Cortisol profiles and clinical severity in MECP2 duplication syndrome

Sarika U Peters,Jeffrey L Neul,Douglas A Granger,Cary Fu

doi:10.1186/s11689-020-09322-5

Abstract

BackgroundMECP2 duplication syndrome (MDS) is a rare X-linked genomic disorder primarily affecting males which is caused by interstitial chromosomal duplications at Xq28 encompassing the MECP2 gene. Core clinical features of MDS include choreiform movements, progressive spasticity, recurrent respiratory infections, developmental delays in the first 6 months of life, hypotonia, vasomotor disturbances, constipation, drooling, and bruxism. Prior studies suggest that HPA axis activity may be altered in MDS and measures of HPA axis activity may offer insight into disease severity.MethodsTo ascertain whether cortisol profiles are a potential biomarker of clinical severity, diurnal profiles of cortisol and the cortisol awakening response were examined from saliva samples in 31 participants with MDS (ages 2–24 years), and 27 of these samples were usable. Documentation of a positive diagnostic test for MECP2 duplication was required for entry into the study. Samples were collected on each of two consecutive weekdays at four time points during the day: immediately after waking, 30 min after waking, between 3 and 4 PM, and in the evening before bedtime. Correlations with duplication size, clinical severity, sleep problems, and behavior were also examined.ResultsResults revealed that a majority of participants with MDS exhibit a declining cortisol awakening response (n = 17). A declining CAR was significantly associated with increased clinical severity scores (r = − .508; p = .03), larger duplication size, waking later, and an increased number of hospitalizations for infections.ConclusionsFuture mechanistic studies will have to determine whether the declining CAR in MDS is attributable to problems with “flip-flop switching” of regional brain activation (involving the suprachiasmatic nucleus and the hippocampus, and the HPA axis) that is responsible for the switch from reduced to increased adrenal sensitivity. Taken together, results suggest the possibility that cortisol profiles could potentially be a biomarker of clinical severity and utilized for the purposes of patient stratification for future clinical trials in MDS.

Highlights

MECP2 duplication syndrome (MDS) is a rare X-linked genomic disorder primarily affecting males which is caused by interstitial chromosomal duplications at Xq28 encompassing the MECP2 gene [1]
We discovered duplication size and specific gene content play a role in clinical severity [3]
Individuals with MECP2 duplication syndrome who had not experienced regression showed more typical patterns of higher cortisol levels in the morning with linear decreases throughout the day. To expand on this initial work, and to begin to ascertain whether cortisol profiles are a potential biomarker of clinical severity, we examine diurnal profiles of cortisol and the cortisol awakening response (CAR) in participants with MDS and examine relationships with duplication size, clinical severity, sleep problems, and behavior

Summary

Introduction

MECP2 duplication syndrome (MDS) is a rare X-linked genomic disorder primarily affecting males which is caused by interstitial chromosomal duplications at Xq28 encompassing the MECP2 gene [1] This gene encodes methyl CpG binding protein 2 (MeCP2), a regulator of neuronal gene transcription that is required for normal. MECP2 duplication syndrome (MDS) is a rare X-linked genomic disorder primarily affecting males which is caused by interstitial chromosomal duplications at Xq28 encompassing the MECP2 gene. Prior studies suggest that HPA axis activity may be altered in MDS and measures of HPA axis activity may offer insight into disease severity

Methods

Results

Discussion

Conclusion