Clinical and Molecular Assessment in a Female with Fragile X Syndrome and Tuberous Sclerosis

Details

• Alternative Title:
  J Genet Disord Genet Rep
• Personal Author:
  Yrigollen, Carolyn M ; Pacini, Laura ; Nobile, Veronica ; Lozano, Reymundo ; Hagerman, Randi J. ; Bagni, Claudia ; Tassone, Flora
• Description:
  Objective
  
  Fragile X syndrome (FXS) and tuberous sclerosis (TSC) are genetic disorders that result in intellectual disability and an increased prevalence of autism spectrum disorders (ASD). While the clinical presentation of each disorder is distinct, the molecular causes are linked to a disruption in the mTORC1 (mammalian Target of Rapamycin Complex 1) and ERK1/2 (Extracellular signal-Regulated Kinase) signaling pathways.
  
  Methods
  
  We assessed the clinical and molecular characteristics of an individual seen at the UC Davis MIND Institute with a diagnosis of FXS and TSC. Clinical evaluation of physical, behavioral, and cognitive impairments were performed. Additionally, total and phosphorylated proteins along the mTORC1 and ERK1/2 pathways were measured in primary fibroblast cell lines from the proband.
  
  Results
  
  In this case the phenotypic effects that result in a human with both FXS and TSC are shown to be severe. Changes in mTORC1 and ERK1/2 signaling proteins and global protein synthesis were not found to be noticeably different between four cohorts (typically developing, FMR1 full mutation, FMR1 full mutation and TSC1 loss of function mutation, and TSC1 loss of function mutation); however cohort sizes prevented stringent comparisons.
  
  Conclusion
  
  It has previously been suggested that disruption of the mTORC1 pathway was reciprocal in TSC and FXS double knock-out mouse models so that the regulation of these pathways were more similar to wild-type mice compared to mice harboring a Fmr1−/y or Tsc2−/+ mutation alone. However, in this first reported case of a human with a diagnosis of both FXS and TSC, substantial clinical impairments, as a result of these two disorders were observed. Differences in the mTORC and ERK1/2 pathways were not clearly established when compared between individuals with either disorder, or both.
  
  
• Keywords:
  ERK1/2 Fragile X Syndrome MTORC1 Protein Synthesis Tuberous Sclerosis
• Source:
  J Genet Disord Genet Rep. 5(3)
• Pubmed ID:
  28232951
• Pubmed Central ID:
  PMC5319728
• Document Type:
  Journal Article
• Funding:
  P30 HD002274/HD/NICHD NIH HHSUnited States/ ; R01 HD036071/HD/NICHD NIH HHSUnited States/ ; U50 DD000596/DD/NCBDD CDC HHSUnited States/
• Volume:
  5
• Issue:
  3
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:0524a32d3d6c5b141fc6ce0de5e30afd857a22ccbdf3dab96e9aa0a7e41bf5f3
• Download URL:
  https://stacks.cdc.gov/view/cdc/158003/cdc_158003_DS1.pdf
• File Type:
  [PDF - 840.90 KB ]