David E C Cole

Publications (81)378.65 Total impact

• Article: Common variants of the vitamin D binding protein gene and adverse health outcomes.

  Suneil Malik, Lei Fu, David James Juras, Mohamed Karmali, Betty Y L Wong, Agnes Gozdzik, David E C Cole
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  ABSTRACT: Abstract The vitamin D binding protein (DBP) is the major plasma carrier for vitamin D and its metabolites, but it is also an actin scavenger, and is the precursor to the immunomodulatory protein, Gc-MAF. Two missense variants of the DBP gene - rs7041 encoding Asp432Glu and rs4588 encoding Thr436Lys - change the amino acid sequence and alter the protein function. They are common enough to generate population-wide constitutive differences in vitamin D status, based on assay of the serum metabolite, 25-hydroxyvitamin D (25OHD). Whether these variants also influence the role of vitamin D in an immunologic milieu is not known. However, the issue is relevant, given the immunomodulatory effects of DBP and the role of protracted innate immune-related inflammation in response to tissue injury or repeated infection. Indeed, DBP and vitamin D may jointly or independently contribute to a variety of adverse health outcomes unrelated to classical notions of their function in bone and mineral metabolism. This review summarizes the reports to date of associations between DBP variants, and various chronic and infectious diseases. The available information leads us to conclude that DBP variants are a significant and common genetic factor in some common disorders, and therefore, are worthy of closer attention. In view of the heightened interest in vitamin D as a public health target, well-designed studies that look simultaneously at vitamin D and its carrier in relation to genotypes and adverse health outcome should be encouraged.
  Critical Reviews in Clinical Laboratory Sciences 02/2013; · 5.25 Impact Factor
• Article: Genetic defects associated with familial and sporadic hyperparathyroidism.

  Geoffrey N Hendy, David E C Cole
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  ABSTRACT: Primary hyperparathyroidism (PHPT) occurs sporadically, but occasionally it may be a feature of a familial condition, such as multiple endocrine neoplasia type 1 (MEN1), MEN2A, or the HPT-jaw tumor syndrome (HPT-JT), and familial hypocalciuric hypercalcemia/neonatal severe hyperparathyroidism (FHH/NSHPT). PHPT may also occur as familial isolated hyperparathyroidism (FIHP), and has been observed as a consequence of mutations in the CDKN1B gene (MEN4). Tumorigenesis in these conditions may be the result of protooncogene activation (e.g. RET in MEN2) or two-hit losses of a tumor suppressor (e.g. MEN1, HPT-JT). In patients with MEN1, HPT-JT or FHH/NSHPT, the hyperparathyroidism manifests at a younger age and affects both sexes equally. In MEN1, mutations of the MEN1 gene also cause enteropancreatic and anterior pituitary tumors. In MEN2, activating mutations in the RET protooncogene also cause medullary thyroid carcinoma and pheochromocytoma. In HPT-JT, mutations of CDC73/HRPT2 are associated with parathyroid carcinoma, but tumors of the kidneys and uterus are additional features. In some FIHP families, a CASR mutation may be identified. In parathyroid carcinoma, even if sporadic, molecular diagnostics for CDC73/HRPT2 should be considered, as it should be for younger patients. Further exploration of these hereditary syndromes may shed light on the molecular mechanisms giving rise to nonhereditary PHPT.
  Frontiers of hormone research 01/2013; 41:149-65. · 1.71 Impact Factor
• Article: CDC73 mutations and parafibromin immunohistochemistry in parathyroid tumors: clinical correlations in a single-centre patient cohort.

