Biomarkers predict outcome in Charcot-Marie-Tooth disease 1A

J Neurol Neurosurg Psychiatry. 2017 Nov;88(11):941-952. doi: 10.1136/jnnp-2017-315721. Epub 2017 Aug 31.


Background: Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited neuropathy, a debilitating disease without known cure. Among patients with CMT1A, disease manifestation, progression and severity are strikingly variable, which poses major challenges for the development of new therapies. Hence, there is a strong need for sensitive outcome measures such as disease and progression biomarkers, which would add powerful tools to monitor therapeutic effects in CMT1A.

Methods: We established a pan-European and American consortium comprising nine clinical centres including 311 patients with CMT1A in total. From all patients, the CMT neuropathy score and secondary outcome measures were obtained and a skin biopsy collected. In order to assess and validate disease severity and progression biomarkers, we performed qPCR on a set of 16 animal model-derived potential biomarkers in skin biopsy mRNA extracts.

Results: In 266 patients with CMT1A, a cluster of eight cutaneous transcripts differentiates disease severity with a sensitivity and specificity of 90% and 76.1%, respectively. In an additional cohort of 45 patients with CMT1A, from whom a second skin biopsy was taken after 2-3 years, the cutaneous mRNA expression of GSTT2, CTSA, PPARG, CDA, ENPP1 and NRG1-Iis changing over time and correlates with disease progression.

Conclusions: In summary, we provide evidence that cutaneous transcripts in patients with CMT1A serve as disease severity and progression biomarkers and, if implemented into clinical trials, they could markedly accelerate the development of a therapy for CMT1A.

Keywords: Charcot Marie Tooth disease 1A; biomarker; disease progression; disease severity; skin biopsy.

MeSH terms

  • Adult
  • Aged
  • Biopsy
  • Cathepsin A / genetics
  • Charcot-Marie-Tooth Disease / blood
  • Charcot-Marie-Tooth Disease / genetics
  • Charcot-Marie-Tooth Disease / therapy*
  • Disease Progression*
  • Female
  • Genetic Markers / genetics*
  • Glutathione Transferase / genetics
  • Glycoproteins / genetics
  • Humans
  • Male
  • Middle Aged
  • Neuregulin-1 / genetics
  • Nuclear Proteins
  • PPAR gamma / genetics
  • Phosphoric Diester Hydrolases / genetics
  • Prognosis
  • Pyrophosphatases / genetics
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Skin / pathology*
  • Transcription, Genetic / genetics
  • Treatment Outcome*


  • CDAN1 protein, human
  • Genetic Markers
  • Glycoproteins
  • NRG1 protein, human
  • Neuregulin-1
  • Nuclear Proteins
  • PPAR gamma
  • RNA, Messenger
  • GSTT2 protein, human
  • Glutathione Transferase
  • Phosphoric Diester Hydrolases
  • ectonucleotide pyrophosphatase phosphodiesterase 1
  • CTSA protein, human
  • Cathepsin A
  • Pyrophosphatases