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

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

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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.

Original languageEnglish (US)
Article numbere01285
JournalBrain and Behavior
Issue number5
StatePublished - May 2019


  • MECP2
  • Rett syndrome
  • epidermal nerve fiber innervation
  • sensory phenotype

PubMed: MeSH publication types

  • Journal Article

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    Symons, F. J., Barney, C. C., Byiers, B. J., McAdams, B. D., Foster, S. X. Y. L., Feyma, T. J., Wendelschafer-Crabb, G., & Kennedy, W. R. (2019). A clinical case–control comparison of epidermal innervation density in Rett syndrome. Brain and Behavior, 9(5), [e01285]. https://doi.org/10.1002/brb3.1285