Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A child with hypophosphatemic vitamin D-resistant rickets was treated for three years with the conventional vitamin D-inorganic phosphate supplementation followed by a new therapeutic regimen consisting of 1,25 dihydroxyvitamin D3 (1,25 (OH)2D3) and half of the previous phosphate supplementation. The effectiveness of the two treatment regimens was compared by calcium, phosphate, and magnesium balance techniques and by serial radiological examinations as well as careful height measurements. In addition, the lowering of the urinary pH with ascorbic acid supplementation seems to be associated with improvement in the renal tubular reabsorption of phosphate, but its distinct effect, separate from the rest of the treatment modalities, was not tested in this study. The conventional treatment did not correct the hypophosphatemia and alkaline phosphatase elevation, whereas the 1,25 (OH)2 D3-inorganic phosphate regimen is well tolerated and effective in achieving a sustained normalization of these variables. In addition, the improved growth and healing of rickets further attest to the efficacy of the new treatment.
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PMID:Hypophosphatemic vitamin D-resistant rickets: metabolic balance studies in a child receiving 1,25 dihydroxyvitamin D3, phosphate, and ascorbic acid. 2 11

The long-term effects of the vitamin D metabolite, 25-hydroxycholecalciferol (25-HCC), were evaluated in 2 children with hypophosphatemic vitamin D-resistant rickets. Serial total balance studies demonstrated an apparent lack of correlation between the effects of the vitamin on intestinal absorption of calcium and phosphorus and both the onset of healing in 1 of the 2 patients treated with 5,000 to 7,500 u of the metabolite and the absence of demonstrable radiologic improvement in another patient in whom the final dosage was 20,000 u. per day. At first, the metabolite induced a positive calcium balance in both patients resulting largely from a reduction in intestinal calcium excretion. Despite a continued positive calcium balance, 1 of the 2 patients did not demonstrate further healing, while in the other patient healing was noted even when total calcium balance was negative. Serum phosphate levels did not return to normal in either patient, nor was phosphate excretion altered by 25-HCC. Serum alkaline phosphatase remained elevated in both. Serum immunoassayable parathyroid hormone levels were consistently normal to high-normal in the 2 patients throughout more than 24 months of observation. No instances of hypercalcemia and only occasional hypercalciuric episodes were noted.
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PMID:Long-term therapy of viramin D-resistant richets with 25-hydroxycholecalciferol. 16 13

A 5-year-old boy was found to have severe rickets in association with hyperpigmented, linear, verrucous, epidermal tumors, typical of the epidermal nevus syndrome. Normocalcemia (9.6 mg/dl), hypophosphatemia (2.0 mg/dl), elevated serum alkaline phosphatase concentration (313 IU), decreased renal tubular reabsorption of phosphorus (35%), radiologic evidence of rickets, and lack of response to usual therapeutic doses of vitamin D suggested hypophosphatemic vitamin D-resistant rickets. Therapy with vitamin D in doses to 750,000 IU and oral phosphate, 2.0 gm/day, failed to induce healing of the rickets. A subtotal parathyroidectomy performed when the patient was 9 years old was also without effect. When he was 12 years old several fibroangiomas on the face and left lower limb were excised. Within three months all biochemical abnormalities resolved and radiologic evidence of healing was observed. A portion of excised tissue was homogenized and injection of the supernate into a 6-week-old puppy induced excessive phosphaturia. The data suggest that the rickets was induced by a phosphaturic substance extractable from the tumors.
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PMID:Vitamin D-resistant rickets associated with epidermal nevus syndrome: demonstration of a phosphaturic substance in the dermal lesions. 19 29

To further explore the hypothesis of an osteoblast inappropriate response to 1,25-(OH)2D3 in hypophosphatemic vitamin D-resistant rickets (HYP), osteoblasts were isolated from Hyp mice, the animal model for human HYP, and their response to a physiologic dose of 1,25-(OH)2D3 (10(-10) M) was investigated with respect to alkaline phosphatase (ALP) activity and cell proliferation, and compared to that of normal osteoblasts. Cells in secondary culture were incubated for 72 h while in log phase, with or without 1,25-(OH)2D3, at various medium phosphate (P) concentrations ranging from 0.5 to 4.5 mM. Stimulation of ALP activity and inhibition of cell proliferation was induced by 10(-10)M 1,25-(OH)2D3 in normal cells exposed to medium P concentration corresponding to serum levels observed in normal mice (2.1-2.7 mM P). By contrast, Hyp cells failed to respond to 1,25-(OH)2D3 in that range of P concentrations. Stimulation of ALP activity and inhibition of proliferation of mutant cells were evident at higher medium P concentrations (over 3 mM). 1,25-(OH)2D3 at the supraphysiologic level of 10(-9)M had no consistent effect on ALP activity in normal and Hyp mouse osteoblasts, but inhibited cell proliferation in cultures of both genotypes at all P concentrations tested. These results indicate that extracellular P modulates the action of 1,25-(OH)2D3 on osteoblasts, and that this modulation was altered in osteoblasts from Hyp mice. The failure of Hyp cells to respond to a physiologic dose of 1,25-(OH)2D3 upon normal P concentration may reflect the abnormal response of bone to 1,25-(OH)2D3 observed in Hyp mice and HYP patients.
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PMID:Abnormal response of osteoblasts from Hyp mice to 1,25-dihydroxyvitamin D3. 132 49

