Co-occurrence of a novel PDGFRB variant and likely pathogenic variant in CASR in an individual with extensive intracranial calcifications and hypocalcaemia.
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ABSTRACT:
SUBMITTER: DeMeo NN
PROVIDER: S-EPMC5771904 | biostudies-literature | 2018 Jan
REPOSITORIES: biostudies-literature
Publications
Co-occurrence of a novel <i>PDGFRB</i> variant and likely pathogenic variant in <i>CASR</i> in an individual with extensive intracranial calcifications and hypocalcaemia.
DeMeo Natasha N NN Burgess Jeremy D JD Blackburn Patrick R PR Gass Jennifer M JM Richter John J Atwal Herjot K HK van Gerpen Jay A JA Atwal Paldeep S PS
Clinical case reports 20171120 1
This case report describes an individual with brain calcifications, cognitive decline, motor dysfunction, and hypocalcaemia. Exome sequencing revealed a previously reported variant in the <i>CASR</i> gene and a variant of uncertain significance in <i>PDGFRB</i>. The clinical phenotype is likely explained by the <i>CASR</i> variant, but we discuss how the <i>PDGFRB</i> variant could also participate in the phenotype. ...[more]
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Project description:RationaleAutosomal dominant hypocalcaemia type 1 (ADH1) is a genetic disease characterized by benign hypocalcemia, inappropriately low parathyroid hormone levels and mostly hypercalciuria. It is caused by the activating mutations of the calcium-sensing receptor gene (CASR), which produces a left-shift in the set point for extracellular calcium.Patient concernsA 50-year-old man presenting with muscle spasms was admitted into the hospital. He has a positive familial history for hypocalcemia. Auxiliary examinations demonstrated hypocalcemia, hyperphosphatemia, normal parathyroid hormone level and nephrolithiasis. A missense heterozygous variant in CASR, c 613C > T (p. Arg205Cys) which has been reported in a familial hypocalciuric hypercalcemia type 1 patient was found in the patient's genotype. It is the first time that this variant is found associating with ADH1. The variant is predicted vicious by softwares and cosegregates with ADH1 in this pedigree. CASR Arg205Cys was deduced to be the genetic cause of ADH1 in the family.DiagnosisThe patient was diagnosed with ADH1 clinically and genetically.InterventionsOral calcitriol, calcium and hydrochlorothiazide were prescribed to the patient.OutcomesAfter the treatments for 1 week, the patient's symptom was improved and the re-examination revealed serum calcium in the normal range. A 3-month follow-up showed his symptom was mostly relieved.LessonsThe variant of CASR Arg205Cys, responsible for ADH1 in this family, broadened the genetic spectrum of ADH1. Further and more studies are required to evaluate the correlation between genotype and phenotype in ADH1 patients.
| S-EPMC8238359 | biostudies-literature
Project description:PurposeTo compare gradient-echo (GRE) phase magnetic resonance (MR) imaging and quantitative susceptibility mapping (QSM) in the detection of intracranial calcifications and hemorrhages.Materials and methodsThis retrospective study was approved by the institutional review board. Thirty-eight patients (24 male, 14 female; mean age, 33 years ± 16 [standard deviation]) with intracranial calcifications and/or hemorrhages diagnosed on the basis of computed tomography (CT), MR imaging (interval between examinations, 1.78 days ± 1.31), and clinical information were selected. GRE and QSM images were reconstructed from the same GRE data. Two experienced neuroradiologists independently identified the calcifications and hemorrhages on the QSM and GRE phase images in two randomized sessions. Sensitivity, specificity, and interobserver agreement were computed and compared with the McNemar test and k coefficients. Calcification loads and volumes were measured to gauge intermodality correlations with CT.ResultsA total of 156 lesions were detected: 62 hemorrhages, 89 calcifications, and five mixed lesions containing both hemorrhage and calcification. Most of these lesions (146 of 151 lesions, 96.7%) had a dominant sign on QSM images suggestive of a specific diagnosis of hemorrhage or calcium, whereas half of these lesions (76 of 151, 50.3%) were heterogeneous on GRE phase images and thus were difficult to characterize. Averaged over the two independent observers for detecting hemorrhages, QSM achieved a sensitivity of 89.5% and a specificity of 94.5%, which were significantly higher than those at GRE phase imaging (71% and 80%, respectively; P < .05 for both readers). In the identification of calcifications, QSM achieved a sensitivity of 80.5%, which was marginally higher than that with GRE phase imaging (71%; P = .08 and .10 for the two readers), and a specificity of 93.5%, which was significantly higher than that with GRE phase imaging (76.5%; P < .05 for both readers). QSM achieved significantly better interobserver agreements than GRE phase imaging in the differentiation of hemorrhage from calcification (?: 0.91 vs 0.55, respectively; P < .05).ConclusionQSM is superior to GRE phase imaging in the differentiation of intracranial calcifications from hemorrhages and with regard to the sensitivity and specificity of detecting hemorrhages and the specificity of detecting calcifications.
