Clinical and Biochemical Features of Patients with CYP24A1 Mutations

Abstract

The CYP24A1 gene encodes 1,25-hydroxyvitamin-D 3 -24-hydroxylase, a key enzyme responsible for the catabolism of active vitamin D (1,25-dihydroxyvitamin D 3 ). Loss-offunction mutations in CYP24A1 lead to increased levels of active vitamin D metabolites. Clinically, two distinct phenotypes have been recognised from this: infants with CYP24A1 mutations present with infantile idiopathic hypercalcaemia, often precipitated by prophylactic vitamin D supplementation. A separate phenotype of nephrolithiasis, hypercalciuria and nephrocalcinosis often presents in adulthood. CYP24A1 mutations should be suspected when a classical biochemical profile of high active vitamin D metabolites, high or normal serum calcium, high urine calcium and low parathyroid hormone is detected. Successful treatment with fluconazole, a P450 enzyme inhibitor, has been shown to be effective in individuals with CYP24A1 mutations. Although CYP24A1 mutations are rare, early recognition can prompt definitive diagnosis and ensure treatment is commenced.

Dietary branched-chain amino acids modulate the dynamics of calcium absorption and reabsorption in protein-restricted pigs

“…In the current study, LB50 increased the transcript of CYP24A1 and in kidney. The active form of vitamin D is converted to 24hydroxylated inactive product under the action of 1,25hydroxyvitamin-D 3 -24-hydroxylase encoded by CYP24A1 gene [68]. The increased expression of CYP24A1 in kidney is suggestive of a decreased concentration of active form of vitamin D. As discussed earlier, LB50 decreased the plasma VD 3 concentration as well.…”

Nephrocalcinosis: A Review of Monogenic Causes and Insights They Provide into This Heterogeneous Condition

“…The second stage of vitamin D activation takes place within the kidney, resulting in production of the active metabolite 1,25-dihydroxyvitamin D 3 . Mutations in CYP24A1, which encodes 1,25-hydroxyvitamin-D 3 -24-hydroxylase, result in an inability to catabolise this active vitamin D metabolite [19]. CYP24A1 mutations were first detected following reports of a small cohort of babies developing adverse effects (including hypercalcemia and nephrocalcinosis) as a result of the public health intervention to routinely supplement formula milk with vitamin D [20].…”

“…CYP24A1 mutations were first detected following reports of a small cohort of babies developing adverse effects (including hypercalcemia and nephrocalcinosis) as a result of the public health intervention to routinely supplement formula milk with vitamin D [20]. Following further analysis, two distinct phenotypes resulting from CYP24A1 mutations have been recognised, both of which frequently include nephrocalcinosis [19].…”

“…Treatment strategies focus upon low calcium and oxalate diet, avoidance of vitamin D supplementation and excessive sunlight exposure [19]. Use of azole antifungal agents (fluconazole, ketoconazole) have shown benefit as non-specific P450 enzyme inhibitors which inhibit 1α-hydroxylase (encoded by CYP27B1), thereby reducing production of the active form of vitamin D [19,23]. However, lifelong treatment with these agents may be undesirable owing to their side effect profile, including hepatotoxicity.…”