A clinical case–control comparison of epidermal innervation density in Rett syndrome

Abstract

Introduction: Rett syndrome (RTT), a rare neurodevelopmental disorder occurring primarily in females (1:10–15,000 female live births), is most often caused by loss-of-function mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). Clinical observations and preclinical findings indicate apparent abnormal sensory and nociceptive function. There have been no direct investigations of epidermal sensory innervation in patients with RTT. Methods: We compared 3 mm epidermal punch biopsy specimens from adolescent female RTT patients (N = 4, aged 12–19 years) against an archived approximate age-, sex-, body-site matched comparison sample of healthy adolescent females (N = 8, ages 11–17). Results: Confocal imaging revealed, on average, statistically significant increased epidermal nerve fiber (ENF) peptidergic (co-stained calcitonin gene-related protein [CGRP]) innervation density compared with healthy female control individuals. Conclusions: Given the clinical phenotype of disrupted sensory function along with diagnostic criteria specific to cold hands/feet and insensitivity to pain, our preliminary observations of ENF peptidergic fiber density differences warrants further investigation of the peripheral neurobiology in RTT.