Normalization of serum calcium by cinacalcet in a patient with hypercalcaemia due to a de novo inactivating mutation of the calcium‐sensing receptor

Abstract

. Familial benign hypocalciuric hypercalcaemia (FHH) results from a heterozygous inactivating mutation of the calcium‐sensing receptor (CaR) and is characterized by hypercalcaemia, hypocalciuria and inappropriately normal plasma levels of parathyroid hormone. In a minority of patients, a loss of function mutation of the CaR results in severe hypercalcaemia associated with complications for which no effective surgical or medical treatment is available. We investigated the effects of the calcimimetic agent cinacalcet, an allosteric modulator of the CaR, in a 26‐year‐old man presenting with hypercalcaemia due to a de novo inactivating mutation of the CaR. Complicating features were recurrent psychosis and progressive severe osteoporosis. A single dose of either 30 or 60 mg of cinacalcet resulted in a 63–88% decline in plasma parathyroid hormone levels within 2 h of administration of the agent, reverting to baseline levels after 12 h. Normalization of serum calcium was more gradual but sustained for up to 12 months of treatment with a maintenance twice‐daily oral dose of 60 + 30 mg cinacalcet. In addition to its beneficial effects in primary and secondary hyperparathyroidism, cinacalcet may open new therapeutic avenues in the management of a subset of patients with severe hypercalcaemia due to inactivating mutations of the CaR.

Effect of the Calcimimetic R-568 [3-(2-Chlorophenyl)-N-((1R)-1-(3-methoxyphenyl)ethyl)-1-propanamine] on Correcting Inactivating Mutations in the Human Calcium-Sensing Receptor

“…For instance, we found that R-568 was able to potentiate orthosteric agonist potency and maximal agonist response of F809L, R185Q, F180C, P39A, Y218C, and L13P mutant hCaSRs that have been described in the literature (Aida et al, 1995;Heath et al, 1996;Bai et al, 1997;Chikatsu et al, 1999;Cetani et al, 2003;Miyashiro et al, 2004;Timmers et al, 2006;Zajickova et al, 2007). It is interesting to note that the L13P mutation occurs in the 19 amino acid signal peptides of the hCaSR.…”

“…shown to be an effective therapy for the treatment of a patient suffering from a heterozygous de novo inactivating mutation in the hCaSR in which phenylalanine at position 809 was replaced by leucine (Timmers et al, 2006). The patient harboring this mutation presented symptoms of hypercalcemia, elevated PTH, osteoporosis, and recurrent psychosis.…”

“…Our interest in inactivating mutations of the hCaSR was prompted by a recent report in which a 26-year-old male patient was found to suffer from persistent hyperparathyroidism, hypercalcemia, and osteoporosis (Timmers et al, 2006). The patient was diagnosed with FHH after sequence analysis revealed a heterozygous de novo mutation in which phenylalanine at position 809 was changed to leucine (F809L) in the hCaSR gene.…”

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

“…Two reports studied the dynamics of calcium and PTH after a single oral dose of cinacalcet in FHH type 1 patients. A significant decrease of PTH was detected as early as 2 h and effects on serum calcium were seen 8-48 h after the administration of cinacalcet (59,62,63). If clinically relevant the rapid effect of cinacalcet on PTH may be used to quickly assess the effectiveness of cinacalcet in individual patients (see below).…”

A novel germline inactivating mutation in the CASR gene in an Italian kindred affected by familial hypocalciuric hypercalcemia

“…Indeed, in FHH patients, the need for a very detailed clinical data collection is urgently felt. This would make possible in the future to describe clinical entities, possibly associated with this disease, such as psychotic symptoms (18).…”