  Vito Guarnieri, Claudia Battista, Lucia Anna Muscarella, Michele Bisceglia, Danilo de Martino, Filomena Baorda, Evaristo Maiello, Leonardo D'Agruma, Iacopo Chiodini, Celeste Clemente, [......], Raffaella Viti, Cristina Eller-Vainicher, Anna Spada, Michela Iacobellis, Nazzarena Malavolta, Massimo Carella, Lucie Canaff, Geoffrey N Hendy, David E C Cole, Alfredo Scillitani
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  ABSTRACT: OBJECTIVE: To determine if molecular and immunohistochemical (IHC) features of the HRPT2/CDC73 gene and its product, parafibromin, predict the natural history of parathyroid malignancy, particularly atypical adenoma, as seen in a single-centre patient cohort. METHODS: Matched tumor and non-tumor tissues were obtained from 46 patients with parathyroid carcinoma (CA) (n = 15), atypical adenoma (AA) (n = 14) and typical adenoma (TA) (n = 17), as defined by standardized histopathological criteria. Exons and exon-intron boundaries of the CDC73 gene were sequenced to identify germline or somatic mutations. IHC staining for parafibromin was performed and scored as positive if nuclear staining was at least partially IHC-positive. RESULTS: Mutations of CDC73 were observed in 9/15 (60 %) CA, 2/14 (14 %) AA, and 1/17 (6 %) TA tumors. A recurrent two basepair mutation in exon 7 -- c.679_680delAG -- accounted for half of all identified mutations. Absence of parafibromin nuclear staining was noted in 8/12 (67 %) CA, 2/13 (15 %) AA, and 3/17 (18 %) TA tumors. Median follow up times were 88 months for CA, 76 months for AA, and 104 months for TA patients. One patient, a member of a previously reported multiplex family with a germline CDC73 mutation was found to have a second adenoma after removal of an atypical adenoma. CONCLUSIONS: Molecular screening and IHC are both useful tools in the differential diagnosis of parathyroid tumors, but both have limited sensitivity and specificity. CDC73 mutations and negative immunostaining were common in atypical adenomas, but no local recurrence was observed in any case with successful surgical removal after follow-up periods of 27 to 210 months.
  Cellular oncology (Dordrecht). 09/2012;
• Source

  Available from: Esteban Parra

  Article: Vitamin D binding protein is a key determinant of 25-hydroxyvitamin D levels in infants and toddlers.

  Thomas O Carpenter, Jane H Zhang, Esteban Parra, Bruce K Ellis, Christine Simpson, William M Lee, Jody Balko, Lei Fu, Betty Y-L Wong, David E C Cole
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  ABSTRACT: Circulating 25-OHD levels vary among human populations. Only limited information regarding determinants of these measures is available in infants and children, particularly in minority groups at greatest risk for vitamin D deficiency. We identified demographic determinants of circulating 25-OHD in a large cohort of minority children, and now extend our studies to examine potential roles of vitamin D binding protein (DBP) as a determinant of 25-OHD levels. Serum DBP level and common single nucleotide polymorphisms (SNPs) at positions 432 and 436 in the GC gene, encoding DBP, were examined. We confirmed self-reported ancestry using ancestry informative markers (AIMs), and included quantitative AIMs scores in the analysis. The multivariate model incorporated previously identified demographic and nutritional determinants of 25-OHD in this cohort, as well as GC SNPs and circulating DBP. Genetic variants in GC differed by self-reported ancestry. The 1f allele (D432/T436) was enriched in African Americans, occurring in 71%. Homozygosity for the 1f allele (DDTT) occurred in 53% of African Americans but only 6% of Caucasians and 13% of Hispanics. Circulating DBP was significantly correlated with 25-OHD. GC SNPs were associated with both circulating DBP and 25-OHD. It appears that progressive substitution of lysine for threonine at the 436 position results in lower circulating 25-OHD. Multivariate analysis revealed that genetic variance in GC significantly contributes to circulating DBP as well as 25-OHD. Moreover, the effect of GC SNPs on 25-OHD are evident after adjusting for their effects on circulating DBP. Thus in young children genetic variance of the common GC T436K SNP affects circulating levels of the DBP protein, which in turn affects circulating 25-OHD. However, GC genotype also affects circulating 25-OHD independently of its effect on circulating DBP. These findings provide data which may be important in the interpretation of vitamin D status in children of varying ancestral backgrounds. © 2012 American Society for Bone and Mineral Research.
  Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 08/2012; · 6.04 Impact Factor
• Article: Can bone markers guide more effective treatment of bone metastases from breast cancer?

  Mark Clemons, David E.C. Cole, Mary C. Gainford
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  ABSTRACT: Bone metastases are a common problem for breast cancer patients, causing significant disease-related morbidity and mortality. Bisphosphonates and other cancer therapies can assist in managing these patients. However, assessing treatment efficacy in bone metastases is hampered by the inability to accurately measure disease response within a clinically desirable time frame. Bone-specific biochemical markers, notably type I collagen telopeptide cross-link by-products such as N-telopeptide (NTx) and C-telopeptide (CTx), have been shown to be effective tools for assessing the severity and extent of bone metastases, and the response to bisphosphonates. Elevated NTx levels correlate with adverse clinical outcomes. Normalization of NTx and CTx excretion rates are associated with relief of symptoms and a reduced incidence of skeletal-related events (SRE). This review discusses the expanding role of these bone markers in guiding treatment of bone metastases from breast cancer.
  Breast Cancer Research and Treatment 04/2012; 97(1):81-90. · 4.43 Impact Factor
• Article: Evaluation of the warfarin-resistance polymorphism, VKORC1 Asp36Tyr, and its effect on dosage algorithms in a genetically heterogeneous anticoagulant clinic.

