Hypoparathyroidism

Mannstadt, Michael; Bilezikian, John P.; Thakker, Rajesh; Hannan, Fadil; Clarke, B.L.; Rejnmark, Lars; Mitchell, Deborah M.; Vokes, Tamara; Winer, Karen K.; Shoback, Dolores

doi:10.1038/nrdp.2017.55

Cited by 193 publications

(222 citation statements)

References 167 publications

Supporting

Mentioning

208

Contrasting

Unclassified

Order By: Relevance

“…Indeed, subjects with CAN often complain symptoms such as exercise intolerance and weakness, (26) as well as patients with hypoPT do. (2) Our hypothesis seems to be supported by previous studies that have demonstrated a relationship between fatigue and autonomic dysfunction during different chronic diseases, namely Parkinson's disease, (27) multiple sclerosis, (28) and chronic fatigue syndrome. (29) Evaluations of fatigue have not yet been performed, and therefore, we are conducting further analyses to investigate the relationship between fatigue and CAN.…”

Section: Discussionsupporting

confidence: 82%

“…On the other hand, the worsening of CAN in our population with lower calcium levels may highlight the importance of calcium in the development of autonomic neuropathy. It has been demonstrated that low calcium level determines an increase of neuromuscular irritability and hypocalcemia increases the probability of triggering action potentials in the membrane of a neuron …”

Section: Discussionmentioning

confidence: 99%

“…It has been demonstrated that low calcium level determines an increase of neuromuscular irritability and hypocalcemia increases the probability of triggering action potentials in the membrane of a neuron. (2,25) In subjects with chronic hypoPT, European Society of Endocrinology and Endocrine Society guidelines (1) suggest maintaining serum calcium concentrations slightly below normal (ie, no more than 0.5 mg/dL below normal) or in the low normal range to reduce the long term incidence of chronic kidney complications, namely, nephrocalcinosis and renal function impairment. However, no strong evidence supports this therapeutic approach, and whereas it could reduce the risk of hypercalciuria, it may increase the risk of CAN.…”

Section: Discussionmentioning

confidence: 99%

“…(1,2) Indeed, studies have shown that hypocalcemia and/or a lack of PTH may affect muscle function (3,4) and various aspects of quality of life (QoL). (2) These symptoms include physical (eg, fatigue, muscle spasms, pain, and paresthesia), cognitive (eg, "brain fog" and an inability to concentrate), and emotional complaints (eg, depression and/or anxiety). (5) The nature of the impairment of QoL and its relationship to biochemical control or other aspects of the disease has not been well described.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Cardiovascular Autonomic Neuropathy as a New Complication of Postsurgical Chronic Hypoparathyroidism

Tabacco

Naciu

Maggi

et al. 2018

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Postsurgical hypoparathyroidism (hypoPT) increases fatigue and seems to affect the risk of mortality. Cardiovascular autonomic neuropathy (CAN) is an impairment of the cardiovascular autonomic system, a cause of increased mortality, and associated with increased fatigability. The aim of this study is to evaluate CAN in hypoPT and its relationship with hypocalcemia, PTH levels, and hyperphosphatemia. This is a cross‐sectional study comparing 51 postsurgical hypoPT patients treated with calcium and calcitriol and 43 control subjects without any PTH/calcium/phosphate disorders who underwent thyroidectomy. CAN was assessed by heart rate (HR) response to deep breathing, HR response to the lying‐to‐standing test, HR response to the Valsalva maneuver, and blood pressure response to standing. Participants were considered to have “early CAN” if they had one abnormal result in the HR tests and “definite CAN” with two or more abnormal results. The prevalence of CAN was 23% in the control group and 78% in the hypoPT group (OR 11.48; 95% CI, 4.48 to 32.17). Patients with hypoPT and serum calcium (sCa) ≥8.5 mg/dL had a prevalence of early CAN of 72.4% and the prevalence was 86.4% in those with sCa <8.5 mg/dL. Definite CAN was found in 2.3% of the control group, 24.1% of the hypoPT group without hypocalcemia, and 59.1% of the hypoPT group with hypocalcemia. In the hypoPT group, the OR for definite CAN in the patients with hypocalcemia compared to the patients with normocalcemia was 4.54 (95% CI, 1.36 to 15.11). The association between low sCa and definite CAN was confirmed after adjustment for confounders with OR 13.62 (95% CI, 2.12 to 149.84). No association was found between definite CAN and PTH levels or high phosphate levels. HypoPT is associated with CAN and hypocalcemia seems to affect its severity. Larger and prospective studies are needed to confirm our findings. © 2018 American Society for Bone and Mineral Research.

show abstract

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cardiovascular Autonomic Neuropathy as a New Complication of Postsurgical Chronic Hypoparathyroidism

