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PubMed1993

Sodium-phosphate transport in the kidney and intestine of the hypophosphatemic mouse.

X-linked hypophosphatemic vitamin D-resistant rickets is the most common inherited form of vitamin D-resistant rickets in man. The current studies were designed to characterize the defect in the sodium (Na+)-phosphate transporter in the (Hyp) mouse model. The slope of initial rate of phosphate uptake was significantly decreased in the kidney but not in intestinal brush border membranes of the (Hyp) mice compared with genetically matched controls. Phosphate uptake by the basolateral membranes of the intestine and kidney was similar in the (Hyp) and control mice. Kinetic analysis of phosphate uptake by renal brush border membranes showed a Vmax of 0.32 +/- 0.06 and 1.6 +/- 0.1 nmol/mg protein per 15 s (P < 0.01) and Km of 0.07 +/- 0.06 and 0.39 +/- 0.05 mM in (Hyp) and control mice respectively (P < 0.05). Vmax and Kmax of jejunal uptake of phosphate were similar in (Hyp) and control mice. To confirm these findings, we expressed the Na(+)-phosphate transporter in Xenopus laevis oocytes. Na(+)-dependent phosphate uptake in the oocytes was expressed 6 days after renal and intestinal poly(A)+ RNA injection, however, uptake values were significantly lower in oocytes injected with renal poly(A)+ RNA from the (Hyp) mice compared with controls (P < 0.01). No differences were noted in phosphate uptake by oocytes injected with poly(A)+ RNA from the jejunum of the (Hyp) or control mice. These studies suggest that the defect in the (Hyp) mice is localized to the kidney and is secondary to diminished activity and/or function of the Na(+)-phosphate transporter.

Animals↗
PubMed1994

Renal tubular disorders and arteriopathy of the lower limbs: risk factors for osteoporosis in men?

In order to clarify the risk-factors for men with vertebral fractures due to osteoporosis, we carried out a study of 51 cases. Twenty-five percent of patients had an endocrine disorder (hyperparathyroidism, hypogonadism, hyperthyroidism) or had received corticosteroids. These patients were compared with 26 age-matched controls. Eleven patients compared with 2 of the 26 control subjects had arteriopathy of the lower limbs; 11 patients had hypercalciuria or hyperphosphaturia compared with 3 of the control subjects. Arteriopathy appears to be associated with osteoporosis in older patients (mean age 71 years), whereas renal tubular disorders were found in younger patients (mean age 45 years).

Aged↗
PubMed1992

X-linked hypophosphataemia: a homologous phenotype in humans and mice with unusual organ-specific gene dosage.

XLH (X-linked hypophosphataemia, gene symbol HYP, McKusick 307800, 307810) and its murine counterparts (Hyp and Gy) map to a conserved segment on the X-chromosome (Xp 22.31-p.21.3, human; distal X, mouse). Gene dosage has received relatively little attention in the long history of research on this disease, which began over 50 years ago. Bone and teeth are sites of the principal disease manifestations in XLH (rickets, osteomalacia, interglobular dentin). Newer measures of quantitative XLH phenotypes reveal gene dose effects in bone and teeth with heterozygous values distributed between those in mutant hemizygotes and normal homozygotes. On the other hand, serum phosphate concentrations (which are low in the mutant phenotype and thereby contribute to bone and tooth phenotypes) do not show gene dosage. In Hyp mice serum values in mutant hemizygotes, mutant homozygotes and heterozygotes are similar. Phosphate homeostasis reflects its renal conservation. Renal absorption of phosphate on a high-affinity, Na+ ion-gradient coupled system in renal brush border membrane is impaired and gene dosage is absent at this level; the mutant phenotype is fully dominant. Synthesis and degradation of 1,25(OH)2D are also abnormal in XLH (and Hyp), but gene dosage in these parameters has not yet been measured. An (unidentified) inhibitory trans-acting product of the X-linked locus, affecting phosphate transport and vitamin D metabolism, acting perhaps through cytosolic protein kinase C, could explain the renal phenotype. But why would it have a normal gene dose effect in bone and teeth? Since the locus may have duplicated (to form Hyp and Gy), and shows evidence of variable expression in different organs (inner ear, bone/teeth, kidney), it may have been recruited during evolution to multiple functions.