  Andrew Y Shuen, Betty Y L Wong, Lei Fu, Rita Selby, David E C Cole
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  ABSTRACT: To assess allele frequency and potential predictive value of recurrent polymorphisms affecting warfarin metabolism in an unselected patient cohort attending an anticoagulant clinic (n=186). Genotyping of ten SNPs in five candidate genes (VKORC1, CYP2C9, CALU, EPHX and GGCX) was carried out by ABI PRISM SNaPshot multiplex method. We confirm the association between high-frequency SNPs, VKORC1 c.-1639G>A and CYP2C9 *2/*3 and warfarin sensitivity, and contribute additional evidence that the VKORC1 p.Asp36Tyr variant is recurrent and independently associated with warfarin resistance in our population. Other SNPs made little contribution. Warfarin sensitivity was predicted by known VKORC1 and CYP2C9 SNPs. However, resistance associated with p.Asp36Tyr in VKORC1 would not be predicted by the usual markers. Despite its relatively low frequency (3/186 or 1.6%) clinical considerations may warrant its inclusion in pharmacogenetic screening for initial warfarin dosing in clinic populations with a heterogeneous population base.
  Clinical biochemistry 01/2012; 45(6):397-401. · 2.02 Impact Factor
• Article: Genetic defect in CYP24A1, the vitamin D 24-hydroxylase gene, in a patient with severe infantile hypercalcemia.

  Andrew Dauber, Thutrang T Nguyen, Etienne Sochett, David E C Cole, Ronald Horst, Steven A Abrams, Thomas O Carpenter, Joel N Hirschhorn
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  ABSTRACT: Idiopathic infantile hypercalcemia (IIH) is a disorder the genetic etiology and physiological basis of which are not well understood. The objective of the study was to describe the underlying physiology and genetic cause of hypercalcemia in an infant with severe IIH and to extend these genetic findings into an additional cohort of children with IIH. This was an inpatient study of a single patient with consanguineous parents at an academic medical center with follow-up in a specialty clinic cohort. The patient population was one patient with severe IIH for gene discovery and physiological testing and 27 patients with idiopathic infantile hypercalcemia in the replication cohort. Interventions included a calcium isotopic absorption study as well as homozygosity mapping and whole-exome sequencing in a single patient followed up by gene sequencing in replication cohort. Fractional absorption of calcium and genetic variants causing hypercalcemia were measured. Intestinal calcium absorption was extremely elevated (∼90%). A rare homozygous deletion in the CYP24A1 gene was found, leading to the loss of a single highly conserved amino acid. In vivo functional studies confirmed decreased 24-hydroxylase activity because the subject had undetectable levels of 24,25-dihydroxyvitamin D. No coding variants in CYP24A1 were found in the 27 additional patients with IIH. Our study confirms that CYP24A1 plays a causal role in some but not all cases of IIH via markedly increased intestinal absorption of calcium, suggesting that genetic diagnosis could be helpful in a subset of IIH patients. This case demonstrates the power of an unbiased, genome-wide approach accompanied by informative physiological studies to provide new insights into human biology.
  The Journal of clinical endocrinology and metabolism 11/2011; 97(2):E268-74. · 6.50 Impact Factor
• Article: A rare S33C mutation of CTNNB1 encoding β-catenin in a parathyroid adenoma found in an Italian primary hyperparathyroid cohort.

  Vito Guarnieri, Filomena Baorda, Claudia Battista, Michele Bisceglia, Teresa Balsamo, Elisa Gruppioni, Michelangelo Fiorentino, Lucia A Muscarella, Michelina Coco, Raffaela Barbano, Sabrina Corbetta, Anna Spada, David E C Cole, Lucie Canaff, Geoffrey N Hendy, Massimo Carella, Alfredo Scillitani
  Endocrine 11/2011; 41(1):152-5. · 1.42 Impact Factor
• Source

  Available from: Esteban Parra

  Article: Association of vitamin D binding protein (VDBP) polymorphisms and serum 25(OH)D concentrations in a sample of young Canadian adults of different ancestry.

