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      Reply to tzoulis et al.: genetic and clinical heterogeneity of essential tremor

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      Author
      Gülsuner, Hilal Ünal
      Gülsuner, S.
      Mercan, F.
      Onat, Onur Emre
      Walsh, T.
      Shahin, H.
      Lee, M.
      Dogu, O.
      Kansu, T.
      Topaloglu, H.
      Elibol, B.
      Akbostanci, C.
      King, M. -C.
      Özçelik, Tayfun
      Tekinay, Ayse B.
      Date
      2015
      Source Title
      PNAS
      Print ISSN
      0027-8424
      Electronic ISSN
      1091-6490
      Publisher
      National Academy of Sciences
      Volume
      112
      Issue
      18
      Pages
      E2269
      Language
      English
      Type
      Article
      Item Usage Stats
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      Abstract
      In addressing our recent report of HTRA2 p.G399S as the gene and mutation responsible for essential tremor and subsequent Parkinson disease in a large kindred (1), Tzoulis et al. (2) screened this mutation in patients with Parkinson disease, essential tremor, tremulous cervical dystonia, and nontremulous cervical dystonia patients, and did not find a significant difference in carrier frequency compared with the general population. Their observation replicates our experience, in that in the kindred of our study, HTRA2 p.G399S was responsible for essential tremor and, among homozygotes, for Parkinson disease, but as we reported, this allele was not responsible for essential tremor in other families from the same population. Both these observations support the conclusion that essential tremor is a heterogeneous disease, both clinically and genetically (3). In addition to HTRA2, two other genes for essential tremor have been identified: DNAJC13 and FUS, and still other responsible genes have been mapped to chromosomes 2p22-24, 3q13, and 6p23 (1, 4). In any one patient, mutation at only one of these genes is sufficient for development of essential tremor, but the responsible gene differs among patients. These two features—the severity of individual causal mutations and different responsible genes in different families—are characteristic of genetic heterogeneity of complex diseases generally (5). Phenotypic features of a genetically heterogeneous disease may offer clues as to the responsible gene. In the family harboring mutation in HTRA2, Parkinson disease appeared after more than a decade of essential tremor. Also, cervical dystonia was not among the presenting signs in any of the family members. These clinical features differ from the series of patients screened by Tzoulis et al. Some of the patients screened by Tzoulis et al. may harbor HTRA2 mutations other than p.G399S that would be revealed by more complete sequencing; this would be interesting to learn. It is also possible that mutations in the other known genes for essential tremor may be present in these patients. If not, then these patients, like those from the other kindreds in our series, offer the opportunity to identify additional causal genes for essential tremor.
      Permalink
      http://hdl.handle.net/11693/53595
      Published Version (Please cite this version)
      https://doi.org/10.1073/pnas.1503756112
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      • Aysel Sabuncu Brain Research Center (BAM) 196
      • Department of Molecular Biology and Genetics 442
      • Nanotechnology Research Center (NANOTAM) 1026
      • Work in Progress 354
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