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

Frank J Symons,Timothy J Feyma,Shawn X Y L Foster,Brian D Mcadams,William R Kennedy,Breanne J Byiers,Gwen Wendelschafer‐Crabb,Chantel C Barney

doi:10.1002/brb3.1285

Frank J Symons, Timothy J Feyma + Show 6 more

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https://doi.org/10.1002/brb3.1285

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Abstract

IntroductionRett 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.MethodsWe 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).ResultsConfocal 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.ConclusionsGiven 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.

Highlights

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)
There have been preclinical observations in a rodent model from the periphery documenting cutaneous hyperinnervation by nonpeptidergic sensory axons (Bhattacherjee et al, 2017). In part, on this finding, we designed a small clinically based discovery‐oriented study to test whether peripheral innervation in patients with RTT would show a similar pattern of hyperinnervation as that observed in the preclin‐ ical model
In addition to the tested epidermal nerve fiber density (ENFd) values as per our hypothesis, given reported clinical cutaneous/sensory and auto‐ nomic phenotypic features, we investigated Merkel cells (Figure 1 c,d), arteriole innervation (Figure 1 e,f), mast cells (Figure 1 g,h), and densely innervated hair follicles in RTT and healthy con‐ trols

Summary

| INTRODUCTION

Rett syndrome (RTT) is a rare neurodevelopmental disorder oc‐ curring primarily in females (1:10–15,000 female live births) most often caused by loss‐of‐function mutations in the X‐linked methyl‐ CpG‐binding protein 2 gene (MECP2; Amir et al, 1999). There are well‐documented clinical observations and emerging preclin‐ ical findings consistent with abnormal cutaneous sensitivity sug‐ gesting disrupted sensory function. A subsequent report on four additional cases from sural and tibial nerve showed intact myelinated fibers, but a possible relative increase in small unmyelinated axons (Jellinger, Armstrong, Zoghbi, & Percy, 1988). There have been preclinical observations in a rodent model from the periphery documenting cutaneous hyperinnervation by nonpeptidergic sensory axons (Bhattacherjee et al, 2017). In part, on this finding, we designed a small clinically based discovery‐oriented study to test whether peripheral innervation in patients with RTT would show a similar pattern of hyperinnervation as that observed in the preclin‐ ical model. We explored additional peripheral markers with relevance to somatosensory and nociceptive function

| METHODS

| DISCUSSION

Findings

CONFLICT OF INTEREST