# Natural History of the Inherited Neuropathies (Project 1)

> **NIH NIH U54** · UNIVERSITY OF IOWA · 2021 · $238,970

## Abstract

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.

## Key facts

- **NIH application ID:** 10254264
- **Project number:** 5U54NS065712-14
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** MICHAEL E. SHY
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $238,970
- **Award type:** 5
- **Project period:** 2009-09-30 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10254264

## Citation

> US National Institutes of Health, RePORTER application 10254264, Natural History of the Inherited Neuropathies (Project 1) (5U54NS065712-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10254264. Licensed CC0.

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