Endocrine and behavioural features of Lowe syndrome and their potential molecular mechanisms.

Abstract

Lowe syndrome (LS) is an X linked disease caused by pathogenic variants in the <i>OCRL</i> gene that impacts approximately 1 in 500 000 children. Classic features include congenital cataract, cognitive/behavioural impairment and renal tubulopathy. This study is a retrospective review of clinical features reported by family based survey conducted by Lowe Syndrome Association. Frequency of non-ocular clinical feature(s) of LS and their age of onset was summarised. An LS-specific therapy effectiveness scale was used to assess the response to the administered treatment. Expression of <i>OCRL</i> and relevant neuropeptides was measured in postmortem human brain by qPCR. Gene expression in the mouse brain was determined by reanalysis of publicly available bulk and single cell RNA sequencing. A total of 137 individuals (1 female, 89.1% white, median age 14 years (range 0.8-56)) were included in the study. Short stature (height <3rd percentile) was noted in 81% (n=111) individuals, and 15% (n=20) received growth hormone therapy. Undescended testis was reported in 47% (n=64), and median age of onset of puberty was 15 years. Additional features were dental problems (n=77, 56%), bone fractures (n=63, 46%), hypophosphataemia (n=60, 44%), developmental delay and behavioural issues. <i>OCRL</i> is expressed in human and mouse hypothalami, and in hypothalamic cell clusters expressing <i>Ghrh</i>, <i>Sst</i>, <i>Oxt</i>, <i>Pomc</i> and pituitary cells expressing <i>Gh</i> and <i>Prl</i>. There is a wide spectrum of the clinical phenotype of LS. Some of the features may be partly driven by the loss of function of <i>OCRL</i> in the hypothalamus and the pituitary.