An update on clinical presentation and responses to therapy of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH).

Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics and Genomics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.

Expression of vasopressin mRNA in the hypothalamus of individuals with a diagnosis of schizophrenia.

OBJECTIVE: This study investigates the expression of mRNA encoding vasopressin in the hypothalamus of autopsy brains of individuals diagnosed with schizophrenia. METHODS: Ten brains of individuals with schizophrenia and 10 brains from individuals without any disease were examined during autopsy. The hypothalamic block was dissected and immersion fixed in paraformaldehyde, sucrose substituted, frozen, and cut into 20-µm-thick coronal cryostat sections. The sections were hybridized with an S-35-labeled DNA antisense oligo probe and after washing covered by an X-ray film. The hybridization signals on the films were transferred to a computer and densitometrically quantified. RESULTS: The densitometry signals showed a statistically significant lower mRNA expression (53% decrease; p = 0.014) in the paraventricular nucleus of the individuals with schizophrenia compared to the controls. In the supraoptic nucleus, the decrease in the group with schizophrenia was 39% compared to the controls, but this decrease was not statistically significant (p = 0.194). CONCLUSIONS: Our results show a low expression of mRNA encoding vasopressin in the paraventricular nucleus of the individuals with schizophrenia. We suggest that vasopressin is not directly involved in the pathogenesis of schizophrenia, but might influence schizophrenic symptoms via vasopressin receptors located in the social behavioral neural network in the forebrain.

The accessory magnocellular neurosecretory system of the rostral human hypothalamus.

The morphology and neurophysin expression of the magnocellular accessory neuroendocrine system located in the rostral human hypothalamus is investigated in a series of brains obtained at autopsy. The hypothalami were fixed in formalin and embedded in paraffin, or after cryoprotection, frozen for cryostat sectioning. Paraffin sections were either stained with Luxol Fast blue or immunoreacted for neurophysin I or neurophysin II, the precursor molecule for oxytocin and vasopressin. Further, 50-µm-thick serial cryostat sections were immunoreacted with the same antibodies. Both the paraventricular and supraoptic nuclei as well as the hypothalamo-hypophysial tracts exhibited strong immunoreactivity for the neurophysin antibodies. In addition, large collections of immunoreactive accessory magnocellular nuclei and single scattered neurophysin-positive neurons were located in the preoptic region between the paraventricular and supraoptic nucleus among the hypothalamo-hypophysial nerve fibers. In addition, smaller collections of neurophysin-immunoreactive neurons were located in the basal part of this region. Among the accessory magnocellular nuclei, the classical circular nucleus was identified. Accessory magnocellular neurons were often located along the blood vessels and projections of some of these neurons penetrated the vascular endothelium. The accessory magnocellular cell bodies expressed either neurophysin I or neurophysin II immunoreactivity. Summarizing, the accessory magnocellular system in the human brain is large and differs in morphology compared to the system seen in other vertebrates. The neurons of this system contain both vasopressin and oxytocin. Some neurons of the accessory neuronal systems might secrete vasopressin or oxytocin directly into the blood stream.