Dominant-intermediate Charcot-Marie-Tooth neuropathy subtype C (DI-CMTC) is associated with mutations in the YARS gene. The aim of this study is to investigate the long-term natural history of the disease. In a 5-generation DI-CMTC family, we compared data from 2016 to that of 2000 in 13 of 21 original participants. Five women and 8 men were examined. While most symptoms and signs progressed, only gait progression was statistically significant (P = .016). The median CMT Neuropathy Score was 6.08 in 2000 and 11 in 2016 (P = .001). Quality of life (QOL) deteriorated in mobility (P = .008), pain/discomfort (P = .011), and anxiety/depression (P = .014). Median and ulnar compound muscle action potential amplitudes decreased from 9.35 ± 2.90 mV to 6.0 ± 2.9 mV (P = .002), and from 9.24 ± 2.10 mV to 6.06 ± 1.81 mV (P = .004), respectively, whereas motor nerve conduction velocities remained unchanged. DI-CMTC in this family is a slowly progressive disease with axonal degeneration, deteriorating mobility and QOL.

Dominant intermediate Charcot-Marie-Tooth neuropathy subtype C (DI-CMTC) was associated with mutations in the YARS gene, encoding tyrosyl-tRNA synthetase, in two large unrelated Bulgarian and US pedigrees and one sporadic case. Here for the first time we describe the clinical, neurophysiological and histopathological features, and phenotypic differences between these two DI-CMTC families. Twenty-one affected individuals from the US family and 27 from the Bulgarian family were evaluated. The mean age of onset in US subjects was 10.7 years in men and 7.3 years in women, while in the Bulgarian participants it was 18.2 years in men and 33.7 years in women. The course was slowly progressive. Extensor digitorum brevis atrophy was uniform. Atrophy and/or weakness of upper and lower limb muscles were found in over 50 % of the subjects. Nerve conduction studies (NCS) were abnormal in all US adults and five of six children and all Bulgarian patients except one asymptomatic 25-year-old man. Median motor NCS were in the range of 29.5-45.6 m/s in the US family and 24.7-57.8 m/s in the Bulgarian family. Sural sensory nerve action potentials were absent in 14/21 and 4/12 NCS from adult US and Bulgarian participants, respectively. Analysis of sural nerve biopsies from US patients revealed age-dependent morphological changes of axonal degeneration, absence of onion bulbs, and <10 % fibers with segmental remyelination. Our findings provide further insights into the diagnosis and pathology of intermediate CMT. They also extend the phenotypic spectrum of peripheral neuropathies associated with aminoacyl-tRNA synthetase mutations.