  Agnes Gozdzik, Justin Zhu, Betty Y-L Wong, Lei Fu, David E C Cole, Esteban J Parra
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  ABSTRACT: Variants of the vitamin D binding protein (VDBP) gene appear to be associated with levels of the main circulating vitamin D metabolite, 25-hydroxyvitamin D [(25(OH)D]. We examined the associations between the common variants of the VDBP (GC) gene and concentrations of 25(OH)D in a sample of young Canadian adults of East Asian, European and South Asian ancestry, taking into account the effect of vitamin D intake, skin pigmentation, sex, BMI, sun exposure and season. Three hundred and fifty-one (351) healthy young adults were genotyped for two non-synonymous single nucleotide polymorphisms (SNPs), T436K (rs4588) and D432E (rs7041), using a method that ascertains the GC diplotypes of each individual. After controlling for relevant predictor variables in multiple regression models, the number of GC-2 (436K) alleles was found to be associated with lower 25(OH)D concentrations in the East Asian sample at fall and winter visits. The number of GC-2 alleles also showed a significant negative association with fall 25(OH)D concentration in the European sample. No associations were noted between the number of GC-2 alleles and 25(OH)D in the South Asian sample at either season. Vitamin D intake was also significantly predictive of serum 25(OHD) concentrations, and similarly to what was observed for the GC polymorphisms, the relative strength of the association was influenced by ancestry and season.
  The Journal of steroid biochemistry and molecular biology 06/2011; 127(3-5):405-12. · 2.66 Impact Factor
• Article: The ratio of serum 24,25-dihydroxyvitamin D(3) to 25-hydroxyvitamin D(3) is predictive of 25-hydroxyvitamin D(3) response to vitamin D(3) supplementation.

  Dennis Wagner, Heather E Hanwell, Kareena Schnabl, Mehrdad Yazdanpanah, Samantha Kimball, Lei Fu, Gloria Sidhom, Dérick Rousseau, David E C Cole, Reinhold Vieth
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  ABSTRACT: 24,25-Dihydroxyvitamin D (24,25VD) is a major catabolite of 25-hydroxyvitamin D (25VD) metabolism, and may be physiologically active. Our objectives were to: (1) characterize the response of serum 24,25VD(3) to vitamin D(3) (VD(3)) supplementation; (2) test the hypothesis that a higher 24,25VD(3) to 25VD(3) ratio (24,25:25VD(3)) predicts 25VD(3) response. Serum samples (n=160) from wk 2 and wk 6 of a placebo-controlled, randomized clinical trial of VD(3) (28,000IU/wk) were analyzed for serum 24,25VD(3) and 25VD(3) by mass spectrometry. Serum 24,25VD(3) was highly correlated with 25VD(3) in placebo- and VD(3)-treated subjects at each time point (p<0.0001). At wk 2, the 24,25:25VD(3) ratio was lower with VD(3) than with placebo (p=0.035). From wk 2 to wk 6, the 24,25:25VD(3) ratio increased with the VD(3) supplement (p<0.001) but not with placebo, such that at wk 6 this ratio did not significantly differ between groups. After correcting for potential confounders, we found that 24,25:25VD(3) at wk 2 was inversely correlated to the 25VD(3) increment by wk 6 in the supplemented group (r=-0.32, p=0.02) but not the controls. There is a strong correlation between 24,25VD(3) and 25VD(3) that is only modestly affected by VD(3) supplementation. This indicates that the catabolism of 25VD(3) to 24,25VD(3) rises with increasing 25VD(3). Furthermore, the initial ratio of serum 24,25VD(3) to 25VD(3) predicted the increase in 25VD(3). The 24,25:25VD(3) ratio may therefore have clinical utility as a marker for VD(3) catabolism and a predictor of serum 25VD(3) response to VD(3) supplementation.
  The Journal of steroid biochemistry and molecular biology 05/2011; 126(3-5):72-7. · 2.66 Impact Factor
• Article: Polymorphisms at the regulatory regions of the CASR gene influence stone risk in primary hyperparathyroidism.

