To investigate the natural history of dominant intermediate Charcot-Marie-Tooth neuropathy subtype C (DI-CMTC) over 16 years.

DI-CMTC is associated with mutations in the YARS gene, encoding tyrosyl-tRNA synthetase. We were the first to report the phenotype and genotype of DI-CMTC from a U.S. and a Bulgarian family. As per the original study design in 2000 to investigate the disease across the lifespan, we repeated assessments in original DI-CMTC participants from the U.S. family.

Five women and 8 men were examined at ages 8–77 in 2000 and 24–93 in 2016. While most symptoms and signs progressed, this only reached statistical significance for gait (p=0.016). The median CMTNSv2 was 6.08 in 2000 and 11 in 2016 (p=0.001). MRS did not change significantly. QOL deteriorated in mobility (p=0.008), pain/discomfort (p=0.011), and anxiety/depression (p=0.014). The median nerve compound muscle action potential (CMAP) amplitudes decreased from 9.35±2.90 mV to 6.0±2.9 mV (p=0.002), whereas motor nerve conduction velocities (MNCV) were largely unchanged at 36–37 m/s (p=0.236). The ulnar CMAP amplitudes decreased from 9.24±2.10 mV to 6.06±1.81 mV (p=0.004), while MNCV remained unchanged at 39 m/s (p=0.914). In 2000 and 2016 all adults had absent peroneal motor responses. In the interval, all sensory nerve amplitudes and conduction velocities further diminished. Scatter graphs showed a trend for progressive reduction in median and ulnar CMAP amplitudes with age.

Our study demonstrates that DI-CMTC is a slowly progressive disease with lower greater than upper limb involvement, deteriorating mobility and QOL. EDX confirms previously reported morphological findings indicative of axonal degeneration.