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

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Abstract

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.

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Acknowledgments

The American team received support for design and conduct of the study and collection of data from The Neuropathy Association and the St. Louis Chapter of The Neuropathy Association. The Bulgarian team received support for collection of data from the Research Fund of Sofia Medical University and National Science Fund of the Bulgarian Ministry of Education and Science. The Belgian team received support for design and conduct of the study and collection of data from the Fund for Scientific Research (FWO-Flanders), the Research Fund of the University of Antwerp (BOF-UA), the Medical Foundation Queen Elisabeth (GSKE), the Association Belge contre les Maladies Neuro-Musculaires (ABMM), and the US Muscular Dystrophy Association. The authors thank the study participants for their cooperation, Professors Mitko Abadjiev and Veneta Georgieva for pedigree data, and the Bulgarian Association for Neuromuscular Disorders and Ethnic Minorities Health Problems Foundation for assistance during patient visits.

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    Authors and Affiliations

    1. Department of Neurology, St. Louis University School of Medicine, 1438 South Grand Boulevard, St. Louis, MO, 63104, USA

      Florian P. Thomas, Laurence J. Kinsella, Yi Pan & Thomas J. Geller

    2. Department of Physical Therapy and Athletic Training, Institute for Molecular Virology, St. Louis University, St. Louis, MO, USA

      Florian P. Thomas

    3. Department of Neurology, Medical University - Sofia, Sofia, Bulgaria

      Velina Guergueltcheva, Ivailo Tournev & Boryana Ishpekova

    4. Current affiliation: Clinic of Neurology, University Hospital Sofiamed, Sofia, Bulgaria

      Velina Guergueltcheva

    5. Neurology Division, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil

      Francisco A. A. Gondim

    6. Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria

      Ivailo Tournev

    7. Department of Neurology, University Medical Center of Princeton, Princeton, NJ, USA

      Chitharanjan V. Rao

    8. Department of Pediatrics, Medical University-Sofia, Sofia, Bulgaria

      Ivan Litvinenko

    9. Division of Neurology, University Hospital Antwerpen (UZA), Antwerp, Belgium

      Peter De Jonghe

    10. Neurogenetics Group, Department of Molecular Genetics, VIB, University of Antwerp, Antwerp, Belgium

      Peter De Jonghe

    11. Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

      Steven S. Scherer

    12. Molecular Neurogenomics Group, Department of Molecular Genetics, VIB, University of Antwerp, Universiteitsplein 1, Antwerp, Belgium

      Albena Jordanova

    13. Department of Medical Chemistry and Biochemistry, Molecular Medicine Center, Medical University-Sofia, Sofia, Bulgaria

      Albena Jordanova

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    1. Florian P. Thomas
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    Correspondence to Florian P. Thomas or Albena Jordanova.

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    The authors declare that they have no conflicts of interest.

    Ethical standards

    All human studies were approved by the ethics committees of St. Louis University and Medical University-Sofia and were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

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    F. P. Thomas and V. Guergueltcheva have contributed equally to the manuscript.

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    Thomas, F.P., Guergueltcheva, V., Gondim, F.A.A. et al. Clinical, neurophysiological and morphological study of dominant intermediate Charcot-Marie-Tooth type C neuropathy. J Neurol 263, 467–476 (2016). https://doi.org/10.1007/s00415-015-7989-8

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    • DOI: https://doi.org/10.1007/s00415-015-7989-8

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