  Giuseppe Vezzoli, Alfredo Scillitani, Sabrina Corbetta, Annalisa Terranegra, Elena Dogliotti, Vito Guarnieri, Teresa Arcidiacono, Vera Paloschi, Francesco Rainone, Cristina Eller-Vainicher, [......], Antonio Nouvenne, Angela Guerra, Tiziana Meschi, Franca Allegri, Daniele Cusi, Anna Spada, David E C Cole, Geoffrey N Hendy, Donatella Spotti, Laura Soldati
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  ABSTRACT: Single nucleotide polymorphisms (SNPs) of the calcium-sensing receptor (CASR) gene at the regulatory region were associated with idiopathic calcium nephrolithiasis. To confirm their association with nephrolithiasis, we tested patients with primary hyperparathyroidism (PHPT). A genotype-phenotype association study. In all, 332 PHPT patients and 453 healthy controls were genotyped for the rs7652589 (G>A) and rs1501899 (G>A) SNPs sited in the noncoding regulatory region of the CASR gene. Allele, haplotype, and diplotype distribution were compared between PHPT patients and controls, and in stone forming and stone-free PHPT patients. The allele frequency at rs7652589 and rs1501899 SNPs was similar in PHPT patients and controls. The A minor alleles at these two SNPs were more frequent in stone forming (n=157) than in stone-free (n=175) PHPT patients (rs7652589: 36.9 vs 27.1%, P=0.007; rs1501899: 37.1 vs 26.4%, P=0.003). Accordingly, homozygous or heterozygous PHPT patients for the AA haplotype (n=174, AA/AA or AA/GG diplotype) had an increased stone risk (odds ratio 1.83, 95% confidence interval 1.2-2.9, P=0.008). Furthermore, these PHPT patients had higher serum concentrations of ionized calcium and parathyroid hormone (1.50 ± 0.015 mmol/l and 183 ± 12.2 pg/ml) than patients with the GG/GG diplotype (n=145, 1.47 ± 0.011 mmol/l (P=0.04) and 150 ± 11.4 pg/ml (P=0.049)). Using a logistic regression model, the increase in stone risk in PHPT patients was predicted by AA/AA or AA/GG diplotype, the highest tertile of serum ionized calcium values and the lowest tertile of age. Polymorphisms located in the regulatory region of the CASR gene may increase susceptibility of the PHPT patients to kidney stone production.
  European Journal of Endocrinology 03/2011; 164(3):421-7. · 3.42 Impact Factor
• Article: Mild infantile hypercalcemia: diagnostic tests and outcomes.

  Dror Koltin, Marianna Rachmiel, Betty Y L Wong, David E C Cole, Elizabeth Harvey, Etienne Sochett
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  ABSTRACT: To assess outcome in a cohort of patients with infantile hypercalcemia followed over 3 years. Patients (n = 32) presenting to the calcium clinic between July 2002 and September 2008 were studied. In addition to tests of calcium phosphate metabolism, serum insulin-like growth factor-1, calcitonin, urine citrate, and calcium-sensing receptor gene analysis were obtained. Mean age at presentation was 6.0 ± 6.3 months. Mean calcium level was 11.4 ± 0.7 mg/dL (2.84 ± 0.17 mmol/L). A recognized cause was found in 14% and a probable cause in 14% of the cohort. Those with nephrocalcinosis (n = 11) had significantly lower mean weight SDS and higher mean calcium levels. The biochemical profile of those in whom no cause could be determined included nonsuppressed parathyroid hormone with either normal or increased 1,25(OH)(2)D. Hypercalcemia resolved in 20 patients. However, in approximately a third, there was persistence in hypercalcemia, hypercalciuria, or nephrocalcinosis. The addition of 1,25(OH)(2)D and calcium-sensing receptor mutation analysis to a panel of investigations may improve diagnostic yield. Clinical outcome is overall good, however, one-third need ongoing follow-up.
  The Journal of pediatrics 03/2011; 159(2):215-21.e1. · 4.02 Impact Factor
• Article: Neonatal hyperparathyroidism with a heterozygous calcium-sensing receptor (CASR) R185Q mutation: clinical benefit from cinacalcet.