Animals↗
PubMed1987

Effect of the X-linked Hyp mutation on N-ethylmaleimide labelling of proteins in renal brush border membrane.

The X-linked dominant mutation, hypophosphataemia (gene symbol, Hyp) is expressed in the laboratory mouse as deficient phosphate transport at the renal brush border membrane (BBM) of proximal nephron. In an attempt to identify proteins which mediate phosphate transport, we treated renal BBM vesicles prepared from mutant male (Hyp/Y) and normal male (+/Y) littermates, with radiolabelled N-ethylmaleimide (NEM), in the presence or absence of arsenate of arsenate which is a competitive inhibitor of phosphate transport. Polyacrylamide gel electrophoresis revealed labelling of membrane proteins in the 40-45 kDa range; addition of arsenate during NEM treatment inhibited labelling. These findings indicate a 40-45 kDa protein as a component of the renal BBM phosphate transport system(s). We found no difference between protein labelling of the renal BBM from Hyp/Y and +/Y mice.

Alkaline Phosphatase↗
PubMed1992

The pattern of growth and growth retardation of patients with hypophosphataemic vitamin D-resistant rickets: a longitudinal study.

Growth in height of 16 patients (5 boys and 11 girls) with hypophosphataemic rickets (HR) was studied in a longitudinal survey. The data shortly before and during puberty were analysed on the basis of Preece Baines curves, fitted to the original data; for the analysis at the age of 5 years, the original data were used. It appeared that the overall shape of the individual and average growth pattern could be adequately described by the Preece Baines method. The results further showed that from the age of 5 years onwards, average height was approximately two standard deviations below the normal mean for Dutch children. The patients showed a normal pubertal growth spurt which was, in general, insufficient to restore the growth retardation already established before adolescence. The four children who did show catch-up growth between the age of 5 years and adulthood had minimal rachitic lesions. The greater impact of the disease on growth in early childhood than on adolescent growth could be explained by the fact that HR mainly affects the growth of the legs, the major contributor to body size in early childhood. Finally, it was found that the difference between bone age, as determined by the Tanner Whitehouse (TW2)-method, and chronological age was not significant and the adult height in all patients except two could be adequately predicted from bone age and height.

Adolescent↗
PubMed1989

Two siblings with vitamin-D-dependent rickets type II: no recurrence of rickets for 14 years after cessation of therapy.

Rickets in a 3-year-old boy and his 1-year-old sister, both with alopecia, was cured by treatment with 50,000 IU of vitamin D2 daily for 2 years and did not recur within 14 years after cessation of therapy. A diagnosis of vitamin-D-dependent rickets type II was made in these patients at the ages of 20 and 18 years based on the findings that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] did not inhibit DNA biosynthesis in phytohaemagglutinin-stimulated lymphocytes and that cultured skin fibroblasts showed impaired nuclear uptake and normal cytosol binding of [3H]1,25(OH)2D3. Surprisingly, the serum 1,25(OH)2D levels of these patients were high and their serum 24,25-dihydroxyvitamin D levels were low, although neither patient showed any symptoms except alopecia. The presence of vitamin D metabolite imbalances in the absence of rickets in these patients might be explained by differences in sensitivity to 1,25(OH)2D3 of bone formation and vitamin D metabolism. In addition, changes of sensitivity to treatment with vitamin D derivatives might be a consequence of differentiation of target cells. From the present findings, it is suggested that in this disease treatment with a sufficient dose of vitamin D derivatives should be initiated in the active phase of rickets.

Alopecia↗
PubMed1985

Adult hypophosphatemic osteomalacia: report of two cases.

