. 7 ( 2017-07), p. 1589-1596
Kurzfassung:
CYP24A1 mutations are now accepted as a cause of idiopathic infantile hypercalcemia (IIH). A rapid liquid‐chromatography tandem mass spectrometry (LC‐MS/MS)‐based blood test enabling measurement of the 25‐OH‐D 3 :24,25‐(OH) 2 D 3 ratio (R) can identify IIH patients on the basis of reduced C24‐hydroxylation of 25‐OH‐D 3 by CYP24A1 in vivo. Although values of this ratio are significantly elevated in IIH, somewhat surprisingly, serum 24,25‐(OH) 2 D 3 remains detectable. The current study explores possible explanations for this including: residual CYP24A1 enzyme activity in individuals with certain CYP24A1 genotypes, expression of alternative C24‐hydroxylases, and the possibility of isobaric contamination of the 24,25‐(OH) 2 D 3 peak on LC‐MS/MS. We employed an extended 20‐min run time on LC‐MS/MS to study serum vitamin D metabolites in patients with IIH due to mutations of CYP24A1 or SLC34A1 ; in unaffected heterozygotes and dialysis patients; in patients with vitamin D deficiency; as well as in normal subjects exhibiting a broad range of 25‐OH‐D levels. We identified 25,26‐(OH) 2 D 3 as a contaminant of the 24,25‐(OH) 2 D 3 peak. In normals, the concentration of 24,25‐(OH) 2 D 3 greatly exceeds 25,26‐(OH) 2 D 3 ; however, 25,26‐(OH) 2 D 3 becomes more significant in IIH with CYP24A1 mutations and in dialysis patients, where 24,25‐(OH) 2 D 3 levels are low when CYP24A1 function is compromised. Mean R in 30 IIH‐CYP24A1 patients was 700 (range, 166 to 2168; cutoff = 140) as compared with 31 in 163 controls. Furthermore, patients possessing CYP24A1 L409S alleles exhibited higher 24,25‐(OH) 2 D 3 levels and lower R (mean R = 268; n = 8) than patients with other mutations. We conclude that a chromatographic approach which resolves 24,25‐(OH) 2 D 3 from 25,26‐(OH) 2 D 3 produces a more accurate R that can be used to differentiate pathological states where CYP24A1 activity is altered. The origin of the residual serum 24,25‐(OH) 2 D 3 in IIH patients appears to be multifactorial. © 2017 American Society for Bone and Mineral Research.
Materialart:
Online-Ressource
ISSN:
0884-0431
,
1523-4681
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2017
ZDB Id:
2008867-X