Tumor-induced osteomalacia is a clinicopathological entity in which vitamin D-resistant osteomalacia or rickets occurs in association with a tumor. A total of 72 cases (three current, 69 from review of literature) has been reported to date. Men and women are equally affected. The majority are adults over 30 years old who exhibit progressive lower leg and back pain. Forty bone and 31 soft-tissue tumors were responsible for this syndrome; two-thirds occurred in the extremities. Chemical findings are typical: low serum phosphorus, normal serum calcium, and elevated alkaline phosphatase. Serum levels of 1,25-dihydroxyvitamin D were low or undetectable. Histologically, more than a third were classified as vascular tumors, and half of these cases were hemangiopericytomas that were distributed equally between bone and soft tissues. Other common diagnoses included nonossifying fibromas, "mesenchymal" and giant-cell tumor variants. Features common to all tumors were prominent vascularity, and giant and primitive stromal cells. Only 10 were histologically malignant. Ultrastructural studies have not shown any secretory granules suggestive of a hormone-secreting tumor. It is clear, however, that the tumor is responsible for the osteomalacia because the complete removal generally results in a dramatic reversal of all symptoms and signs.
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PMID:Tumor-induced osteomalacia and rickets. 254 16

A severe form of vitamin D-resistant rickets is associated with the linear sebaceous nevus syndrome. We investigated the pathophysiology underlying defective bone mineralization in two individuals and examined the effects of 1,25-dihydroxyvitamin D (1,25(OH)2D, calcitriol) therapy on the clinical and biochemical abnormalities. Both patients had fasting hypophosphatemia, markedly diminished TmP/GFR, and elevated alkaline phosphase activity in the presence of normocalcemia. Before treatment with calcitriol, serum 1,25(OH)2D concentrations were reduced but serum 25-hydroxyvitamin D (25(OH)D) concentrations were normal. Administration of calcitriol increased serum 1,25(OH)2D concentrations and led to an increase in TmP/GFR and serum phosphorus levels and to a decrease in alkaline phosphatase activity. However, the renal tubular maximum for reabsorption of inorganic phosphate, normalized according to glomerular filtration rate, and serum phosphorus levels remained abnormally low even in the patient who also received phosphate supplementation. Bone histomorphologic studies in the adult patient showed extreme osteomalacia, which partially improved with calcitriol. These data demonstrate that the putative skin lesion-derived factor results in both a renal tubular defect in phosphate reabsorption and in 1,25-(OH)2 D deficiency. The vitamin D-resistant rickets of linear sebaceous nevus syndrome is a variant of tumor-induced osteomalacia.
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PMID:Hypophosphatemic rickets/osteomalacia in linear sebaceous nevus syndrome: a variant of tumor-induced osteomalacia. 302 99

X-linked hypophosphatemic (Hyp) mice are a model of human sex-linked vitamin D-resistant rickets. Young adult Hyp mice are characterized by osteomalacia and decreased bone mineral content. However, older heterozygous Hyp female mice increase in bone mineral content with age so that by one year of age the bone mass/mm femoral length equals or exceeds normal females. To test for the occurrence of this mineral accretion in Hyp male mice and in homozygous Hyp female mice, femora from all 3 Hyp genotypes as well as normal male and female mice were analyzed at various ages from one to 52 weeks of age. Compared to normal mice, all three Hyp genotypes were depressed in bone ash, femoral length, and ash/length ratio at 13 weeks of age. After that age the femora of both heterozygous and homozygous Hyp females showed a slow mineral accretion and, by 52 weeks of age, a normal ash/length ratio. However, the femora of Hyp males, as well as those of normal males, failed to increase in bone mineral content or ash/length ratio after 13 weeks of age. The differences between male and female Hyp mice could not be explained by differences in the plasma levels of calcium, phosphate, or alkaline phosphatase. Increased bone mineral content in older Hyp mice was seen in both heterozygous and homozygous females but not in hemizygous males. Thus, the basis for this increase is not incomplete dominance of the Hyp gene in females nor the Lyon hypothesis. The accretion of mineral in older female Hyp mice despite lifelong reduced plasma phosphate levels suggests that there are factors other than phosphate that also regulate mineral accretion in this bone disease.
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PMID:Mineral uptake by the femora of older female X-linked hypophosphatemic (HYP) mice but not older male HYP mice. 304 Mar 11

