Absence of parathyroid tissue in sex-linked recessive hypoparathyroidism.
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Humans↗
Biomedical subjects
M P Whyte
Publications and source records attributed to M P Whyte.
Infantile hypophosphatasia: normalization of circulating bone alkaline phosphatase activity followed by skeletal remineralization. Evidence for an intact structural gene for tissue nonspecific alkaline phosphatase.
After a 3-month course of weekly intravenous infusions of pooled normal plasma in an attempt at enzyme replacement therapy, we observed gradual and prolonged normalization of circulating alkaline phosphatase (AP) activity in a boy with infantile hypophosphatasia. During this 4-month period, when hypophosphatasemia had been corrected, electrophoretic and heat denaturation studies suggested that the AP in serum was skeletal in origin. Serial radiographic and histologic studies of bone demonstrated skeletal remineralization and the appearance of AP activity in osteoblasts and chondrocytes after the infusions. Considerable clinical improvement coincided with the skeletal remineralization. Our observations indicate that in one patient with infantile hypophosphatasia the structural gene for the tissue-nonspecific (bone/liver/kidney) AP isoenzyme was intact and could be expressed with marked physiologic effect. Infantile hypophosphatasia may result from absence or inactivation of a circulating factor(s) that regulates the expression of the gene for tissue nonspecific AP.
Alkaline Phosphatase↗
Normal activity of nucleoside triphosphate pyrophosphatase in alkaline phosphatase-deficient fibroblasts from patients with infantile hypophosphatasia.
Inorganic pyrophosphate (PPi) influences the formation of bone mineral. In the rare inherited disease hypophosphatasia, abnormal extracellular metabolism of PPi occurs together with defective skeletal mineralization. The primary biochemical defect in this condition is a deficiency of the bone/liver/kidney (tissue nonspecific) isoenzyme of alkaline phosphatase (AP), an enzyme that catalyzes the extracellular breakdown of PPi. Fibroblast lines derived from patients with hypophosphatasia manifest the deficiency of AP activity that occurs in vivo and thus are a suitable model for this condition. Using these cells from patients with the severe (infantile) form of the disease, we examined aspects of PPi metabolism in hypophosphatasia, in particular the formation of PPi from ATP by ecto-nucleoside triphosphate (NTP) pyrophosphatase. This enzyme is believed to catalyze the extracellular generation of PPi in vivo. We found that normal fibroblasts possess ecto-NTP pyrophosphatase and that infantile hypophosphatasia cell lines have normal activity and cellular distribution of this enzyme compared with cell lines derived from age-matched normal subjects. This suggests that extracellular generation of PPi is normal in hypophosphatasia. The results also provide further evidence that ecto-NTP pyrophosphatase and AP are distinct entities and that hypophosphatasia does not involve a general loss of enzyme activities from cell surfaces.
Alkaline Phosphatase↗
Management of femoral fractures and pseudofractures in adult hypophosphatasia.
Ten pseudofractures and six complete fractures occurred in five patients with adult hypophosphatasia. The four pseudofractures that were treated non-operatively progressed to complete fracture. The six pseudofractures and six complete fractures that were treated by internal fixation united. New fractures occurred in four patients after the removal of the internal fixation. We recommend that complete fractures, symptomatic pseudofractures, and progressive asymptomatic pseudofractures in patients with adult hypophosphatasia be treated with load-sharing internal-fixation devices, such as rigid intramedullary nails. These should not be removed unless it is absolutely essential. If removal is necessary, however, they should be replaced, preferably during the same anesthetic session. In our opinion, the guidelines developed from this study may be applied reasonably to patients with osteomalacia from causes other than hypophosphatasia, especially if medical therapy has been unsuccessful.
Adult↗
Carbonic anhydrase II deficiency in 12 families with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification.
