Relation between circulating levels of GH, IGF-1, ghrelin and somatic growth in Rett syndrome

Background: Most cases of Rett syndrome (RTT) are caused by mutations in methyl CpG binding protein 2 (MECP2), and individuals with RTT have somatic growth failure, growth arrest of brain, epilepsy, and intellectual disability (ID). Ghrelin is a peptide hormone which stimulates growth hormone (GH) secretion from the pituitary gland. Ghrelin and GH regulate insulin-like growth factor-1 (IGF-1) synthesis, and this GH/IGF-1 axis is an endocrine axis involved in energy and sleep homeostasis and plays crucial roles in somatic and brain growth. This study aimed to determine whether circulating ghrelin, GH and IGF-1 reflect somatic and brain growth in RTT patients. Methods: We examined anthropometric data and circulating ghrelin, GH, and IGF-1 in 22 female RTT patients with epilepsy and ID (RTT-Ep/ID) and 14 age-matched females with epilepsy and ID (non-RTT-Ep/ID). Results: Body mass index (BMI) and height/length were significantly lower in RTT-Ep/ID than in non-RTT-Ep/ID in patients less than 20 years old. Plasma ghrelin in RTT-Ep/ID patients showed a significant inverse correlation with weight but had no significant correlations with BMI or height. Head circumference in both groups showed a significant positive correlation with circulating ghrelin and a significant negative correlation with circulating IGF-1. The ratio of octanoyl-ghrelin to total-ghrelin (O/T-ratio) is used as an indicator to estimate the biological activity of ghrelin. Among pre-adolescents, O/T-ratios were significantly higher in the RTT-Ep/ ID group than in the non-RTT-Ep/ID group (P < 0.05). Conclusions: Timing of growth-spurts differed between the RTT-Ep/ID and non-RTT-Ep/ID groups, possibly due to a common (but yet unknown) mechanism of growth failure. Ghrelin/GH/IGF-1 axis function was aberrant in both the RTT-Ep/ID and non-RTT-Ep/ID groups. The initial clinical course of Rett syndrome affects the development of the sleep–wake cycle and locomotion in early infancy, both of which may be based on the dysfunction of the aminergic neurons modulated by ghrelin/GH/IGF-1 axis. Further study with a larger sample size should help clarify the precise mechanisms controlling the somatic growth and hormonal features in Rett syndrome.