Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Idiopathic infantile hypercalcemia (IIH) is characterized by severe hypercalcemia with failure to thrive, vomiting, dehydration, and nephrocalcinosis. Recently, mutations in the vitamin D catabolizing enzyme 25-hydroxyvitamin D3-24-hydroxylase (CYP24A1) were described that lead to increased sensitivity to vitamin D due to accumulation of the active metabolite 1,25-(OH)2D3. In a subgroup of patients who presented in early infancy with renal phosphate wasting and symptomatic hypercalcemia, mutations in CYP24A1 were excluded. Four patients from families with parental consanguinity were subjected to homozygosity mapping that identified a second IIH gene locus on chromosome 5q35 with a maximum logarithm of odds (LOD) score of 6.79. The sequence analysis of the most promising candidate gene, SLC34A1 encoding renal sodium-phosphate cotransporter 2A (NaPi-IIa), revealed autosomal-recessive mutations in the four index cases and in 12 patients with sporadic IIH. Functional studies of mutant NaPi-IIa in Xenopus oocytes and opossum kidney (OK) cells demonstrated disturbed trafficking to the plasma membrane and loss of phosphate transport activity. Analysis of calcium and phosphate metabolism in Slc34a1-knockout mice highlighted the effect of phosphate depletion and fibroblast growth factor-23 suppression on the development of the IIH phenotype. The human and mice data together demonstrate that primary renal phosphate wasting caused by defective NaPi-IIa function induces inappropriate production of 1,25-(OH)2D3 with subsequent symptomatic hypercalcemia. Clinical and laboratory findings persist despite cessation of vitamin D prophylaxis but rapidly respond to phosphate supplementation. Therefore, early differentiation between SLC34A1 (NaPi-IIa) and CYP24A1 (24-hydroxylase) defects appears critical for targeted therapy in patients with IIH.
...
PMID:Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia. 2604 94

Idiopathic infantile hypercalcemia (IIH) is a mineral metabolism disorder characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis. The periodical increase in incidence of IIH, which occurred in the twentieth century in the United Kingdom, Poland, and West Germany, turned out to be a side effect of rickets over-prophylaxis. It was recently discovered that the condition is linked to two genes, CYP24A1 and SLC34A1. The aim of the study was to search for pathogenic variants of the genes in adult persons who were shortlisted in infancy as IIH caused by "hypersensitivity to vit. D". All persons were found to carry mutations in CYP24A1 or SLC34A1, nine and two persons respectively. The changes were biallelic, with one exception. Incidence of IIH in Polish population estimated on the basis of allele frequency of recurrent p.R396W CYP24A1 variant, is 1:32,465 births. It indicates that at least a thousand homozygotes and compound heterozygotes with risk of IIH live in the country. Differences in mechanism of developing hypercalcemia indicate that its prevention may vary in both IIH defects. Theoretically, vit. D restriction is a first indication for CYP24A1 defect (which disturbs 1,25(OH)2D degradation) and phosphate supplementation for SLC34A1 defect (which impairs renal phosphate transport). In conclusion, we suggest that molecular testing for CYP24A1 and SLC34A1 mutations should be performed in each case of idiopathic hypercalcemia/hypercalciuria, both in children and adults, to determine the proper way for acute treatment and complications prevention.
 ...
PMID:Biallelic mutations in CYP24A1 or SLC34A1 as a cause of infantile idiopathic hypercalcemia (IIH) with vitamin D hypersensitivity: molecular study of 11 historical IIH cases. 2847 Mar 90

Idiopathic infantile hypercalcemia is characterized by hypercalcemia, dehydration, vomiting, and failure to thrive, and it is due to mutations in 24-hydroxylase (CYP24A1). Recently, mutations in sodium-phosphate cotransporter (SLC34A1) expressed in the kidney were discovered as an additional cause of idiopathic infantile hypercalcemia. This report describes a female infant admitted for evaluation of nephrocalcinosis. She presented with hypercalcemia, hypercalciuria, low intact parathyroid hormone level, and high 1,25-dihydroxyvitamin D3 level. Exome sequencing identified novel compound heterozygous mutations in SLC34A1 (c.1337G>A, c.1483C>T). The patient was treated with fluids for hydration, furosemide, a corticosteroid, and restriction of calcium/vitamin D intake. At the age of 7 months, the patient's calcium level was within the normal range, and hypercalciuria waxed and waned. Renal echogenicity improved on the follow-up ultrasonogram, and developmental delay was not noted. In cases of hypercalcemia with subsequent hypercalciuria, DNA analysis for SLC34A1 gene mutations and CYP24A1 gene mutations should be performed. Further studies are required to obtain long-term data on hypercalciuria and nephrocalcinosis.
 ...
PMID:Infantile hypercalcemia with novel compound heterozygous mutation in SLC34A1 encoding renal sodium-phosphate cotransporter 2a: a case report. 3094 83