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Biomedical subjects

M P Whyte

Publications and source records attributed to M P Whyte.

At least 109 records · Page 6Linked to original sources
PubMed1989

X-linked hypophosphatemia in adults: prevalence of skeletal radiographic and scintigraphic features.

The radiologic studies of 38 essentially untreated adults with X-linked hypophosphatemia (XLH) were reviewed to determine the prevalence of radiologic features, to compare the findings in men and in women, and to elucidate the natural history of the disease by comparing the findings in young, intermediate-age, and older patients. Bone-reinforcement lines were common, but no characteristic mineral mass alteration was established. Looser zones were more prevalent in older subjects. Osteoarthritis was common, occurring in the ankles, knees, feet, sacroiliac joints, and wrists. Enthesopathy was infrequent in the younger group but was present in every member of the intermediate and older groups and was often accompanied by extra ossicles. Curvatures of the lower-extremity long bones were common in all age groups. Three new skeletal alterations in XLH were found to be common: flaring of the iliac wings, trapezoidal distal femoral condyles, and alterations in talar morphology, including shortening of the talar neck and flattening of the talar dome. Technetium-99m methylene diphosphonate scintigrams of 17 subjects were often abnormal, depicting bowing deformity and focal tracer accumulation in diaphyseal cortices and in periarticular and extraarticular regions. The mean metabolic index was moderately elevated (4.0). Both radiographic and scintigraphic findings were more severe in men, consistent with hemizygosity. The natural history of untreated XLH in both sexes is characterized by the development of a variety of age-related skeletal abnormalities during adulthood.

Adult↗
PubMed1989

First identification of a gene defect for hypophosphatasia: evidence that alkaline phosphatase acts in skeletal mineralization.

Hypophosphatasia is a heritable disorder characterized by defective osteogenesis and deficient liver/bone/kidney alkaline phosphatase (L/B/K ALP) activity. Severe forms of the disease are inherited in an autosomal recessive fashion. We examined cultured skin fibroblasts from twelve patients with severe hypophosphatasia. All were deficient in L/B/K ALP activity, yet produced normal levels of the corresponding mRNA. Sequence analysis of L/B/K ALP cDNA isolated from one of the patient-derived fibroblast lines revealed a point mutation that converted amino acid 162 of mature L/B/K ALP from alanine to threonine. The patient was homozygous and the parents, who are second cousins, heterozygous for this mutation. Introduction of the mutation into an otherwise normal cDNA disrupted the expression of active enzyme, demonstrating that a defect in the L/B/K ALP gene resulted in hypophosphatasia and that the enzyme is, therefore, essential for normal skeletal mineralization.

Alkaline Phosphatase↗
PubMed1989

Analysis of liver/bone/kidney alkaline phosphatase mRNA, DNA, and enzymatic activity in cultured skin fibroblasts from 14 unrelated patients with severe hypophosphatasia.

Hypophosphatasia is a heritable disorder characterized by defective bone mineralization and a deficiency of liver/bone/kidney alkaline phosphatase (L/B/K ALP) activity in serum and tissues. Severe forms of the disease, which are generally lethal in infancy, are inherited in an autosomal recessive fashion. The gene defects that produce hypophosphatasia are poorly understood, but many are likely to occur at the L/B/K ALP locus. To investigate these gene defects, we analyzed L/B/K ALP DNA, RNA, and enzyme activity in cultured dermal fibroblasts from 14 patients with perinatal or infantile hypophosphatasia and from 12 normal individuals. Southern blot analyses of the L/B/K ALP genes from patients and controls revealed identical restriction patterns. Control fibroblast ALP activity correlated with the corresponding L/B/K ALP mRNA levels estimated by blot hybridization analysis and densitometry (r = .94, P less than .0001). In contrast, fibroblasts from the hypophosphatasia patients were deficient in ALP enzyme activity but expressed apparently full-sized L/B/K ALP mRNA at normal levels. Bone specimens from one of the patients were examined and found to be deficient in histochemical ALP but contained immunologic cross-reactive material detected by anti-human liver ALP antiserum. Our results demonstrate that the deficiency of ALP activity in fibroblasts from 14 patients with severe hypophosphatasia is not due to decreased steady-state levels of the corresponding mRNA. The presence of enzymatically inactive L/B/K ALP protein in one of these patients is consistent with a point mutation or small in-frame deletion in the coding region of L/B/K ALP gene.