Osteopetrosis with renal tubular acidosis and cerebral calcification was identified as a recessively inherited syndrome in 1972. In 1983, we reported a deficiency of carbonic anhydrase II, one of the isozymes of carbonic anhydrase, in three sisters with this disorder. We now describe our study of 18 similarly affected patients with this syndrome in 11 unrelated families of different geographic and ethnic origins. Virtual absence of the carbonic anhydrase II peak on high-performance liquid chromatography, of the esterase and carbon dioxide hydratase activities of carbonic anhydrase II, and of immunoprecipitable isozyme II was demonstrated on extracts of erythrocyte hemolysates from all patients studied. Reduced levels of isozyme II were found in obligate heterozygotes. These observations demonstrate the generality of the findings that we reported earlier in one family and provide further evidence that a deficiency of carbonic anhydrase II is the enzymatic basis for the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. We also summarize the clinical findings in these families, propose mechanisms by which a deficiency of carbonic anhydrase II could produce this metabolic disorder of bone, kidney, and brain, and discuss the clinical evidence for genetic heterogeneity in patients from different kindreds with this inborn error of metabolism.
Acidosis, Renal Tubular↗
Failure of acetazolamide to decrease intraocular pressure in patients with carbonic anhydrase II deficiency.
The effect of the carbonic anhydrase inhibitor acetazolamide on intraocular pressure was studied in two patients with carbonic anhydrase II deficiency and in six control subjects. The deficient patients had the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. A dose of 125 mg of intravenous acetazolamide caused a significant (P less than .01) decrease in intraocular pressure from baseline (15.0 +/- 1.5 mm Hg) in the control subjects one hour (11.3 +/- 1.5 mm Hg) and four hours (13.8 +/- 1.2 mm Hg) after drug administration. In contrast, the patients with carbonic anhydrase deficiency showed no such decrease in intraocular pressure; baseline intraocular pressure (19.2 +/- 0.2 mm Hg) was significantly unchanged (P greater than .5) at one hour (20.0 +/- 0.1 mm Hg) and four hours (19.2 +/- 0.2 mm Hg).
Acetazolamide↗
Normal circulating acid phosphatase activity in hypophosphatasia.
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Acid Phosphatase↗
Osteolytic Paget's bone disease in a young man. Rapid healing with human calcitonin therapy.
Paget's bone disease is rare in young adults. Severe osteolytic Paget's bone disease in a 28-year-old man was found to respond, clinically, biochemically, and radiographically, within one month to daily subcutaneous injections of 0.5 mg of synthetic human calcitonin. After two years of therapy, he remains asymptomatic and has no biochemical evidence of Paget's bone disease while receiving injections three times a week. Despite aggressive disease, young patients may rapidly demonstrate the same beneficial response to synthetic human calcitonin therapy as has been observed in middle-aged or elderly patients with Paget's bone disease.
Adult↗
Markedly increased circulating pyridoxal-5'-phosphate levels in hypophosphatasia. Alkaline phosphatase acts in vitamin B6 metabolism.
Markedly increased circulating concentrations of pyridoxal-5'-phosphate (PLP) were found in each of 14 patients representing all clinical forms of hypophosphatasia, an inborn error characterized by deficient activity of the tissue nonspecific (bone/liver/kidney) isoenzyme of alkaline phosphatase (AP). The mean PLP concentration in plasma was 1174 nM (range, 214-3839 nM) in the patients and 57 +/- 26 nM (mean +/- SD) in 38 control subjects. In four affected children, urinary excretion of the PLP degradation product, 4-pyridoxic acid, was unremarkable during consumption of normal quantities of dietary vitamin B6. Our findings identify increased circulating PLP concentration as a marker for hypophosphatasia and provide further evidence that tissue nonspecific AP acts in vitamin B6 metabolism. Tissue nonspecific AP appears to function as an ectoenzyme to regulate extracellular but not intracellular levels of PLP substrate. Performing assays of circulating PLP concentration alone to assess vitamin B6 nutrition may be misleading in disorders associated with altered AP activity.
Adult↗
Cystinosis presenting with features suggesting Bartter syndrome. Case report and literature review.