Two cases of late hypophosphatemic osteomalacia are described: a male aged 30 who had the disease since he was 22 and a woman of 23 who had the disease since she was 14. Both presented with myopathy and bone pain, and showed hypophosphatemia, hyperglycinuria, reduced tubular phosphate reabsorption (TPR), increased hydroxyprolinuria and normal iPTH and iCT values. Radiologically the male had no Looser's zones and the woman did. Bone biopsy confirmed hypophosphatemic osteomalacia. Both cases were treated with vitamin D and oral phosphate and no improvement was observed. When treatment with 25(OH)D3 was initiated, no improvement was seen and afterwards this was combined with treatment using 1.25(OH)2D3 and from this time on a clinical improvement of the myopathy became evident in both patients. In the woman, healing of the bone lesions occurred at the same time as that of the myopathy, whereas in the male the bone lesions became worse. Healing of the myopathy was only obtained when treatment with 1.25(OH)2D3 was begun. Both patients had reduced values of 2.3 erythrocytic DPG and low level of serum phosphorus when the myopathy was cured, which suggests a lack of effect of 2.3 DPG or serum phosphorus as a cause of the myopathy. Although this had been attributed to a deficiency in the function of 25(OH)D3, the response to 1.25(OH)2D3 and due to the effects of this metabolite on calcium transport in muscle, suggests that the myopathy which occurs in late hypophosphatemic osteomalacia is a result of deficiency or resistance to the muscular effect of this metabolite. We cannot explain the lack of bone healing in the man and further therapeutic studies are required.

Adolescent↗
PubMed1991

Vitamin D dependent rickets type II with myelofibrosis and immune dysfunction.

We present a new patient with vitamin D dependent rickets type II. A 20-month-old Arabian boy whose parents are first cousins showed florid rickets, myelofibrosis and recurrent septicaemia. In addition to absent specific binding for 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). 25-Hydroxyvitamin D3-24-hydroxylase activity could not be induced in cultured fibroblasts. The patient did not respond to 99 micrograms 1,25(OH)2D3 per day, but skeletal and haematological abnormalities improved with daily infusion of 100 mg/kg calcium, as serum parathyroid hormone levels fell to normal values. At the age of 7 years, he died from pneumonia. The improvement of haematological abnormalities with calcium infusions but not with 1.25(OH)2D3 suggests a pathogenetic relationship of myelofibrosis and hyperparathyroidism. Having anti-lipid A IgM antibody titres up to 1:10.000 after Gram negative septicaemias, the patient never produced corresponding IgG antibodies. His neutrophil chemotaxis was persistently reduced to 57% +/- 3% of age-matched controls (P less than 0.028). The patient showed two pathological immune functions considered to contribute to the well-known susceptibility to infection in rickets.

Calcium↗
PubMed1996

The gene for X-linked hypophosphataemic rickets maps to a 200-300kb region in Xp22.1, and is located on a single YAC containing a putative vitamin D response element (VDRE).

The location of the HYP gene, which determines X-linked hypophosphataemic rickets, has been refined considerably by linkage analysis, and three new microsatellite primers isolated, Cap32 (DXS7473), Cap29 (DXS7474) and 7v2 (DXS7475). The locations of four other markers have also been determined (DXS1226, AFMa176zb1, AFMa152wc5, and AFM346azc1). Markers Cap29 and Cap32 are the closest distal markers to the gene with zetamax=11.93, thetamax= 0.018 and zetamax=12.03, thetamax = 0.015 respectively. Both Cap29 and Cap32 are proximal to DXS365 and AFMa176zb1, as deduced by screening non-chimaeric yeast artificial chromosomes (YACs) from a contig spanning the HYP gene. A single crossover places AFMa176zbl distal to the disease gene. There are no recombinations between 7v2 and HYP (zetamax=12.9, thetamax=0.0), or between 7v2 and adjacent markers Cap32, Cap29, AFMa176zb1, DXS1683 and DXS365. However screening of YAC clones encompassing the HYP gene and also P1 clones localises 7v2 distal to Cap29 and Cap32, and proximal to DXS443. Marker DXS1226 is placed outside the region containing the gene, and is located proximal to DXS274 as confirmed by a crossover for this marker and DXS41 against HYP and its presence on YAC 83B05. Genetic mapping of CEPH pedigrees, and screening of YACs places AFMa152wc5 and AFMa346zcl between DXS1683 and DXS1052. The following gene marker map presents the best order for the HYP region: Xptel-DXS43-DXS999-DXS443-(DXS365/DXS74 75/AFMa176zb1)-(DXS7474/DXS7473)-HYP- DXS1683-(AFMa152wc5/AFMa346zc1)-DXS1052-DXS 274 -(DXS41/DXS1226)-Xcen. The distance between the cluster of distal flanking markers Cap29 (DXS7474), Cap32 (DXS7473), and DXS1683 is approximately 300 kb, as deduced from physical map data from a YAC contig spanning the gene. Thus the gene for HYP is contained within a single YAC (900AO472). Of further interest, is the location of a putative vitamin D response element (VDRE) on this YAC.

