Searching for CYP24A1 mutations in cohorts of patients with calcium nephrolithiasis

Abstract

IntroductionThe genetics underlying the idiopathic hypercalciuria leading to calciumcontaining renal stones remains elusive. The discovery of rare monogenic tubulopathies, often leading to hypercalciuria, has increased our understanding of tubular physiology and patho-physiology. However, insights into idiopathic calcium stone formation have not been gained from these disorders. The aim of this study is to examine CYP24A1 mutations in cohorts of patients with calcium nephrolithiasis. Materials and MethodsWe examined two cohorts of stoneforming patients for mutations in CYP24A1, which encodes the vitamin D24-hydroxylase enzyme. The first cohort had a biochemical phenotype of suppressed parathyroid hormone and high normal serum calcium, whilst the second cohort had a hypercalciuria phenotype. We did not identify bi-allelic sequence variants in CYP24A1 in our cohorts. ResultsIn cohort 1, we identified 9 known sequence variants. In cohort 2 we identified 7 known sequence variants. Conclusion CYP24A1 mutations remain a rare cause of calcium nephrolithiasis and hypercalciuria.

LC-MS/MS for Identifying Patients with CYP24A1 Mutations

“…Depending on calcium and phosphorus demands, D (10, 11 ). Inactivating mutations of CYP24A1 (cytochrome P450, family 24, subfamily A, polypeptide 1) cause hypercalcemia, hypercalciuria, and increased 1,25(OH) 2 D concentrations (12)(13)(14)(15)(16)(17)(18)(19)(20). In studies describing LC-MS/MS assays for 24,25(OH) 2 D quantification, the relationship between 25(OH)D and 24,25(OH) 2 D has been used as a nutritional marker for assessment of optimum vitamin D supplementation (21 ).…”

Clinical and Biochemical Features of Patients with CYP24A1 Mutations

“…A recent study screening patients with known calcium nephrolithiasis for CYP24A1 mutations did not identify any biallelic variants in a cohort of 166 patients, suggesting CYP24A1 mutations are a rare cause of idiopathic nephrolithiasis [8]. However, given our increased understanding of this phenotype, it is imperative that recognition of the typical biochemical pattern (suppressed PTH, hypercalcaemia, hypercalciuria) in any patients with nephrolithiasis prompts investigation for CYP24A1 mutations [4,6,8]. Establishing a molecular diagnosis in this small cohort of patients can facilitate correct treatment and lifestyle modification (Table 1) [9].…”

“…A typical biochemistry profile was found within this phenotype group, with normal/high serum calcium levels, suppressed parathyroid hormone, high levels of active vitamin D metabolites (25-hydroxyvitamin D 3 and 1,25-dihydroxyvitamin D 3 ) and low levels of inactivated vitamin D (24,25-dihydroxyvitamin D 3 ). A recent study screening patients with known calcium nephrolithiasis for CYP24A1 mutations did not identify any biallelic variants in a cohort of 166 patients, suggesting CYP24A1 mutations are a rare cause of idiopathic nephrolithiasis [8]. However, given our increased understanding of this phenotype, it is imperative that recognition of the typical biochemical pattern (suppressed PTH, hypercalcaemia, hypercalciuria) in any patients with nephrolithiasis prompts investigation for CYP24A1 mutations [4,6,8].…”

Vitamin D – what is normal according to latest research and how should we deal with it?

“…4 At present, the population frequency of CYP24A1 variants has not been established. 5 The rarity of these presentations often leads to delayed diagnosis, a feature that will hopefully change with increased awareness and easier access to diagnostic testing.…”

“…4 Twenty one cases of Zika have been diagnosed in the UK since April 2015 in travellers returning from affected countries (predominantly the Americas and the Caribbean). 5 Returning travellers presenting with a maculopapular rash and/or fever with at least one of the following symptoms (not explained by other medical conditions) meet the World Health Organization criteria of a suspected case: conjunctivitis, arthralgia, or arthritis. 6 Other symptoms may include itching/pruritus, headache, myalgia, lower back pain, and retro-orbital painall of which are compatible with a diagnosis of Dengue fever or Chikungunya.…”