Tabacco

Naciu

Maggi

et al. 2018

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

show abstract

“…Hypoparathyroidism, in particular ADH1, is a disease for which there remains a need for better therapeutics . Given that ADH1 results from gain‐of‐function mutations in the CAR , negative allosteric modulators of the CaR, calcilytics, represent a rational, precision medicine approach to treating this disease.…”

Section: Discussionmentioning

confidence: 99%

Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635)

Roberts

Gafni

Brillante

et al. 2019

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism caused by heterozygous, gain‐of‐function mutations of the calcium‐sensing receptor gene (CAR). Individuals are hypocalcemic with inappropriately low parathyroid hormone (PTH) secretion and relative hypercalciuria. Calcilytics are negative allosteric modulators of the extracellular calcium receptor (CaR) and therefore may have therapeutic benefits in ADH1. Five adults with ADH1 due to four distinct CAR mutations received escalating doses of the calcilytic compound NPSP795 (SHP635) on 3 consecutive days. Pharmacokinetics, pharmacodynamics, efficacy, and safety were assessed. Parallel in vitro testing with subject CaR mutations assessed the effects of NPSP795 on cytoplasmic calcium concentrations (Ca2+i), and ERK and p38MAPK phosphorylation. These effects were correlated with clinical responses to administration of NPSP795. NPSP795 increased plasma PTH levels in a concentration‐dependent manner up to 129% above baseline (p = 0.013) at the highest exposure levels. Fractional excretion of calcium (FECa) trended down but not significantly so. Blood ionized calcium levels remained stable during NPSP795 infusion despite fasting, no calcitriol supplementation, and little calcium supplementation. NPSP795 was generally safe and well‐tolerated. There was significant variability in response clinically across genotypes. In vitro, all mutant CaRs were half‐maximally activated (EC50) at lower concentrations of extracellular calcium (Ca2+o) compared to wild‐type (WT) CaR; NPSP795 exposure increased the EC50 for all CaR activity readouts. However, the in vitro responses to NPSP795 did not correlate with any clinical parameters. NPSP795 increased plasma PTH levels in subjects with ADH1 in a dose‐dependent manner, and thus, serves as proof‐of‐concept that calcilytics could be an effective treatment for ADH1. Albeit all mutations appear to be activating at the CaR, in vitro observations were not predictive of the in vivo phenotype or the response to calcilytics, suggesting that other parameters impact the response to the drug. © 2019 American Society for Bone and Mineral Research.

show abstract

A case of severe TBCE‐negative hypoparathyroidism‐retardation‐dysmorphism syndrome: Case report and literature review

Ryabets-Lienhard

Ayuthaya

Graham

et al. 2018

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Hypoparathyroidism-retardation-dysmorphism syndrome (HRD) is a rare autosomal recessive disorder attributed to the mutations in the tubulin-specific chaperone E (TBCE) gene, which is vital for microtubule function during mitosis, organelle positioning, and neuronal cytokinesis. HRD is a congenital syndromic hypoparathyroidism associated with growth deficiency, microcephaly, intellectual disability, ocular anomalies, and facial dysmorphism. To our knowledge, there is only one published case of mild HRD-like syndrome with no identifiable genetic etiology. We report a case of severe TBCE-negative phenotypic HRD in a 4-year-old female from India presenting with hypocalcemic seizures due to congenital hypoparathyroidism, extreme microcephaly, growth deficiency, ocular anomalies, and facial dysmorphism. SNP microarray and whole exome sequencing (WES) did not detect any abnormalities in TBCE or other genes of interest. WES revealed two variants of unknown clinical significance in CASC5 gene, which codes for a protein in the kinetochore and, interestingly similar to TBCE, is essential for proper microtubule function during mitosis and cell proliferation and has been implicated in primary microcephaly disorders. However, further targeted sequencing in the parents revealed both variants inherited from the unaffected mother. Significant copy number variant noise in the proband and her parents limited further analysis. At this time the role of variants in the CASC5 gene is unclear and cannot explain our patient's phenotype. In conclusion, we report a severe case of phenotypic HRD syndrome, in which extensive genetic evaluation failed to reveal an etiology. Our case demonstrates that the pathogenesis of HRD may be genetically heterogenous, meriting further genetic investigations.

show abstract

Hypoparathyroidism

Cited by 193 publications

References 167 publications

Cardiovascular Autonomic Neuropathy as a New Complication of Postsurgical Chronic Hypoparathyroidism

Cardiovascular Autonomic Neuropathy as a New Complication of Postsurgical Chronic Hypoparathyroidism

Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635)

A case of severe TBCE‐negative hypoparathyroidism‐retardation‐dysmorphism syndrome: Case report and literature review

Contact Info

Product

Resources

About