Hypercalcemia With Non Suppressed Parathyroid Hormone in a Young Female- A Rare Case of Calcium Sensing Receptor Gene Related Familial Hypocalciuric Hypercalcemia-1

Background: Familial Hypocalciuric Hypercalcemia (FHH) is a rare disorder, associated with hypercalcemia and hypocalciuria and inherited in an autosomal dominant manner. Its true prevalence is unknown, and is estimated to be around 1 in 78,000 as compared to primary hyperparathyroidism (PHPT) which is around 1 in 1000. There are 3 mutations known to cause FHH. FHH-1 is caused by inactivating mutation in the calcium sensing receptor (CaSR) gene. Mutations associated with FHH-2 and FHH-3 are GNA11 and AP2S1 respectively. Case Presentation: 38-year-old female presented to endocrinology, for evaluation of hypercalcemia (10.8 mg/dL, with normal albumin). She was not on any calcium supplements or any other medications which can cause hypercalcemia. She did not have any prior fracture or nephrolithiasis or renal insufficiency. Her father reported to have hypercalcemia; no further evaluations of her father were available. Examination revealed an obese female with no skeletal or dental or other physical abnormalities. Laboratory evaluations: PTH= 37 pg/ml (15–65), 25 OH vitamin=D-30 pg/ml, Mg=2 mg/dL (1.5–2.6), phosphorus=3.1 mg/dl (2.5–4.8), 24 hour urine calcium=0.151 g/24 hours-with 24 hour urine calcium clearance of 0.008. Therefore, evaluations were highly suggestive of FHH. Subsequently, she had genetic evaluation which confirmed heterozygous CaSR mutation, confirming FHH-1. Her mother had genetic testing and was not found to have the mutation. So, it was concluded that the patient likely inherited the gene from her father, who also had hypercalcemia. She is being monitored clinically and with serial laboratory evaluations to monitor her calcium levels. Discussion: CaSR is expressed in parathyroid glands and kidneys which plays a key role in calcium regulation. CaSR inactivating mutation (seen in FHH-1) leads to hypocalciuria and hypercalcemia. 24 hour urine calcium clearance (urine Ca x serum Cr/ serum Ca x urine Cr) of <0.01 is highly suggestive of FHH. Furthermore, higher concentration of calcium is required to suppress PTH release leading to high or nonsuppressed PTH. This finding can mislead towards the diagnosis of PHPT and unnecessary parathyroid surgery, if the diagnosis of FHH is missed. FHH is usually a benign disorder; subtotal parathyroidectomy does not cure the disease. FHH, rarely can cause atypical complications such as pancreatitis and total parathyroidectomy may be indicated to prevent further episodes of pancreatitis. Conclusions: This is a rare case presentation of hypercalcemia due to CaSR inactivating mutation related FHH. FHH and PHPT are competing diagnoses, when a patient presents with hypercalcemia and has nonsuppressed PTH. FHH is rare, however needs to be suspected in a young patient with family history of hypercalcemia, to avoid misdiagnosis of PHPT and unnecessary surgical intervention.

Differences in Calcium Clearance at Inner Hair Cell Active Zones May Underlie the Difference in Susceptibility to Noise-Induced Cochlea Synaptopathy of C57BL/6J and CBA/CaJ Mice

Noise exposure of a short period at a moderate level can produce permanent cochlear synaptopathy without seeing lasting changes in audiometric threshold. However, due to the species differences in inner hair cell (IHC) calcium current that we have recently discovered, the susceptibility to noise exposure may vary, thereby impact outcomes of noise exposure. In this study, we investigate the consequences of noise exposure in the two commonly used animal models in hearing research, CBA/CaJ (CBA) and C57BL/6J (B6) mice, focusing on the functional changes of cochlear IHCs. In the CBA mice, moderate noise exposure resulted in a typical fully recovered audiometric threshold but a reduced wave I amplitude of auditory brainstem responses. In contrast, both auditory brainstem response threshold and wave I amplitude fully recovered in B6 mice at 2 weeks after noise exposure. Confocal microscopy observations found that ribbon synapses of IHCs recovered in B6 mice but not in CBA mice. To further characterize the molecular mechanism underlying these different phenotypes in synaptopathy, we compared the ratio of Bax/Bcl-2 with the expression of cytochrome-C and found increased activity in CBA mice after noise exposure. Under whole-cell patch clamped IHCs, we acquired two-photon calcium imaging around the active zone to evaluate the Ca2+ clearance rate and found that CBA mice have a slower calcium clearance rate. Our results indicated that excessive accumulation of calcium due to acoustic overexposure and slow clearance around the presynaptic ribbon might lead to disruption of calcium homeostasis, followed by mitochondrial dysfunction of IHCs that cause susceptibility of noise-induced cochlear synaptopathy in CBA mice.

A mathematical model of mitochondrial calcium-phosphate dissolution as a mechanism for persistent post-CSD vasoconstriction

Cortical spreading depolarization (CSD) is the propagation of a relatively slow wave in cortical brain tissue that is linked to a number of pathological conditions such as stroke and migraine. Most of the existing literature investigates the dynamics of short term phenomena such as the depolarization and repolarization of membrane potentials or large ion shifts. Here, we focus on the clinically-relevant hour-long state of neurovascular malfunction in the wake of CSDs. This dysfunctional state involves widespread vasoconstriction and a general disruption of neurovascular coupling. We demonstrate, using a mathematical model, that dissolution of calcium that has aggregated within the mitochondria of vascular smooth muscle cells can drive an hour-long disruption. We determine the rate of calcium clearance as well as the dynamical implications on overall blood flow. Based on reaction stoichiometry, we quantify a possible impact of calcium phosphate dissolution on the maintenance of F0F1-ATP synthase activity.

Remodeling of calcium handling in skeletal muscle through PGC-1α: impact on force, fatigability, and fiber type

Regular endurance exercise remodels skeletal muscle, largely through the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). PGC-1α promotes fiber type switching and resistance to fatigue. Intracellular calcium levels might play a role in both adaptive phenomena, yet a role for PGC-1α in the adaptation of calcium handling in skeletal muscle remains unknown. Using mice with transgenic overexpression of PGC-1α, we now investigated the effect of PGC-1α on calcium handling in skeletal muscle. We demonstrate that PGC-1α induces a quantitative reduction in calcium release from the sarcoplasmic reticulum by diminishing the expression of calcium-releasing molecules. Concomitantly, maximal muscle force is reduced in vivo and ex vivo. In addition, PGC-1α overexpression delays calcium clearance from the myoplasm by interfering with multiple mechanisms involved in calcium removal, leading to higher myoplasmic calcium levels following contraction. During prolonged muscle activity, the delayed calcium clearance might facilitate force production in mice overexpressing PGC-1α. Our results reveal a novel role of PGC-1α in altering the contractile properties of skeletal muscle by modulating calcium handling. Importantly, our findings indicate PGC-1α to be both down- as well as upstream of calcium signaling in this tissue. Overall, our findings suggest that in the adaptation to chronic exercise, PGC-1α reduces maximal force, increases resistance to fatigue, and drives fiber type switching partly through remodeling of calcium transients, in addition to promoting slow-type myofibrillar protein expression and adequate energy supply.