  Christina M S Reh, Geoffrey N Hendy, David E C Cole, Debra D Jeandron
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  ABSTRACT: Neonatal hyperparathyroidism can be caused by a heterozygous inactivating mutation in the calcium-sensing receptor. Calcimimetics, allosteric activators of the calcium-sensing receptor, may provide an effective means of reducing PTH secretion in such patients. OBJECTIVE/PATIENT: The objective of the study was to identify the molecular defect and to monitor the postnatal course of a 1-wk-old infant with elevated blood ionized calcium, serum PTH, and alkaline phosphatase and low calcium excretion. The parents were normocalcemic. CASR gene mutation analysis was performed on genomic DNA of the proband and her parents. The infant was treated initially with pamidronate and then cinacalcet. A heterozygous mutation (R185Q, CGA > CAA) in exon 4 of the CASR gene was identified in the proband. The CASR gene of both parents was normal. At 1 wk of age, iv fluids and furosemide were initiated, but hypercalcemia, hyperparathyroidism, and low calcium excretion persisted. At 2 wk of age, a single iv dose of pamidronate resulted in hypocalcemia and further increase in PTH levels, but hypercalcemia recurred within 1 wk. At 3 wk of age, a single oral dose of cinacalcet resulted in decreased PTH levels at 2 h; blood-ionized calcium reached a nadir at 10 h. Three days later daily cinacalcet was initiated, resulting in normalization of ionized calcium. The suppression of serum PTH and reduction in total serum calcium was maintained long term. In neonatal hyperparathyroidism secondary to presumed de novo heterozygous CASR mutation, treatment with cinacalcet decreases PTH secretion and serum calcium levels and mitigates the need for parathyroidectomy.
  The Journal of clinical endocrinology and metabolism 02/2011; 96(4):E707-12. · 6.50 Impact Factor
• Source

  Available from: Esteban Parra

  Article: Serum 25-hydroxyvitamin D concentrations fluctuate seasonally in young adults of diverse ancestry living in Toronto.

  Agnes Gozdzik, Jodi L Barta, Alison Weir, David E C Cole, Reinhold Vieth, Susan J Whiting, Esteban J Parra
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  ABSTRACT: Previous research indicates that circulating vitamin D levels are low in many otherwise healthy adults and that there is considerable seasonal variation in 25-hydroxyvitamin D [25(OH)D] concentrations at high latitudes. We examined seasonal variation in 25(OH)D levels in a sample of young adults of diverse ancestry living in the Greater Toronto Area. Three hundred and fifty-one (351) healthy young adults completed both a fall and winter visit during this study. The study was conducted over 2 y (y 1: fall 2007 to winter 2008 and y 2: fall 2008 to winter 2009). At both visits, each participant's serum 25(OH)D concentration was measured. Information was also obtained on skin pigmentation (measured via reflectometer), vitamin D intake, and extent of sun exposure. Overall, the serum 25(OH)D concentration was 54.4 ± 1.3 nmol/L in the fall and 38.4 ± 1.1 nmol/L in the winter. Concentrations differed among ancestral groups at both visits (P < 0.001), with South Asians and East Asians having substantially lower concentrations than Europeans. Skin pigmentation (r(2) = 0.14; P < 0.001), supplemental vitamin D intake (r(2) = 0.09; P < 0.001), sun exposure (r(2) = 0.04; P < 0.001), and study year (r(2) = 0.02; P = 0.017) were predictors of fall 25(OH)D concentrations. During the wintertime, serum 25(OH)D concentrations were associated with concentrations taken in the fall (r(2) = 0.45; P < 0.001), supplemental (r(2) = 0.15; P < 0.001) and dietary vitamin D intake (r(2) = 0.06; P < 0.001), and with study year (r(2) = 0.02; P = 0.009). Our study confirms that serum 25(OH)D concentrations undergo strong seasonal variation at high latitudes and are influenced by vitamin D intake, skin pigmentation, and sun exposure.
  Journal of Nutrition 10/2010; 140(12):2213-20. · 3.92 Impact Factor
• Article: Vitamin D in adult health and disease: a review and guideline statement from Osteoporosis Canada.

  David A Hanley, Ann Cranney, Glenville Jones, Susan J Whiting, William D Leslie, David E C Cole, Stephanie A Atkinson, Robert G Josse, Sidney Feldman, Gregory A Kline, Cheryl Rosen
  Canadian Medical Association Journal 09/2010; 182(12):E610-8. · 8.22 Impact Factor
• Source

  Available from: Miles Thompson

  Article: Hyperphosphatasia with seizures, neurologic deficit, and characteristic facial features: Five new patients with Mabry syndrome.

