PILOT PROJECTS Despite scientific advances into the pathogenesis of CMT1, CMT2 and CMT4 there are no successful treatments for any of the subtypes that comprise these three groups of inherited neuropathy. In part this is because progression is often slow, sensitive biomarkers to detect disease progression are not yet available, and emerging outcome instruments have not yet been tested in trials. To address these issues we propose three Pilot Projects, two of which are novel and one of which is a continuation of a previous project. Pilot Project 1 will contain two projects. First, in collaboration with the MRC Neuromuscular Centre in London, we will evaluate an MRC funded and developed MRI technique as a potential multicenter biomarker to detect progression in CMT1. Secondly we will evaluate novel quantitative sensory measures as potential biomarkers for CMT1A. These studies will enable us to determine whether MRI and tactile measures can be used as an outcome measure for patients with CMT1A, the most common form of CMT. Results will also serve as a comparison for studies in other forms of CMT. Pilot Project 2 will investigate the potential utility of skin biopsy for CMT. We will perform RT- PCR studies in skin biopsies of CMT1A to correlate changes between the animal models and patients with CMT1A to determine whether biopsies can be used as biomarkers in trials and natural history studies. We will evaluate morphological abnormalities in myelinated dermal nerves from skin biopsies from CMT1A, CMT1B, CMT1X and CMT2A to determine whether there are morphological markers of severity and progression in the four most common genetic subtypes of CMT. Finally, we will generate, grow and freeze down fibroblasts from skin biopsies from CMT patients for assays and for development into immortalized pluripotential stem cells (iPSC). These fibroblasts will be made available to investigators within and outside of the INC RDCRC. Pilot Project 3 is a continuation of Pilot Project 3 from our original funding cycle. It will investigate safety and provide preliminary data to determine the potential effects of a curcumin derivative to slow disease progression in patients with CMT1B. The project will also allow us to evaluate our two recent outcome instruments, CMTPedS and CMTNSv2 in trials with children and adults.
| Rebelo, Adriana P; Saade, Dimah; Pereira, Claudia V et al. (2018) SCO2 mutations cause early-onset axonal Charcot-Marie-Tooth disease associated with cellular copper deficiency. Brain 141:662-672 |
| Abbott, Jamie A; Meyer-Schuman, Rebecca; Lupo, Vincenzo et al. (2018) Substrate interaction defects in histidyl-tRNA synthetase linked to dominant axonal peripheral neuropathy. Hum Mutat 39:415-432 |
| Abrams, Alexander J; Fontanesi, Flavia; Tan, Natalie B L et al. (2018) Insights into the genotype-phenotype correlation and molecular function of SLC25A46. Hum Mutat 39:1995-2007 |
| Sandelius, Åsa; Zetterberg, Henrik; Blennow, Kaj et al. (2018) Plasma neurofilament light chain concentration in the inherited peripheral neuropathies. Neurology 90:e518-e524 |
| Lassuthova, Petra; Rebelo, Adriana P; Ravenscroft, Gianina et al. (2018) Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2. Am J Hum Genet 102:505-514 |
| Panosyan, Francis B; Kirk, Callyn A; Marking, Devon et al. (2018) Carpal tunnel syndrome in inherited neuropathies: A retrospective survey. Muscle Nerve 57:388-394 |
| Synofzik, Matthis; Helbig, Katherine L; Harmuth, Florian et al. (2018) De novo ITPR1 variants are a recurrent cause of early-onset ataxia, acting via loss of channel function. Eur J Hum Genet 26:1623-1634 |
| Shy, Michael E (2018) Antisense oligonucleotides offer hope to patients with Charcot-Marie-Tooth disease type 1A. J Clin Invest 128:110-112 |
| Jerath, Nivedita U; Mankodi, Ami; Crawford, Thomas O et al. (2018) Charcot-Marie-Tooth Disease type 4C: Novel mutations, clinical presentations, and diagnostic challenges. Muscle Nerve 57:749-755 |
| Tomaselli, Pedro J; Horga, Alejandro; Rossor, Alexander M et al. (2018) IGHMBP2 mutation associated with organ-specific autonomic dysfunction. Neuromuscul Disord 28:1012-1015 |
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