Features suggestive of Bartter syndrome (hypokalemia, hypochloremic metabolic alkalosis, and normal blood pressure despite hyperreninemia and hyperaldosteronism) were found in a 5-year-old black child with cystinosis and Fanconi syndrome. Review of his medical records revealed that these abnormalities had probably been present when he first became clinically ill at 2 years of age. Sodium and potassium chloride supplementation lead to improved growth and strength, partial correction of his electrolyte abnormalities, and a decrease in markedly elevated plasma renin activity. Literature review disclosed a similar presentation in four Caucasian children with cystinosis. Biochemical findings compatible with Bartter syndrome can occur together with evidence of generalized proximal renal tubular dysfunction (Fanconi syndrome) in nephropathic cystinosis.
Anemia, Aplastic↗
Positive renal response to intravenous acetazolamide in patients with carbonic anhydrase II deficiency.
Carbonic anhydrase II (CA II) is the only soluble isozyme of CA which is known to be expressed in kidney. We recently identified a deficiency of this enzyme as the basis for the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. In order to explore the physiological importance of CA II in the kidney, we studied the renal response to intravenously infused acetazolamide in two CA II-deficient patients and two control subjects. Following acetazolamide infusion, the CA II-deficient patients exhibited a prompt rise in urinary pH and HCO3- excretion similar to the response seen in control subjects. These findings indicate that CA II-deficient patients, who lack detectable CA II in their erythrocytes, still expressed an acetazolamide-inhibitable CA activity in their kidneys. These results can be explained in three ways: 1) the CA II deficiency which is profound in the erythrocytes of these patients may not be expressed in their kidney. 2) An acetazolamide-sensitive CA other than CA II, such as CA I and CA III, which is not normally expressed in kidney, is expressed in kidneys of CA II-deficient patients. 3) The CA II deficiency is expressed in kidney in these patients but the acetazolamide response is due to inhibition of the luminal, membrane-bound CA which is the product of a different gene and unaffected by the CA II deficiency mutation. We favor the third possibility.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetazolamide↗
Enzyme replacement therapy for infantile hypophosphatasia attempted by intravenous infusions of alkaline phosphatase-rich Paget plasma: results in three additional patients.
After biochemical and radiographic studies, enzyme replacement therapy in three patients with the infantile form of hypophosphatasia was attempted by weekly intravenous infusions of bone alkaline phosphatase-rich (BAP) plasma from patients with Paget bone disease. Subsequently, circulating BAP activity was substantially increased in each patient, and in one was maintained in the normal range for nearly 2 months. Despite partial or complete correction of the deficiency of circulating BAP activity, we observed no radiographic evidence for arrest of progressive osteopenia or improvement in rachitic defects in any of the patients. Failure of infants with hypophosphatasia to show significant healing of rickets on correction of circulating BAP activity supports the hypothesis that this isoenzyme functions in situ during normal skeletal mineralization.
Alkaline Phosphatase↗
Hypophosphatasia: clinicopathologic comparison of the infantile, childhood, and adult forms.
Histochemical and direct enzyme analysis of osseous tissue from 23 patients with hypophosphatasia revealed that all clinical forms of this inherited metabolic bone disease are characterized by deficiency of alkaline phosphatase (ALP) activity in bone. The severe infantile form has the most profound deficiency, infantile form has the most profound deficiency, yet the cellular source of this enzyme--osteoblasts and their matrix vesicles--are normal by routine light and electron microscopy. Despite radiographic changes in bone metaphyses consistent with rickets, iliac crest biopsy of one affected child revealed no abnormalities; the other had evidence of a mineralization defect, but not as severe as that in affected infants. In this child and several affected adults with osteomalacia, osteoblasts appeared flat and metabolically inactive. Although these histological changes suggested a different pathogenetic mechanism for adult and childhood hypophosphatasia, these changes are most likely secondary to the underlying osteomalacia. Our findings are most consistent with evidence that childhood and adult hypophosphatasia often represent clinical expression of the heterozygous state for ALP deficiency which, when homozygous, results in the clinically severe, recessive, infantile form. Histochemical and direct analysis of bone tissue from controls and patients with hypophosphatasia demonstrated that the severe infantile form is associated with the most severe ALP deficiency. In the milder clinical forms, ALP deficiency in bone is not as profound. In general, the severity of the clinical expression of hypophosphatasia reflects the magnitude of the deficiency of ALP in bone. This is the expected finding for this inborn error of metabolism, which illustrates the major role bone ALP activity has in the process of normal skeletal mineralization.
