Effects of glucose infusion on neuroendocrine and cognitive parameters in Addison disease

Sucrose intake has been shown to suppress increased adrenocorticotropic hormone (ACTH) levels in adrenalectomized rats, suggesting that increased cerebral energy supply can compensate for the loss of glucocorticoid feedback inhibition of the hypothalamo-pituitary-adrenal axis. We hypothesized that glucose infusion might acutely down-regulate increased ACTH secretion in patients with Addison disease. We studied 8 patients with primary adrenal insufficiency (Addison group) with short-term discontinuation of hydrocortisone substitution and 8 matched healthy controls in 2 randomized conditions. Subjects received either intravenous glucose infusion (0.75 g glucose per kilogram body weight for 2.5 hours) or placebo. Concentrations of ACTH, cortisol, catecholamines, growth hormone, glucagon, and insulin were measured; and cognitive functions as well as neuroglycopenic and autonomic symptoms were assessed. The ACTH concentrations were not affected by glucose infusion either in the Addison or in the control group. Likewise, concentrations of cortisol, epinephrine, norepinephrine, growth hormone, and glucagon remained unchanged in both groups. Neurocognitive performance and symptom scores were likewise not affected. Independent of glucose infusion, attention of the Addison patients was impaired in comparison with the control group. Our study in patients with Addison disease was not able to support the assumption of a compensatory effect of intravenous glucose infusion on hormonal parameters and neurocognitive symptoms in states of chronic cortisol deficiency. Further studies should examine whether different regimens of glucose administration are more effective.     

A 127 kb truncating deletion of PGRMC1 is a novel cause of X-linked isolated paediatric cataract

Inherited paediatric cataract is a rare Mendelian disease that results in visual impairment or blindness due to a clouding of the eye’s crystalline lens. Here we report an Australian family with isolated paediatric cataract, which we had previously mapped to Xq24. Linkage at Xq24–25 (LOD = 2.53) was confirmed, and the region refined with a denser marker map. In addition, two autosomal regions with suggestive evidence of linkage were observed. A segregating 127 kb deletion (chrX:g.118373226_118500408del) in the Xq24–25 linkage region was identified from whole-genome sequencing data. This deletion completely removed a commonly deleted long non-coding RNA gene LOC101928336 and truncated the protein coding progesterone receptor membrane component 1 (PGRMC1) gene following exon 1. A literature search revealed a report of two unrelated males with non-syndromic intellectual disability, as well as congenital cataract, who had contiguous gene deletions that accounted for their intellectual disability but also disrupted the PGRMC1 gene. A morpholino-induced pgrmc1 knockdown in a zebrafish model produced significant cataract formation, supporting a role for PGRMC1 in lens development and cataract formation. We hypothesise that the loss of PGRMC1 causes cataract through disrupted PGRMC1-CYP51A1 protein–protein interactions and altered cholesterol biosynthesis. The cause of paediatric cataract in this family is the truncating deletion of PGRMC1, which we report as a novel cataract gene.Subject terms: Genetic linkage study, Next-generation sequencing