  Miles D Thompson, Marjan M Nezarati, Gabriele Gillessen-Kaesbach, Peter Meinecke, Roberto Mendoza-Londono, Roberto Mendoza, Etienne Mornet, Isabelle Brun-Heath, Catherine Prost Squarcioni, Laurence Legeai-Mallet, Arnold Munnich, David E C Cole
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  ABSTRACT: Persistent hyperphosphatasia associated with developmental delay and seizures was described in a single family by Mabry et al. 1970 (OMIM 239300), but the nosology of this condition has remained uncertain ever since. We report on five new patients (two siblings, one offspring of consanguineous parents, and two sporadic patients) that help delineate this distinctive disorder and provide evidence in favor of autosomal recessive inheritance. Common to all five new patients is facial dysmorphism, namely hypertelorism, a broad nasal bridge and a tented mouth. All patients have some degree of brachytelephalangy but the phalangeal shortening varies in position and degree. In all, there is a persistent elevation of alkaline phosphatase activity without any evidence for active bone or liver disease. The degree of hyperphosphatasia varies considerably ( approximately 1.3-20 times the upper age-adjusted reference limit) between patients, but is relatively constant over time. In the first family described by Mabry et al. 1970, at least one member was found to have intracellular inclusions on biopsy of some but not all tissues. This was confirmed in three of our patients, but the inclusions are not always observed and the intracellular storage material has not been identified.
  American Journal of Medical Genetics Part A 07/2010; 152A(7):1661-9. · 2.39 Impact Factor
• Article: Calcium-sensing receptor (CASR) mutations in hypercalcemic states: studies from a single endocrine clinic over three years.

  Vito Guarnieri, Lucie Canaff, Francisco H J Yun, Alfredo Scillitani, Claudia Battista, Lucia A Muscarella, Betty Y L Wong, Angelantonio Notarangelo, Leonardo D'Agruma, Michele Sacco, David E C Cole, Geoffrey N Hendy
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  ABSTRACT: Inactivating mutations of the calcium-sensing receptor (CASR) are implicated in different hypercalcemic syndromes, including familial hypocalciuric hypercalcemia (FHH), primary hyperparathyroidism (PHPT), and familial isolated hyperparathyroidism (FIHP). However, molecular diagnostics applied to large nonselected hypercalcemic cohorts from a single center have not been reported. Our objective was to describe the prevalence, type, and potential pathogenicity of CASR mutations in a series of cases with FHH (n = 17), PHPT (n = 165), and FIHP (n = 3) and controls (n = 198) presenting at a single endocrine clinic. All were prospectively evaluated at the "Casa Sollievo della Sofferenza" Hospital in southern Italy over a 3-yr period. CASR screening was conducted by denaturing HPLC. The variant CASRs were functionally characterized by transient transfection studies in kidney cells in vitro. A single novel missense variant was identified in one PHPT case. However, in FHH probands, mutations were found in eight of 17 (47%). With a hypercalcemic family member, mutation detection rate in FHH rose to seven of eight (87%), whereas only one of nine sporadic cases was positive, and none of the three FIHP cases had detectable CASR mutations. Five missense variant CASRs, identified in control subjects, performed as wild type in functional assays, whereas the missense mutant CASRs identified in the FHH patients, and in the one PHPT case, exhibited significant impairment. A novel intronic mutation (IVS4-19a-->c) found in one FHH family, created an abnormally spliced product in an in vitro minigene assay. CASR testing, with functional analysis, provides critical confirmatory evidence in the differential diagnosis of hypercalcemic states.
  The Journal of clinical endocrinology and metabolism 02/2010; 95(4):1819-29. · 6.50 Impact Factor
• Article: A phase 2 trial exploring the effects of high-dose (10,000 IU/day) vitamin D(3) in breast cancer patients with bone metastases.

  Eitan Amir, Christine E Simmons, Orit C Freedman, George Dranitsaris, David E C Cole, Reinhold Vieth, Wei S Ooi, Mark Clemons
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  ABSTRACT: Vitamin D deficiency has potential roles in breast cancer etiology and progression. Vitamin D deficiency has also been associated with increased toxicity from bisphosphonate therapy. The optimal dose of vitamin D supplementation is unknown, but daily sunlight exposure can generate the equivalent of a 10,000-IU oral dose of vitamin D(3). This study therefore aimed to assess the effect of this dose of vitamin D(3) in patients with bone metastases from breast cancer. Patients with bone metastases treated with bisphosphonates were enrolled into this single-arm phase 2 study. Patients received 10,000 IU of vitamin D(3) and 1000 mg of calcium supplementation each day for 4 months. The effect of this treatment on palliation, bone resorption markers, calcium metabolism, and toxicity were evaluated at baseline and monthly thereafter. Forty patients were enrolled. No significant changes in bone resorption markers were seen. Despite no change in global pain scales, there was a significant reduction in the number of sites of pain. A small but statistically significant increase in serum calcium was seen, as was a significant decrease in serum parathyroid hormone. Treatment unmasked 2 cases of primary hyperparathyroidism, but was not associated with direct toxicity. Daily doses of 10,000 IU vitamin D(3) for 4 months appear safe in patients without comorbid conditions causing hypersensitivity to vitamin D. Treatment reduced inappropriately elevated parathyroid hormone levels, presumably caused by long-term bisphosphonate use. There did not appear to be a significant palliative benefit nor any significant change in bone resorption.
  Cancer 11/2009; 116(2):284-91. · 4.77 Impact Factor
• Article: Genetic determinants of extracellular magnesium concentration: analysis of multiple candidate genes, and evidence for association with the estrogen receptor alpha (ESR1) locus.