Base Sequence↗
PubMed1994

Growth hormone secretion in poorly growing children with renal hypophosphataemic rickets.

We evaluated growth hormone (GH) secretion and baseline serum free insulin-like growth factor-I (IGF-I) levels in 12 poorly growing patients (5 males and 7 females; age 1.6-12.5 years, median 6.4) with renal hypophosphataemic rickets treated with 1,25-dihydroxy-vitamin D3 plus inorganic oral phosphate salts. Eleven healthy normally growing children (6 males and 5 females; age 3.1-10.8 years, median 6.6) were studied as control group. All patients had a normal GH response (GH peak > or = 10 micrograms/l) to at least one provocative pharmacological stimulus (levodopa or insulin tolerance test), as well as all the controls. Mean growth hormone concentrations (MGHC), mean pulse amplitude, number of GH peaks above 5 micrograms/l, and IGF-I values overlapped between patients and controls, even though four patients had MGHC below the lower limit of MGHC of controls. In these patients, however, height-SDS, serum calcium, phosphate, alkaline phosphatase, intact parathyroid hormone, 1,25-dihydroxyvitamin D concentrations and maximum tubular phosphate reabsorption/glomerular filtration rate ratio did not differ in respect to the patients who showed MGHC in the range of controls (n = 6). MGHC IGF-I and biochemical parameters of phospho-calcium metabolism did not differ when the patients were subdivided in two groups on the basis of the median (-2.4) of height-SDS. No relationship was found between MGHC or IGF-I and height-SDS or growth velocity-SDS. Height-SDS and years of treatment or age at which therapy was started were not related.(ABSTRACT TRUNCATED AT 250 WORDS)

Child↗
PubMed1993

Skeletal manifestations of moderate phosphate diabetes.

Six patients, with vertebral osteoporosis and reflex sympathetic algodystrophy syndrome of the lower limbs, due to moderate diabetes, are presented. Osteoporosis was documented by low CT scan bone density and moderate decrease of bone trabecular volume. Histomorphometric studies found a mild increase of resorption areas. All patients had unremarkable serum phosphorus level (mean: 0.91 +/- 0.13) but increase of urinary phosphorus excretion was documented by phosphate clearance higher than 20ml/mm, phosphate tubular reabsorption lower than 80% and TmPo4/GFR lower than 0.8mmol/l. Phosphate clearance and phosphate tubular reabsorption are studied in two control groups. Mild phosphate diabetes, of unknown incidence and prevalence (need for prospective studies) may be the vector of osteoporosis, vertebral and peripheral. The diagnosis of PD requires determination of phosphate clearance, phosphate tubular reabsorption, TmPo4/GFR and these tests may be useful in the diagnostic work up of bone demineralization disorders. We thought that osteoporosis could be the result of progressive dissolution of bone apatite crystals necessary to maintain normal or sub-normal blood phosphate level in spite of the phosphate diabetes.

Adult↗