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Project description:BackgroundTo evaluate the prevalence, density, and distribution of prostate calcification in patients with prostate cancer.MethodsPatients who underwent both Gallium-68 PSMA PET/CT and MRI of the prostate over the course of a year were selected for analysis. The CT images with visible calcifications within the prostate were included and calcifications automatically isolated using a threshold of 130 HU. The corresponding multiparametric MRI was assessed and the peripheral zone, transition zone, MRI-visible tumor, and urethra manually contoured. The contoured MRI and CT images were registered using rigid registration, and calcifications mapped automatically to the MRI contours.ResultsA total of 85 men (age range 50-88, mean 69 years, standard deviation 7.2 years) were assessed. The mean serum Prostate Specific Antigen PSA was 16.7, range 0.12 to 94.4. Most patients had intermediate-risk disease (68%; Gleason grade group 2 and 3), 26% had high-risk disease (Gleason grade group 4 and 5), and 6% had low-risk disease (Gleason grade group 1). Forty-six patients out of 85 (54%) had intraprostatic calcification. Calcification occurred more in transition zone than the peripheral zone (65% vs. 35%). The mean density of the calcification was 227 HU (min 133, max 1,966 HU). In 12 patients, the calcification was within an MRI-visible tumor, in 24 patients, there were calcifications within a 9 mm distance of the tumor border, and in 9 patients, there were calcifications located between the urethra and tumor.ConclusionsCalcifications are common in patients with prostate cancer. Their density and location may make them a significant consideration when planning treatment or retreatment with some types of minimally invasive therapy.
| S-EPMC8492071 | biostudies-literature
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| S-EPMC9279580 | biostudies-literature
Project description:Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and inappropriately low PTH concentrations. ADH type 1 is caused by activating mutations in the calcium-sensing receptor (CASR), a G-protein-coupled receptor signaling through ?11 (G?11) and ?q (G?q) subunits. Heterozygous activating mutations in GNA11, the gene encoding G?11, underlie ADH type 2. This study describes disease characteristics in a family with ADH caused by a gain-of-function mutation in GNA11.A three-generation family with seven members (3 adults, 4 children) presenting with ADH.Biochemical parameters of calcium metabolism, clinical, genetic and brain imaging findings were analyzed.Sanger sequencing revealed a heterozygous GNA11 missense mutation (c.1018G>A, p.V340M) in all seven hypocalcemic subjects, but not in the healthy family members (n=4). The adult patients showed clinical symptoms of hypocalcemia, while the children were asymptomatic. Plasma ionized calcium ranged from 0.95 to 1.14mmol/L, yet plasma PTH was inappropriately low for the degree of hypocalcemia. Serum 25OHD was normal. Despite hypocalcemia 1,25(OH)2D and urinary calcium excretion were inappropriately in the reference range. None of the patients had nephrocalcinosis. Two adults and one child (of the two MRI scanned children) had distinct intracranial calcifications. All affected subjects had short stature (height s.d. scores ranging from -3.4 to -2.3 vs -0.5 in the unaffected children).The identified GNA11 mutation results in biochemical abnormalities typical for ADH. Additional features, including short stature and early intracranial calcifications, cosegregated with the mutation. These findings may indicate a wider role for G?11 signaling besides calcium regulation.