  Andrew Y Shuen, Betty Y L Wong, Cuihong Wei, Zhanqin Liu, Mei Li, David E C Cole
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  ABSTRACT: Serum magnesium concentration is a quantitative trait with substantial heritability. Although the pool of candidate genes continues to grow, only the histocompatibility locus has been associated with magnesium levels. To explore other possibilities, we targeted 6 candidate genes physiologically relevant to magnesium metabolism. We studied a large cohort (n=471) derived from a well-characterized population of healthy Caucasian women 18 to 35 years. Total serum magnesium and calcium were measured by atomic absorption spectrophotometry (aaMg & aaCa). Genomic DNA was amplified and SNPs in candidate genes (CASR, VDR, ESR1, CLDN16, EGF1, TRPM6) genotyped by routine methods. We found a significant association between estrogen receptor alpha (ESR1) polymorphisms, PvuII and XbaI, and magnesium (r=-0.116, p=0.012 and r=-0.126, p=0.006, respectively). Stratifying by PvuII genotype (P/p alleles), the mean adjusted total magnesium (aaMg) concentration was significantly higher (p=0.01) in the pp group (0.823+/-0.005 mmol/l, n=130) than in PP homozygotes (0.805+/-0.006 mmol/l, n=70), and the mean in Pp heterozygotes was intermediate (0.810+/-0.005 mmol/l, n=180). No significant associations were observed with the other candidate genes tested. The significant association between magnesium and ESR1 polymorphisms supports previous studies linking physiologic changes in serum magnesium to estrogen status.
  Clinica chimica acta; international journal of clinical chemistry 08/2009; 409(1-2):28-32. · 2.54 Impact Factor
• Article: Altered calcium metabolism in patients on long-term bisphosphonate therapy for metastatic breast cancer.

  Christine Simmons, Eitan Amir, George Dranitsaris, Mark Clemons, Betty Wong, Reinhold Veith, David E C Cole
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  ABSTRACT: Bisphosphonates (BPs) are considered the standard of care in metastatic breast cancer (MBC) patients with bone metastases. Because the survival for these patients may be prolonged compared with those patients with visceral metastases, they may be prescribed BPs for several years. The effects of this long-term BP use on calcium metabolism in MBC patients have not previously been described. The main objective of this study was to evaluate the effect of long-term BP use on calcium homeostasis in MBC patients. The secondary objective was to assess Vitamin D levels in these patients. An exploratory analysis of serum calcium, parathyroid (PTH), and 25 hydroxycholecalsiferol (25-(OH)D) levels and their inter-relationships was undertaken in 46 MBC patients who had been on prolonged BP therapy. These results were compared to a historical control group of 420 patients without bone or mineral disease who were matched for gender, age, baseline renal function and season of seological testing. Patients were similar in the two groups with no significant difference in mean age, baseline creatinine or season of testing. Serum calcium was no different between the two groups. However, PTH was significantly higher in MBC patients, compared to controls (5.7 vs. 4.8 pmol/L, p=0.043). Linear regression analysis showed that PTH was significantly higher in the MBC group at lower serum calcium levels and fell sharply with increasing serum calcium levels (p=0.0001). Among the patients with MBC, 62% had suboptimal levels of vitamin D and 18% were found to have insufficient or deficient levels (25-(OH)D < 40 nM) despite taking dietary supplementation. In MBC patients with prolonged BP use, there appears to be a state of hyperparathyroidism similar to that seen with BP use in benign bone disease. Supplementation with 400 IU per day of Vitamin D per day was not sufficient to correct this metabolic abnormality.
  Anticancer research 07/2009; 29(7):2707-11. · 1.73 Impact Factor