Alkaline Phosphatase↗
PubMed1989

X-linked hypophosphatemia: a clinical, biochemical, and histopathologic assessment of morbidity in adults.

Research and management of XLH have concentrated on the disease in childhood, and the natural history and morbidity of XLH in adult life are thus poorly understood. We have studied 22 adults (6 men) with XLH to clarify these aspects of this most common inherited form of rickets and osteomalacia. Most study participants had presented with rickets in early childhood and had undergone tibial osteotomies on at least 1 occasion. Seventeen individuals had genu varum, 1 had genu valgum, and 4 had straight legs, attributable to successful osteotomies in 2. Five subjects reported increasing lower limb deformity in the late teens or subsequently. Eight subjects complained of bone pain, 6 of whom had radiologic evidence of pseudofractures; pseudofractures were found in 4 additional asymptomatic individuals. None of 16 subjects who underwent transiliac bone biopsy had normal double tetracycline labeling; accordingly, all were considered to have osteomalacia. Bone pain was associated with a relative osteoid volume in excess of 25%. Relative osteoid volume was inversely related to serum 1,25(OH)2D concentration (r = -0.74, p less than 0.02), but unrelated to serum concentrations of calcium and phosphate or their product. Eighteen participants complained of joint pain, predominantly in the knees and ankles. The severity of joint pain correlated with the degree of lower limb deformity (p = 0.011) which, in turn, was related to fasting serum phosphate concentration (r = -0.56, p less than 0.025) and TmP/GFR (r = -0.70, p less than 0.005). Enthesopathy affected 33% of those younger than 30 years, and all those above this age. Nineteen individuals had experienced significant dental problems, most commonly abscess formation. Eight had required complete dental clearance. Twelve women from the group had a total of 22 live births. Fifteen of these were by cesarean section, although radiologic evidence of pelvic narrowing was not found in any subject. Serum ALP was elevated in all but 3 of the 18 untreated subjects. Levels correlated with those of other indices of bone turnover (BGP r = 0.82, p less than 0.005; urine total HP r = 0.60, p less than 0.025; urine free HPr = 0.78, p less than 0.005), but were not related to the degree of osteomalacia found on bone biopsy. Serum levels of iPTH, 25(OH)D, 1,25(OH)2D, and thyroid hormones were generally normal in the untreated patients. We conclude that adults with untreated XLH have osteomalacia that is frequently symptomatic. Even greater morbidity is caused by degenerative joint disease arising from lower limb deformities.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1988

Alkaline phosphatase is an ectoenzyme that acts on micromolar concentrations of natural substrates at physiologic pH in human osteosarcoma (SAOS-2) cells.

Alkaline phosphatase (ALP) was examined in cultured human osteosarcoma cells (SAOS-2) with respect to isoenzyme form, kinetic properties toward two natural substrates, and topography and nature of attachment to the plasma membrane. ALP in SAOS-2 homogenates is the tissue-nonspecific (TNS) isoenzyme and a phosphoethanolamine (PEA) and pyridoxal 5'-phosphate (PLP) phosphatase, as demonstrated by heat and inhibition profiles and electrophoretic mobility. Kinetic studies indicate that TNSALP in SAOS-2 cells has both a low- and a high-affinity activity. The high-affinity activity (showing the greater catalytic efficiency) is active at physiologic pH toward physiologic concentrations (microM) of PEA and PLP. TNSALP was shown to be an ectoenzyme in SAOS-2 cells by our findings in intact cell suspensions, where (i) PEA and PLP degradation in the medium nearly equaled that of whole cell homogenates, (ii) greater than 85% of ALP activity was inactivated by acid treatment, and (iii) ALP activity was quantitatively released by phosphatidylinositol-specific phospholipase C. Our findings indicate that, in SAOS-2 cells, TNS (bone) ALP functions as an ectoenzyme to degrade physiologic concentrations of extracellular natural substrates at physiologic pH.

Alkaline Phosphatase↗
PubMed1988

Transfusion of carbonic anhydrase-replete erythrocytes fails to correct the acidification defect in the syndrome of osteopetrosis, renal tubular acidosis, and cerebral calcification (carbonic anhydrase-II deficiency).

