TY - JOUR
T1 - Biomarkers predict outcome in Charcot-Marie-Tooth disease 1A
AU - Fledrich, Robert
AU - Mannil, Manoj
AU - Leha, Andreas
AU - Ehbrecht, Caroline
AU - Solari, Alessandra
AU - Pelayo-Negro, Ana L.
AU - Berciano, José
AU - Schlotter-Weigel, Beate
AU - Schnizer, Tuuli J.
AU - Prukop, Thomas
AU - Garcia-Angarita, Natalia
AU - Czesnik, Dirk
AU - Haberlová, Jana
AU - Mazanec, Radim
AU - Paulus, Walter
AU - Beissbarth, Tim
AU - Walter, Maggie C.
AU - Hogrel, Jean Yves
AU - Dubourg, Odile
AU - Schenone, Angelo
AU - Baets, Jonathan
AU - De Jonghe, Peter
AU - Shy, Michael E.
AU - Horvath, Rita
AU - Pareyson, Davide
AU - Seeman, Pavel
AU - Young, Peter
AU - Sereda, Michael W.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - 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.
AB - 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.
KW - biomarker
KW - Charcot Marie Tooth disease 1A
KW - disease progression
KW - disease severity
KW - skin biopsy
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U2 - 10.1136/jnnp-2017-315721
DO - 10.1136/jnnp-2017-315721
M3 - Article
C2 - 28860329
AN - SCOPUS:85031708881
VL - 88
SP - 941
EP - 952
JO - Journal of Neurology, Neurosurgery and Psychiatry
JF - Journal of Neurology, Neurosurgery and Psychiatry
SN - 0022-3050
IS - 11
ER -