Hereditary hypophosphataemic rickets: report of a family from the Indian subcontinent.
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Nutritional deficiency continues to be an important cause of rickets in the underdeveloped and developing parts of the world. In the western hemisphere, predominantly non-nutritional forms of rickets and osteomalacia are now seen. In this report we discuss a family with X-linked hypophosphataemic rickets from the Kashmir region of the Indian subcontinent (which is an uncommon entity here). (+info)
Tertiary hyperparathyroidism in X-linked hypophosphatemic rickets.
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We report a case of tertiary hyperparathyroidism in an X-linked familial hypophosphatemic rickets (XLH) patient under regular calcitriol and self-adjusted large doses of oral phosphate salt (2.4-3.6 g/day in 4-5 divided doses) according to his serum phosphate level. Tertiary hyperparathyroidism is an unusual complication of XLH patients during treatment. As there is growing evidence that a high phosphate diet may induce hyperplasia of the parathyroid glands, it is important to avoid the stimulation of the parathyroid glands by high doses of phosphate administration in XLH patients. Serum calcium, phosphate, alkaline phosphatase, and also parathyroid hormone should be measured regularly in order to facilitate an early diagnosis of secondary hyperparathyroidism during the treatment of XLH patients, since this stage is reversible with calcitriol and reduced doses of phosphate salt. (+info)
Final height of Japanese patients with X-linked hypophosphatemic rickets: effect of vitamin D and phosphate therapy.
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X-linked hypophosphatemic rickets (XLH) is one of the most common causes of rickets in infancy and childhood. Combination therapy of vitamin D and phosphate is generally used for patients with XLH. Effect of treatment of vitamin D and phosphate during childhood on final height of XLH has to be elucidated in Japanese. There have been only three Caucasian studies on final height of XLH with treatment since childhood. Purpose of this study is to report adult height and therapeutic effect of 22 Japanese participants (5 males, 17 females) with XLH who were treated with phosphate (33-200 mg/kg/day as phosphorus divided into 3 or 4 doses) and vitamin D (vitamin D2 or 1alpha-hydroxyvitamin D3) for more than five years and evaluate effect of the treatment on the final height retrospectively. Final height (FHt) for all participants was -1.69+/-11.11 SD. FHt (-1.69+/-1.11 SD) was significantly higher than height at the initiation of treatment (-2.38+/-0.88 SD) for all participants (P<0.01). In conclusion, combination therapy of vitamin D and phosphate improved final height of Japanese patients with XLH as is similar to previous Caucasian studies. (+info)
Orthophosphate transport in the erythrocyte of normal subjects and of patients with X-linked hypophosphatemia.
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We have examined the mechanism of TCA-soluble orthophosphate (Pi) transfer across the membrane of mature human erythrocytes in normal subjects and in patients with X-linked hypophosphatemia (X-LH). The studies were carried out largely at pH 7.4 and 37 degrees C, in partial stimulation of conditions in vivo. (a) At physiological concentrations (1-2 mM) Pi enters the intact normal erythrocyte down its chemical gradient and under no conditions could we identify a steady-state trans-membrane gradient for Pi greater than 0.6. Calculations of the phosphate anion distribution ratio using the Nernst equation yield theoretical values that closely approximate observed values. (b) Glycolytic inhibitors have little effect on total entry of 32Pi inti erythrocytes but they do affect the intracellular distribution of Pi. In the presence of iodoacetamide, label accumulates almost exclusively in the orthophosphate pool and less than 1% enters the organic phosphate pool. (c) Specific activity measurements in unblocked cells indicate that Pi anion equilibrates first with its intracellular Pi pool. These initial findings imply that neither group translocation, nor energy coupling, influence Pi permeation into the human erythrocytes. (d) The relationship between 32P entry and extracellular Pi concentration is parabolic in the presence of chloride, and linear in the presence of sulfate. The kinetics of concentration dependent entrance cannot be examined and saturability of Pi entry cannot be identified under these conditions. (e) The competitive inhibitor arsenate partially inhibits the initial rate and steady-state flux of orthophosphate in erythrocytes treated with iodoacetamide to inhibit glycolysis. However, a significant portion of Pi transport escapes arsenate inhibition. (f) Activation energies for Pi entry, in nonglycolizing erythrocytes are much higher than those required by simple diffusion in an aqueous system. (g) Neither the inward or outward movement of Pi is modulated by trans-phosphate. These latter findings suggest that transport of phosphate across the human erythrocyte is compatible with slow facilitated diffusion with symmetry for influex and efflux. The transmembrane chemical distribution ratio, and the equilibrium flux of Pi were not different from normal in the X-LH erythrocyte. Nor did the extracellular Pi concentration, arsenate, or temperature affect Pi entry differently in the two types of cells. We dedjce that different gene products serve the diffusional type of Pi transport in the erythrocyte membrane and the saturable component of transepithelial absorption in the gut and kidney. Only the latter is affected by the X-LH mutation. The former is apparently present not only in erythrocytes but also in epithelial tissue, where it can serve the absorption of pharmacologic amounts of Pi in the therapeutic repair of the depleted phosphate pools in X-LH. (+info)
Hereditary hypophosphatemic rickets with hypercalciuria is not caused by mutations in the Na/Pi cotransporter NPT2 gene.