We explored the effects of transfusion of carbonic anhydrase II (CA-II)-replete erythrocytes on systemic pH, serum electrolytes, and urinary acidification of a patient with CA-II deficiency. Pretransfusion studies documented hyperchloremic acidosis, increased urinary pH with decreased titratable acidity, and profound CA-II deficiency in erythrocytes. During transfusion, CA-II in circulating erythrocytes increased to above the half-normal levels seen in asymptomatic heterozygote carriers of CA-II deficiency. However, no significant change occurred in venous, arterial or urinary pH, serum electrolytes, and urinary acid excretion during the transfusion or during the subsequent 60 hr of observation. These studies argue that the renal acidification defect in CA-II deficiency results from deficiency of CA-II in the renal parenchyma, and is not secondary to deficiency of CA-II in erythrocytes. Bone marrow transplantation is not a promising approach to correct the renal manifestations of CA-II deficiency.

Acidosis, Renal Tubular↗
PubMed1988

Assessment of calcitriol and inorganic phosphate therapy before cure of oncogenous osteomalacia by resection of a mixed mesenchymal tumor.

A 57 year old white male with oncogenous osteomalacia due to a mixed mesenchymal tumor was evaluated by sequential histologic and metabolic studies over a period of 33 mos prior to identifying the location of the tumor. On the basis of these studies we conclude: (i) disorders of the enterohepatic circulation and/or acceleration of metabolism of calcitriol are not responsible for its diminished level in oncogenous osteomalacia, (ii) the Von Kossa stain is preferred to the modified Masson in evaluating osteomalacia, (iii) avascular necrosis of the femoral head may be part of the syndrome, (iv) heterogeneity may be the hallmark of the responsible mesenchymal tumor and account for the different histological interpretations in the literature, (v) in compliant patients with oncogenous osteomalacia, calcitriol and Pi therapy may be effective.

Bone Neoplasms↗
PubMed1988

A missense mutation in the human liver/bone/kidney alkaline phosphatase gene causing a lethal form of hypophosphatasia.

Hypophosphatasia is an inherited disorder characterized by defective bone mineralization and a deficiency of serum and tissue liver/bone/kidney alkaline phosphatase (L/B/K ALP) activity. Clinical severity is variable, ranging from death in utero (due to severe rickets) to pathologic fractures first presenting in adult life. Affected siblings, however, are phenotypically similar. Severe forms of the disease are inherited in an autosomal recessive fashion; heterozygotes often show reduced serum ALP activity. The specific gene defects in hypophosphatasia are unknown but are thought to occur either at the L/B/K ALP locus or within another gene that regulates L/B/K ALP expression. We used the polymerase chain reaction to examine L/B/K ALP cDNA from a patient with a perinatal (lethal) form of the disease. We observed a guanine-to-adenine transition in nucleotide 711 of the cDNA that converts alanine-162 of the mature enzyme to threonine. The affected individual, whose parents are second cousins, is homozygous for the mutant allele. Introduction of this mutation into an otherwise normal cDNA by site-directed mutagenesis abolishes the expression of active enzyme, demonstrating that a defect in the L/B/K ALP gene results in hypophosphatasia and that the enzyme is, therefore, essential for normal skeletal mineralization.

Alkaline Phosphatase↗
PubMed1988

Perinatal hypophosphatasia: tissue levels of vitamin B6 are unremarkable despite markedly increased circulating concentrations of pyridoxal-5'-phosphate. Evidence for an ectoenzyme role for tissue-nonspecific alkaline phosphatase.

"Perinatal" hypophosphatasia is the most severe form of this inborn error of metabolism, which is characterized by deficient activity of the tissue-nonspecific (liver/bone/kidney) isoenzyme of alkaline phosphatase (ALP) (TNSALP). We report that autopsy tissue from three affected subjects, which was profoundly low in ALP activity, had essentially unremarkable levels of pyridoxal-5'-phosphate (PLP), pyridoxal, and total vitamin B6 content despite markedly elevated plasma PLP levels (5,800, 14,500, and 98,500 nM; adult norm, 5-109 nM). Our findings help to explain the general absence of symptoms of vitamin B6 excess or deficiency in hypophosphatasia, and provide evidence that TNSALP acts as an ectoenzyme to regulate extracellular rather than intracellular concentrations of PLP (the cofactor form of vitamin B6) and perhaps other phosphate compounds.

Alkaline Phosphatase↗
PubMed1987

Infantile hypophosphatasia: enzymatic defect explored with alkaline phosphatase-deficient skin fibroblasts in culture.