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Project description:ObjectiveBrain calcifications are associated with several neurodegenerative diseases. Here, we describe the occurrence of intracranial calcifications as a new phenotype in transgenic P301L mice overexpressing four repeat tau, a model of human tauopathy.Materials and methodsThirty-six P301L mice (Thy1.2) and ten age-matched non-transgenic littermates of different ages were assessed. Gradient echo data were acquired in vivo and ex vivo at 7 T and 9.4 T for susceptibility-weighted imaging (SWI) and phase imaging. In addition, ex vivo micro-computed tomography (μCT) was performed. Histochemistry and immunohistochemistry were used to investigate the nature of the imaging lesions.ResultsSW images revealed regional hypointensities in the hippocampus, cortex, caudate nucleus, and thalamus of P301L mice, which in corresponding phase images indicated diamagnetic lesions. Concomitantly, µCT detected hyperdense lesions, though fewer lesions were observed compared to MRI. Diamagnetic susceptibility lesions in the hippocampus increased with age. The immunochemical staining of brain sections revealed osteocalcin-positive deposits. Furthermore, intra-neuronal and vessel-associated osteocalcin-containing nodules co-localized with phosphorylated-tau (AT8 and AT100) in the hippocampus, while vascular osteocalcin-containing nodules were detected in the thalamus in the absence of phosphorylated-tau deposition.DiscussionSWI and phase imaging sensitively detected intracranial calcifications in the P301L mouse model of human tauopathy.
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Project description:Autosomal-dominant hypocalcemia with hypercalciuria (ADHH) is a genetic disease characterized by hypoparathyroidism with hypercalciuria. Most patients with ADHH have calcium-sensing receptor (CaSR) gene mutations. The CaSR gene controls parathyroid secretions, and mutations in this gene can be detected via changes in serum calcium level. The activating mutation of the CaSR gene results in familial or sporadic ADHH. Most activating mutations of the CaSR gene are reportedly de novo missense mutations. This is the first case report of a novel activating variant of the CaSR gene in a neonate with congenital hypoparathyroidism with hypomagnesemia and hypercalciuria. We also report the 3-month follow-up management of the patient.
| S-EPMC6057017 | biostudies-literature
Project description:BackgroundVascular calcifications are a hallmark of atherosclerosis, and in the coronary arteries are routinely used as a prognostic marker. Calcifications of intracranial vessels (ICC) are frequently observed on non-contrast CT (NCCT) and their effect on post-stroke cognitive impairment (PSCI) remains unclear. Our aim was to explore the association of ICC with prospective long-term cognitive function and advanced MRI-measures in a large prospective cohort of cognitively intact mild stroke survivors.MethodsData from the Tel-Aviv brain acute stroke cohort (TABASCO) study [ClinicalTrials.gov #NCT01926691] were analyzed. This prospective cohort study (n = 575) aimed to identify predictors of PSCI, in cognitively intact mild stroke survivors. A quantitative assessment of the intracranial calcium content - The ICC score (ICCS) was calculated semi-automatically on NCCT using a validated calcium quantification application. Participants underwent a 3 T-MRI and prospective comprehensive cognitive clinical and laboratory assessments at enrollment, 6, 12, and 24-months.ResultsData were available for 531 participants (67.4 years, 59.5% males). The incidence of PSCI at two-years doubled in the high ICCS group (26% vs. 13.7%, p < 0.001). The high ICCS group had significantly greater small-vessel-disease (SVD) tissue changes and reduced microstructural-integrity assessed by Diffusion-Tensor-Imaging (DTI) maps (p < 0.05 for all). In multivariate analysis, a higher ICCS was independently associated with brain atrophy manifested by lower normalized white and gray matter, hippocampal and thalamic volumes (β = -0.178, β = -0.2, β = -0.137, β = -0.157; p < 0.05) and independently predicted PSCI (OR 1.83, 95%CI 1.01-3.35).ConclusionOur findings suggest that the ICCS, which is a simple and readily available imaging marker on NCCT, is associated with brain atrophy, microstructural damage, the extent of SVD, and may predict PSCI. This finding has implications for identifying individuals at risk for PSCI and implementing targeted interventions to mitigate this risk.
| S-EPMC10393263 | biostudies-literature