Vitamin D-resistant rickets is characterized by short stature, lower extremity deformities, and defective mineralization of bone. While basic biochemical defects vary among involved individuals, all patients show a failure of the proximal tubule of the kidney to resorb inorganic phosphate. Laboratory findings consist of low serum phosphorus, elevated alkaline phosphatase, and abnormal serum calcium. Previously recommended treatment programs of high doses of vitamin D have effected some roentgenographic improvement in the rachitic lesions, but no related increase in height or severity of deformities has been associated with significant complications resulting from vitamin D toxicity. Daily administration of low doses of vitamin D and oral phosphates has more recently been suggested to be beneficial in promoting growth and preventing deformities. Thirteen children with documented vitamin D-resistant rickets were treated with oral phosphate and low doses of vitamin D for a mean of five years, and followed for a mean of ten years. Partial roentgenographic resolution of rachitic lesions was similar to those who received vitamin D alone. While the majority had consistently lowered alkaline phosphatases, no patient had consistently normal phosphate levels. No patient exceeded the third percentile in height. One half required osteotomies of the lower extremities. All osteotomies (eight) performed before maturity required revision, whereas those done after maturity (12) did not. Since no apparent clinical roentgenographic benefit can be documented by the addition of oral phosphate to low doses of vitamin D, we would not recommend continually doing so at this time.
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PMID:The effect of treatment on growth and deformity in hypophosphatemic vitamin D-resistant rickets. 627 46

Vitamin D-resistant rickets (VDRR) in adults is characterized by low serum phosphorus and osteomalacia. Despite the disappearance of rickets after the closure of epiphyses, some adults with VDRR present with symptomatic bone disease while other are asymptomatic. In order to test the presumption that asymptomatic adults no longer have active bone disease, we have compared bone histology in 10 symptom-free adults to 6 age-comparable symptomatic adults presenting with bone pain and persistent deformities. Both groups had similar low serum phosphorus and increased serum alkaline phosphatase values. Serum calcium, parathyroid hormone, and vitamin D metabolite concentrations were not different in the two groups. Histomorphometric study of bone formation and resorption was made on undecalcified sections of iliac crest bone biopsies obtained after in vivo single or dual tetracycline labeling. Bone histology revealed that both groups of patients had comparable osteomalacia, as evidenced by increased amount of osteoid tissue, prolonged mineralization lag time, and reduced bone formation rate. Despite the presence of osteomalacia, the trabecular calcified bone volume was within or above normal values in the two groups, implying a remodeling imbalance between the rates of bone resorption and formation. The data show that despite the absence of symptoms and the disappearance of rickets, adults with VDRR still have active bone disease characterized by moderate to severe osteomalacia. The normal to increased trabecular bone mass implies that the occurrence of painful symptoms results from factors other than trabecular osteopenia. These observations thus lead one to question the utility of active medical treatment with vitamin D and/or phosphate in asymptomatic adults with VDRR.
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PMID:Bone histomorphometry in asymptomatic adults with hereditary hypophosphatemic vitamin D-resistant osteomalacia. 630 50

Three patients with familial hypophosphataemic vitamin D-resistant rickets (FHR) born to affected mothers have been clinically, radiologically and biochemically observed since birth. The value of the different early diagnostic signs is evaluated, and the efficiency of early phosphate and vitamin D treatment is discussed. Our observations suggest the following conclusions: Infants of FHR affected mothers can be diagnosed as having the disease by careful physical examinations and by a pathological increase of serum alkaline phosphatase with normal serum calcium, before radiological signs of rickets occur. The serum phosphate concentrations in early infancy are variable and of little or no diagnostic help. Early treatment is useful to cure or even to avoid rickets and to normalize serum alkaline phosphatase, but not hypophosphataemia. In spite of some favorable results, the influence of early started treatment on growth and leg deformities is difficult to assess due to the variations of individual expressivity of the disease.
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PMID:Early history of familial hypophosphataemic vitamin D-resistant rickets. Report of three cases observed since birth. 631 14


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