Natural History of the Inherited Neuropathies (Project 1)

点击翻译按钮获取中文摘要

Abstract Charcot Marie Tooth diseases (CMT) are heritable peripheral neuropathies and are the most common genetic neuromuscular disease, affecting 1:2500 individuals. CMT1A is the most common subtype, affecting approximately 1:4000 patients with CMT, caused by a recurring 1.4 Mb duplication within chromosome 17p11.2 in the region containing the PMP22 gene. CMTX1 (1:25,000), CMT1B (1:36,000) and CMT2A (1:36,000) are the next most frequent forms and are caused by many different mutations in the GJB1, MPZ and MFN2 genes respectively. Recent progress on these four forms of CMT has led to clinical trials that have begun or will be ready to begin in the upcoming RDCRN cycle. Although the severity may vary in between patients, individual CMT patients often progress slowly, so that sensitive outcome measures and biomarkers are needed for clinical trials. The Inherited Neuropathy Consortium (INC) has developed clinical outcome assessments (COAs) - including the Rasch modified CMT Neuropathy or Exam Scores (CMTNS-R/CMTES-R) and the CMT Pediatric Score (CMTPedS) - that can measure progression in adults and children with CMT1A within a two-year interval. The INC has recently developed patient reported outcomes (PROs) to measure disease burden (CMT Health Index; CMT-HI) and functional outcome measures (CMT-FOM) in adults. INC sites have also shown that the intramuscular fat accumulation (IMFA) fraction of calf muscles measured by MRI increases over 12 months in patients with CMT1A, as a sensitive marker of chronic denervation of muscle, and this has been confirmed in a collaboration between our London and Iowa sites. The London site also demonstrated that plasma levels of neurofilament light (NFL), a measure of axonal degeneration, are elevated and correlate with severity in CMT1A. In collaboration with Dr. Svaren, a member of the INC External Advisory Committee (EAC) from the University of Wisconsin, our Iowa site demonstrated that PMP22 mRNA and other Schwann cell genes are increased in skin biopsies from patients with CMT1A compared to controls. We believe that the INC is uniquely situated to now integrate these various COAs in longitudinal studies, and that this will enable high quality clinical trials in CMT1A, CMTX1 CMT1B, and CMT2A as well as in rarer forms of CMT, all of which may be amenable to therapy in the upcoming RDCRN cycle. In Clinical Research Project 1 we propose to (1) Complete the longitudinal analysis of COA and biomarkers in adults and children with CMT1A, (2) Determine the relative responsiveness of our prior and novel COAs CMTES-R, CMT-FOM and CMT-HI on a yearly basis for subjects with CMTX1, CMT1B and CMT2A, and (3) Determine the relative responsiveness of the COA CMTES-R, CMT-FOM and CMT-HI on a yearly basis for subjects with rare forms of CMT. We believe that completion of these aims will enable clinical trials for the more common as well as rare forms of CMT.