Evidence that infantile hypophosphatasia may result from defective regulation of an intact structural gene for the tissue nonspecific (bone/liver/kidney) isoenzyme of alkaline phosphatase (TNSALP) was explored by studying physicochemical properties of ALP in sonicates of monolayers of cultured dermal fibroblasts from 7 patients (PT) and 5 age- and sex-matched control (CT) subjects. Both groups had low levels of ALP activity when assayed with 4-methylumbelliferyl phosphate substrate. The mean specific activity of ALP in the PT fibroblasts was markedly subnormal (Vmax less than 1% of CT), but apparently not from extracellular loss of enzyme, since defined medium had less ALP activity when conditioned by PT compared to CT cells. Although the mean Km for the sonicate ALP was similar for both groups at pH 10.1, pH optimum, thermal stability and response to several inhibitors appeared to be different. Nevertheless, it seemed that some TNSALP-like enzyme was present in the PT group. Exposure of cells in culture to 5-azacytidine and several putative inducers of ALP failed to increase the enzyme activity in either the PT or CT groups. Had the physicochemical properties of the constitutive (or inducible) ALP been the same in the PT and CT cell groups, the findings would have provided evidence for the generality of our previous observations in one patient which indicated that defective regulation of an intact structural gene for TNSALP could account for hypophosphatasia.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaline Phosphatase↗
PubMed1987

Infantile hypophosphatasia fibroblasts proliferate normally in culture: evidence against a role for alkaline phosphatase (tissue nonspecific isoenzyme) in the regulation of cell growth and differentiation.

To explore the hypothesis that alkaline phosphatase (ALP) functions in the regulation of cell growth and differentiation, we examined in tissue culture several parameters of cell proliferation demonstrated by dermal fibroblasts from patients with infantile hypophosphatasia--a heritable form of rickets/osteomalacia which is characterized biochemically by marked deficiency of activity of the "tissue nonspecific" (bone/liver/kidney) ALP isoenzyme. Methylumbelliferyl phosphate was used as the fluorogenic substrate to assay ALP activity in cell homogenates from patients and age-, sex-, and passage-matched control cells. The nature of the enzymatic defect in the patient fibroblasts involved their failure to increase the specific activity of ALP during growth to confluency. Patient cell monolayers contained, on average, about 2-3% of control ALP activity (several lines consistently demonstrated less than 1%). Nevertheless, patient cells grew normally both in early and late passage, and in either serum-containing or defined medium. Contact inhibition appeared to be intact in the patient fibroblasts, since the protein and DNA content of their culture dishes were similar to controls just as the cells became visually confluent, and when examined 1 week after they reached monolayer. Light and phase-contrast microscopy revealed no abnormalities in the appearance of patient cells during growth or at confluency. The mean volume of proliferating patient cells was also normal. Despite profound deficiency of constitutive ALP activity, dermal fibroblasts from infants with hypophosphatasia exhibit normal growth parameters in cell culture.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaline Phosphatase↗
PubMed1987

Hypercalcemic hyperparathyroidism complicating oncogenic osteomalacia. Effect of successful tumor resection on mineral homeostasis.

Described herein is a case of oncogenic osteomalacia that ran a course of at least 16 years before curative resection of a mixed mesenchymal tumor. Hypercalcemic hyperparathyroidism developed in the patient, and review of the literature indicated that this occurs in about 10 percent of reported cases. Changes in serum parathyroid hormone levels with and without phosphate supplement therapy and before and after tumor resection suggested that both the high intake of phosphate and the effect of the neoplasm on vitamin D bioactivation engendered the parathyroid overactivity. Despite marked hyperparathyroidism, serum 1,25-dihydroxyvitamin D levels were subnormal preoperatively but showed a sevenfold increase within 48 hours of tumor resection. Thereafter, a gradual increase in the maximal tubular reabsorption of phosphate occurred during several months. Biopsy of the iliac crest confirmed that tumor removal was followed by resolution of osteomalacia, but there was no accompanying increase in vertebral mineral density as assessed by quantitative computed tomography or in total-body bone mineral as measured with dual-photon absorptiometry. The findings presented are consistent with secretion by the tumor of a factor with a short half-life that is potent enough to inhibit renal 25-hydroxyvitamin D-1 alpha-hydroxylase despite hyperparathyroidism. The resulting subnormal circulating 1,25-dihydroxyvitamin D levels may have secondarily contributed to decreased renal tubular reabsorption of phosphate.

Chronic Disease↗
PubMed1987

Bridging markers defining the map position of X linked hypophosphataemic rickets.

