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Abstract Details

Charcot Marie Tooth Disease Type 4C: Genotype Phenotype Correlation and Natural History
Neuromuscular and Clinical Neurophysiology (EMG)
S46 - Neuromuscular and Clinical Neurophysiology (EMG): Motor Neuron/Charcot Marie Tooth (5:06 PM-5:18 PM)
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CMT4c is an autosomal recessive form of Charcot Marie Tooth disease that is primarily demyelinating and due to mutations in the gene SH3TC2.  CMT4c, like other autosomal recessive forms, tends to be severe and is marked by early onset spinal deformities and other unique features. However, its clinical characteristics are quite variable.  Clear relationships between pathogenic mutations and the spectrum of disease manifestations are to date lacking. Gene replacement therapy has been shown to ameliorate the phenotype of CMT4c, emphasizing the need for human clinical trial readiness.
To clarify the natural history of Charcot Marie Tooth 4c (CMT4c) and to characterize phenotype-genotype relationships, to inform and enable clinical trial design.
Data, including both genetic information and clinical characteristics, was compiled from the longitudinal, prospective dataset of the Inherited Neuropathies Consortium, a member of the Rare Disease Clinical Research Network (INC RDCRN). The Charcot Marie Tooth Neuropathy Score was used to describe symptoms, neurologic examinations, and neurophysiologic characteristics.
50 individuals (42% female), age 35 years (range 2 – 83 years) with homozygous or compound heterozygous mutations in SH3TC2 were identified. Several of these mutations have not previously been reported. 21 of these patients had longitudinal data available. While age and exam score correlated, longitudinal data in individual patients did not show significant change in exam scores over the course of 1-7 years. A c.2860C>T nonsense mutation appeared to correlate with earlier onset, although no correlation was noted with other measures of severity.
This was the largest cross-sectional and only longitudinal study of clinical characteristics of patients with CMT4C. With promise of upcoming genetic treatments for the disease, this data will help to clarify the natural history of the disease in preparation for clinical trials.
Authors/Disclosures
Tyler A. Rehbein, MD (University of Rochester Medical Center)
PRESENTER 		The institution of Dr. Rehbein has received research support from Neuromuscular Study Group, American Brain Foundation, and 好色先生.
Simona Treidler, MD (Stony Brook University) Dr. Treidler has nothing to disclose.
Michael E. Shy, MD, FAAN (University of Iowa) Dr. Shy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Applied Therapeutics. The institution of Dr. Shy has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for DTx Pharma. The institution of Dr. Shy has received research support from NIH. The institution of Dr. Shy has received research support from Muscular Dystrophy Association. The institution of Dr. Shy has received research support from Charcot Marie Tooth Association. The institution of Dr. Shy has received research support from Applied Therapeutics.
David N. Herrmann, MD, FAAN (University of Rochester Medical Center) Dr. Herrmann has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Acceleron. Dr. Herrmann has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint global. Dr. Herrmann has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GLG. Dr. Herrmann has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurogene. Dr. Herrmann has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta. Dr. Herrmann has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Regenacy. Dr. Herrmann has received intellectual property interests from a discovery or technology relating to health care.
Michael E. Shy, MD, FAAN (University of Iowa) Dr. Shy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Applied Therapeutics. The institution of Dr. Shy has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for DTx Pharma. The institution of Dr. Shy has received research support from NIH. The institution of Dr. Shy has received research support from Muscular Dystrophy Association. The institution of Dr. Shy has received research support from Charcot Marie Tooth Association. The institution of Dr. Shy has received research support from Applied Therapeutics.