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Hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a renal phosphate (Pi) wasting disease first described in an extended Bedouin kindred, is characterized by hypophosphatemia, elevated serum 1,25-dihydroxyvitamin D levels, hypercalciuria, rickets, and osteomalacia. Correction of all abnormalities, except for renal Pi wasting, can be achieved by oral Pi supplementation. These findings and the demonstration that mice that are homozygous for the disrupted Na/Pi cotransporter gene Npt2 exhibit many of the biochemical features of HHRH suggested that mutations in the human orthologue NPT2 might be responsible for HHRH. The NPT2 gene in affected individuals from the Bedouin kindred and four small families was screened for mutations to test this hypothesis. No putative disease-causing mutation was found. Two single nucleotide polymorphisms (SNP), a silent substitution in exon 7 and a nucleotide substitution in intron 4, were identified, and neither consistently segregated with HHRH in the Bedouin kindred. Linkage analysis indicated that the two NPT2 intragenic SNP as well as five microsatellite markers in the NPT2 gene region were not linked to HHRH in the Bedouin kindred. Therefore, this is evidence to exclude NPT2 as a candidate gene for HHRH in the families that were studied. (+info)
Autosomal recessive hypophosphataemic rickets with hypercalciuria is not caused by mutations in the type II renal sodium/phosphate cotransporter gene.
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BACKGROUND: At present the genetic defect for autosomal recessive and autosomal dominant hypophosphataemic rickets with hypercalciuria (HHRH) is unknown. Type II sodium/phosphate cotransporter (NPT2) gene is a serious candidate for being the causative gene in either or both autosomal recessive and autosomal dominant HHRH. In the present study we tested this hypothesis in one autosomal recessive family. METHODS: The gene structure of human NPT2 is known. We tested the complete open reading frame in the affected siblings by polymerase chain reaction in combination with automatic DNA sequencing for the presence of mutations. RESULTS: We did not observe disease-causing mutations in the NPT2 gene of the affected siblings. A T855C polymorphism resulting in a histidine to arginine transition was present in the open reading frame of NPT2. The polymorphism was present in both affected as well as unaffected family members. CONCLUSION: The hypothesis that a defect in the NPT2 gene could be an underlying cause for autosomal recessive HHRH could not be sustained in our study. (+info)
A rationale for treatment of hereditary vitamin D-resistant rickets with analogs of 1 alpha,25-dihydroxyvitamin D(3).
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Hereditary vitamin D-resistant rickets (HVDRR) is caused by heterogeneous inactivating mutations in the vitamin D receptor (VDR). Treatment of HVDRR patients with high doses of oral calcium and supraphysiologic doses of 1 alpha,25-dihydroxyvitamin D(3) (1,25D(3)) has had limited success. In this study we explored the use of vitamin D analogs as a potential therapy for this disorder. The rationale for the use of vitamin D analogs is that they bind the VDR at different amino acid residues than 1,25D(3), and their ability to modulate VDR functions differs from that of the natural hormone. In this report, we examined the VDR from three HVDRR patients with mutations in the ligand-binding domain of the VDR (histidine 305 to glutamine, arginine 274 to leucine, and phenylalanine 251 to cysteine) for their responses to two vitamin D analogs, 20-epi-1,25D(3) and 1 beta-hydroxymethyl-3-epi-16-ene-26a,27a-bishomo-25D(3) (JK-1626-2). Our results reveal that vitamin D analogs partially or completely restore the responsiveness of the mutated VDR. Analog treatment seemed to be more successful when the mutation affects the amino acids directly involved in ligand binding rather than amino acids that contribute to a functional VDR interface with dimerization partners or coactivators of transcription. (+info)
Disease-causing missense mutations in the PHEX gene interfere with membrane targeting of the recombinant protein.
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PHEX is homologous to the M13 zinc metallopeptidases, a class of type II membrane glycoproteins. Although more than 140 mutations in the PHEX gene have been identified in patients with X-linked hypophosphatemia (XLH), the most prevalent form of inherited rickets, the molecular consequences of disease-causing PHEX mutations have not yet been investigated. We examined the effect of PHEX missense mutations on cellular trafficking of the recombinant protein. Four mutant PHEX cDNAs were generated by PCR mutagenesis: C85R, G579R and S711R, identified in XLH patients, and E581V, previously engineered in neutral endopeptidase 24.11, where it abolished catalytic activity but not plasma membrane targeting. Wild-type and mutant PHEX cDNAs were transfected in HEK(293) cells and PHEX protein expression was characterized. In contrast to the wild-type and E581V PHEX proteins, the C85R, G579R and S711R mutants were completely sensitive to endoglycosidase H digestion, indicating that they were not fully glycosylated. Sequestration of the disease-causing mutant proteins in the endoplasmic reticulum (ER) and plasma membrane localization of wild-type and E581V PHEX proteins was demonstrated by immunofluorescence and cell surface biotinylation. Of the three mutant PHEX proteins, the S711R was the least stable and the only one that could be rescued from the ER to the plasma membrane in cells grown at 26 degrees C. The chemical chaperone glycerol failed to correct defective targeting of all three mutant proteins. Our data provide a mechanism for loss of PHEX function in XLH patients expressing the C85R, G579R and S711R mutations. (+info)