Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy.

Charcot-Marie-Tooth (CMT) neuropathies are common disorders of the peripheral nervous system caused by demyelination or axonal degeneration, or a combination of both features. We previously assigned the locus for autosomal dominant intermediate CMT neuropathy type C (DI-CMTC) to chromosome 1p34-p35. Here we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC. Biochemical experiments and genetic complementation in yeast show partial loss of aminoacylation activity of the mutant proteins, and mutations in YARS, or in its yeast ortholog TYS1, reduce yeast growth. YARS localizes to axonal termini in differentiating primary motor neuron and neuroblastoma cultures. This specific distribution is significantly reduced in cells expressing mutant YARS proteins. YARS is the second aminoacyl-tRNA synthetase found to be involved in CMT, thereby linking protein-synthesizing complexes with neurodegeneration.

HIV-related peripheral neuropathy and glucose dysmetabolism: study of a public dataset.

AIMS AND METHODS: The authors analyzed the public dataset of Multicenter AIDS Cohort Study to examine the association of glucose dysmetabolism with HIV-related peripheral neuropathy. RESULTS: Among 5,622 participants in the data, 282 (5%) had peripheral neuropathy, of which 225 had sensory neuropathy. Of 225 participants with sensory neuropathy, 191 (84.8%) had exposure to highly active antiretroviral therapy. Of 225 with sensory neuropathy, 46 had fasting sugars measured; 26 of them (56.5%) had either impaired fasting glucose (fasting glucose >or=110 mg/dl) or diabetes (fasting glucose >or=126 mg/dl). Among 693 participants without neuropathy, who had fasting sugars measured, 441 (63.7%) had glucose dysmetabolism (p = 0.33). The mean HbA(1c) levels in participants with sensory neuropathy (5.1 +/- 1.02, n = 51) were significantly higher than in those without sensory neuropathy (4.8 +/- 0.6, n = 164, p = 0.02), though its clinical relevance is unclear. Among 739 participants who had fasting sugars measured, 63.2% had glucose dysmetabolism, showing high prevalence of glucose dysmetabolism among participants with HIV infection. CONCLUSIONS: Except for slightly higher HbA(1c) levels, there was no significant difference in prevalence of glucose dysmetabolism among participants with and without sensory neuropathy. The study brings up important aspects of using public datasets for epidemiologic studies including its limitations and a unique opportunity for pilot studies for new investigators.

Clinical, neurophysiological and morphological study of dominant intermediate Charcot-Marie-Tooth type C neuropathy.

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.