CYP24A1 mutations are now accepted as a cause of idiopathic infantile hypercalcemia (IIH). A rapid LC-MS/MS-based blood test enabling measurement of the 25-OH-D3 :24,25-(OH)2 D3 ratio (R) can identify IIH patients on the basis of reduced C24-hydroxylation of 25-OH-D3 by CYP24A1 in vivo. While values of this ratio are significantly elevated in IIH, somewhat surprisingly, serum 24,25-(OH)2 D3 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 D3 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; unaffected heterozygotes and dialysis patients; in patients with vitamin D deficiency; and in comparison with normal subjects exhibiting a broad range of 25-OH-D levels.
We identified 25,26-(OH)2 D3 as a contaminant of the 24,25-(OH)2 D3 peak. In normals, the concentration of 24,25-(OH)2 D3 greatly exceeds 25,26-(OH)2 D3 ; however 25,26-(OH)2 D3 becomes more significant in IIH with CYP24A1 mutations and in dialysis patients, where 24,25-(OH)2 D3 levels are low when CYP24A1 function is compromised. Mean R in 30 IIH-CYP24A1 patients was 700 (range:166-2168, cutoff =140) as compared with 31 in 163 controls. Furthermore, patients possessing CYP24A1 L409S alleles exhibited higher 24,25-(OH)2 D3 levels and lower R (mean R = 268, n = 8) than patients with other mutations.
We conclude that a chromatographic approach that resolves 24,25-(OH)2 D3 from 25,26-(OH)2 D3 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 D3 in IIH patients appears to be multifactorial. This article is protected by copyright. All rights reserved.
Pharmacology, Toxicology and Pharmaceutical Science
5
9%
Nursing and Health Professions
5
9%
Chemistry
3
6%
Other
6
11%
Unknown
16
30%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 3. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 18 October 2021.
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