Hypophosphataemic rickets is commonly an X linked dominant hereditary disorder associated with a renal tubular defect in phosphate transport and bone deformities. The gene causing this disorder has been mapped to Xp22.31----p21.3 by using cloned human X chromosome sequences identifying restriction fragment length polymorphisms (RFLPs) in linkage studies of affected families. The hypophosphataemic rickets gene locus (HPDR) was previously mapped distal to the X linked polymorphic locus DXS41 (99.6) but its position in relation to the distal loci DXS43 (D2) and DXS85 (782) was not established. In order to obtain a precise mapping of the disease locus in relation to these genetic loci, additional affected families informative for these X linked markers have been investigated. The combined results from the two studies have established linkage with the loci DXS41 (99.6) and DXS43 (D2); peak lod score for DXS41 (99.6) = 7.35, theta = 0.09, and peak lod score for DXS43 (D2) = 4.77, theta = 0.16. Multilocus linkage analysis mapped the hypophosphataemic rickets gene distal to the DXS41 (99.6) locus and proximal to the DXS43 (D2) locus, thereby revealing two bridging genetic markers for the disease.

Chromosome Mapping↗
PubMed1987

Tibial bowing exacerbated by partial premature epiphyseal closure in sex-linked hypophosphatemic rickets.

Two girls with sex-linked hypophosphatemic rickets are described in whom premature fusion of the medial proximal tibial epiphyseal plate exacerbated lower-extremity bowing. Early recognition of this complication and appropriate surgical intervention--excision of the bony bridge in the growth plate, or epiphysiodesis of the still open portion of the growth plate--might prevent further shortening or deformity of the affected limb.

Adolescent↗
PubMed1986

Macroepiphyseal dysplasia with symptomatic osteoporosis, wrinkled skin, and aged appearance: a presumed autosomal recessive condition.

We report our detailed investigation of a 7-1/2-year-old girl with short stature, aged appearance, decreased subcutaneous fat and muscle mass, dry coarse hair, foot deformities, macroepiphyses with prominent but lax joints, and osteoporosis with recurrent fractures who is the off-spring of first cousins. This constellation of abnormalities differs from previously reported cases where macroepiphyses were a prominent finding. Our patient appears, therefore, to have a new, autosomal recessively inherited, syndrome.

Aging↗
PubMed1986

Mixed-sclerosing-bone-dystrophy: 42-year follow-up of a case reported as osteopetrosis.

We present a detailed metabolic investigation and 42-year radiological follow-up of a 52-year-old man with mixed-sclerosing-bone-dystrophy, the rare occurrence of two or more distinct patterns of sclerosing-bone-dysplasia (e.g., osteopathia striata, osteopoikilosis, melorheostosis) in a single subject. Review of radiographs from 1942, when he was reported to have osteopetrosis, demonstrated diffuse osteosclerosis, osteopathia striata, osteopoikilosis, and focal cortical hyperostosis. Forty-two years later, there had been significant progression and evolution of his skeletal disease with the appearance of new areas of osteopathia striata and osteopoikilosis and a generalized increase in skeletal mass as assessed radiographically. Presence of subperiosteal bone apposition on biopsy of the iliac crest together with chronic mild hypocalcemia, secondary hyperparathyroidism, and hypophosphatemia suggested that enhanced bone formation, perhaps with defective skeletal resorption, is a fundamental abnormality which accounts for the increased bone mass of this patient.

Diagnostic Errors↗
PubMed1986

Intermittent radiographic changes of rickets without defective trabecular bone mineralization in a case of spondylometaphyseal dysplasia.

Although a variety of metaphyseal and spondylometaphyseal dysplasias have been identified, the natural course of the skeletal defects in these disorders has not been well characterized. We describe an 8-year-old girl with spondylometaphyseal dysplasia, most closely resembling the Kozlowski type, in whom rachitic metaphyseal involvement underwent dramatic radiographic healing when she wore leg braces; discontinuation of the braces was followed by recurrence of the growth plate abnormalities. A generalized disturbance in mineral metabolism or skeletal remodeling to explain these radiographic changes was excluded by extensive biochemical studies and histologic examination of an undecalcified iliac crest specimen. Our observations suggest that the defect in endochondral bone formation in the spondylometaphyseal dysplasias may be responsive to mechanical factors and that interventions that alter stress and strain on the skeleton, such as immobilization or use of orthopedic braces, may considerably modify the radiographic appearance of the growth plate disturbance.

Aging↗