More than 70 different genes have been identified to cause the various forms of CMT. For the demyelinating forms of CMT, a genetic cause can be found most of the time, with CMT1A (PMP22 duplication) explaining ~70% of these cases. In contrast, a mutation in one of the currently known genes can be found in less than 40% of axonal (CMT2) cases, mostly for the severe, early onset cases. Genetic studies have fundamentally transformed our knowledge on CMT and have catalyzed much of the research in neuropathies in the past 20 years. We fully expect that by taking advantage of new technologies, this progress will continue to a point where (1) >90% of CMT1 and CMT2 patients can receive a genetic diagnosis;(2) a sizable number of important genetic modifiers that account for a significant portion of the phenotypic variability in some forms of CMT will be identified;(3) a proportion of the heretofore idiopathic/sporadic neuropathies will be found to have a genetic cause;(4) genetic risk factors for developing neuropathy to diabetes and various medications will be identified. The members of the INC consortium work in a collaborative manner with multiple sources of funding to achieve these goals. In particular, the INC has allowed us to collect high-quality samples for reliable gene modifier studies, as demonstrated by our results on a CMT1A study. In this renewal, we propose to expand our efforts to find new genes that cause CMT and genetic modifiers of CMT. These modifiers will be important targets for intervention, and may well be important in the manifestations of acquired peripheral neuropathies, and even other diseases, such as amyotrophic lateral sclerosis (ALS) and multiple sclerosis, in which axonal degeneration has been implicated in the pathogenesis. Finally, as our collaborative group and others move rapidly towards genomic approaches, we will establish a unified, secure, and accessible resource for all genomic data of the INC that will be open to all CMT researchers, that can also serve as a blueprint for other RDCRN groups interested in inherited diseases.

Public Health Relevance

Clinical Research Project 2 provides the mechanism to identify novel genetic causes of CMT and identify modifier genes that alter the natural history of CMT, both of which are among the most important goals of the INC. Achieving these goals requires large numbers of well characterized patients with common and rare forms of inherited neuropathies that can only be obtained through an international consortium of expert investigators and experts in Next Generation Sequencing such as exist in the INC.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZTR1)
Program Officer
Gwinn, Katrina
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Iowa
Iowa City
United States
Zip Code
Rebelo, Adriana P; Abrams, Alexander J; Cottenie, Ellen et al. (2016) Cryptic Amyloidogenic Elements in the 3' UTRs of Neurofilament Genes Trigger Axonal Neuropathy. Am J Hum Genet 98:597-614
Rossor, Alexander M; Tomaselli, Pedro J; Reilly, Mary M (2016) Recent advances in the genetic neuropathies. Curr Opin Neurol 29:537-48
Merkel, Peter A; Manion, Michele; Gopal-Srivastava, Rashmi et al. (2016) The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network. Orphanet J Rare Dis 11:66
Auer-Grumbach, Michaela; Toegel, Stefan; Schabhüttl, Maria et al. (2016) Rare Variants in MME, Encoding Metalloprotease Neprilysin, Are Linked to Late-Onset Autosomal-Dominant Axonal Polyneuropathies. Am J Hum Genet 99:607-23
Hu, Bo; Arpag, Sezgi; Zuchner, Stephan et al. (2016) A novel missense mutation of CMT2P alters transcription machinery. Ann Neurol 80:834-845
Lunn, Michael P; Ellis, Lauren; Hadden, Robert D et al. (2016) A proposed dosing algorithm for the individualized dosing of human immunoglobulin in chronic inflammatory neuropathies. J Peripher Nerv Syst 21:33-7
Mademan, Inès; Harmuth, Florian; Giordano, Ilaria et al. (2016) Multisystemic SYNE1 ataxia: confirming the high frequency and extending the mutational and phenotypic spectrum. Brain 139:e46
Begg, Lindy; McLaughlin, Patrick; Vicaretti, Mauro et al. (2016) Total contact cast wall load in patients with a plantar forefoot ulcer and diabetes. J Foot Ankle Res 9:2
Manole, Andreea; Chelban, Viorica; Haridy, Nourelhoda A et al. (2016) Severe axonal neuropathy is a late manifestation of SPG11. J Neurol 263:2278-2286
Motley, William W; Palaima, Paulius; Yum, Sabrina W et al. (2016) De novo PMP2 mutations in families with type 1 Charcot-Marie-Tooth disease. Brain 139:1649-56

Showing the most recent 10 out of 136 publications