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

Brain Behav. 2019 May;9(5):e01285. doi: 10.1002/brb3.1285. Epub 2019 Apr 13.


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.

Keywords: MECP2; Rett syndrome; epidermal nerve fiber innervation; sensory phenotype.

MeSH terms

  • Adolescent
  • Biopsy / methods
  • Calcitonin Gene-Related Peptide / metabolism
  • Child
  • Female
  • Humans
  • Methyl-CpG-Binding Protein 2 / genetics
  • Microscopy, Confocal / methods
  • Nociception / physiology*
  • Peripheral Nervous System* / pathology
  • Peripheral Nervous System* / physiopathology
  • Phenotype
  • Rett Syndrome* / diagnosis
  • Rett Syndrome* / metabolism
  • Rett Syndrome* / physiopathology
  • Sensory Receptor Cells* / metabolism
  • Sensory Receptor Cells* / pathology
  • Skin* / innervation
  • Skin* / pathology
  • Young Adult


  • MECP2 protein, human
  • Methyl-CpG-Binding Protein 2
  • Calcitonin Gene-Related Peptide