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.

Preliminary Evidence That Resting State Heart Rate Variability Predicts Reactivity to Tactile Stimuli in Rett Syndrome

“…Although quantitative sensory testing does not localize pathology along the somatosensory axis, our preliminary observations specific to small unmyelinated fibers indicate possible peripheral involvement based on epidermal nerve density values consistent with the preclinical model. 22,23 The lack of response to heat stimulus, along with repeated mechanical stimulation being the highest score, were similar to those in preclinical experimental models at the sensory modality (mechanical, heat) construct level, though we did not see the same patterns for cool and pressure. 22,24 There are important procedural differences in specificity and precision, though.…”

Protective role of mirtazapine in adult female Mecp2+/− mice and patients with Rett syndrome

“…Two recent studies showed marked skin hyperinnervation [59], and mechanical hypersensitivity in one male rat model proposed to study RTT, and somatosensory and viscerosensory alteration in female rats of the same model [59,60]. In striking agreement, another study demonstrated increased sensory fiber innervation in skin biopsies from RTT patients [61]. In RTT people, somatosensory disturbances may range from elevated pain threshold or heat insensitivity [62] to hypersensitivity [63,64].…”

Peripheral Somatosensory Neuron Dysfunction: Emerging Roles in Autism Spectrum Disorders

“…In line with these rodent studies, a recent paper investigated potential abnormalities in peripheral somatosensory neuron innervation of the skin in patients with Rett syndrome. Skin biopsies from subjects with Rett syndrome exhibited an increased number of total epidermal sensory neuron fiber density as well as increased density of peptidergic, calcitonin gene-related peptide-positive fibers (Symons et al, 2019). Lastly, hyperexcitability of trigeminal neurons that innervate the jaw and facial muscles has also been observed in Mecp2 knockout mice, which was linked to alterations in sodium and potassium channel function (Oginsky et al, 2017).…”