Adolescent↗
Mast-cell proliferation in postmenopausal osteoporosis.
Because mast cell proliferation has been reported in disorders of abnormal bone remodeling, we quantitated the number of mast cells in undecalcified section of iliac crest bone from 16 untreated women with postmenopausal osteoporosis and contrasted the findings to values from 10 normal women and 12 normal men. The mean number of marrow mast cells was greater in normal women than men (1.17 vs 0.40 cells per mm2, P less than 0.05). Compared to the normal women, osteoporotic women had a greater number of mast cells in the marrow (3.38 vs 1.17 cells per mm2, P less than 0.01). However, there was no statistically significant correlation between the number of marrow mast cells and either the patient's age or the severity of the bone lesions, as assessed by histomorphometry. Our findings confirm the association between increased numbers of mast cells and postmenopausal osteoporosis.
Aged↗
Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification.
The clinical, radiological, and pathological findings in three siblings affected with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification have been reported. In an effort to explain the pleiotropic effects of the mutation producing this disorder, we postulated a defect in carbonic anhydrase II (CA II), the only one of the three soluble isozymes of carbonic anhydrase that is known to be synthesized in kidney and brain. We report here biochemical and immunological evidence for the virtual absence of CA II in erythrocytes of patients affected with this condition, whereas CA I level is not reduced. Levels of CA II in erythrocyte hemolysates from asymptomatic obligate heterozygotes are about half of normal. These findings: (i) elucidate the basic defect in one form of inherited osteopetrosis; (ii) provide genetic evidence implicating CA II in osteoclast function and bone resorption; (iii) explain previous observations that carbonic anhydrase inhibitors block the normal parathyroid hormone-induced release of calcium from bone; (iv) clarify the role of renal CA II in urinary acidification and bicarbonate reabsorption; and (v) suggest a method to identify heterozygous carriers for the gene for this recessively inherited syndrome.
Acidosis, Renal Tubular↗
Alkaline phosphatase deficiency in cultured skin fibroblasts from patients with hypophosphatasia: comparison of the infantile, childhood, and adult forms.
Alkaline phosphatase (AP) activity was assayed by a sensitive fluorometric method, using 4-methylumbelliferyl phosphate as substrate, in homogenates of confluent skin fibroblasts from 17 patients with the infantile, childhood, or adult form of hypophosphatasia and compared to the AP activity in 22 sex- and age-matched control cell lines. Statistically significant deficiency of AP activity was found in all 3 types of hypophosphatasia (8.2%, 30.2% and 18.5% of control values, respectively); however, there was considerable variation of enzyme activity, especially in the control groups, and some overlap between patient and control values occurred for the childhood and adult age groups. These fibroblast studies suggest that all clinical forms of hypophosphatasia are characterized by deficient activity of the bone/liver/kidney AP isoenzyme. The clinical severity of the infantile form is reflected by a profound lack of AP activity in cultured skin fibroblasts. Further study will be necessary to determine the mechanism(s) of the deficiency in AP activity in each form of hypophosphatasia. Nevertheless, we suggest that AP-deficient infantile hypophosphatasia skin fibroblasts in culture might constitute a good tool by which to explore the unknown physiological role of AP.
Adolescent↗
Serum total hydroxyproline assay: effects of age, sex and Paget's bone disease.
An assay was developed for total hydroxyproline (protein, peptide and free) in 12 h fasted human serum. Values obtained from 80 adults judged normal by laboratory and physical examinations showed age and sex effects; values increased with age and were higher for men. Assay of serum samples from 22 patients with Paget's bone disease revealed values significantly above normal taking age and sex into consideration (p = 0.001). Serum alkaline phosphatase and serum hydroxyproline values for these patients were correlated (r = 0.91). Serum total hydroxyproline may be a useful assay for evaluating metabolic bone diseases but age and sex must be taken into consideration in the interpretation.
Aged↗