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Association of BDNF Met66Met polymorphism with arm tremor in cervical dystonia
Author(s) -
Groen Justus L.,
Ritz Katja,
Velseboer Daan C.,
Aramideh Majid,
van Hilten Jacobus J.,
Boon Agnita J.W.,
van de Warrenburg Bart P.,
Baas Frank,
Tijssen Marina A.J.
Publication year - 2012
Publication title -
movement disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.352
H-Index - 198
eISSN - 1531-8257
pISSN - 0885-3185
DOI - 10.1002/mds.24922
Subject(s) - cervical dystonia , dystonia , medicine , physical medicine and rehabilitation , association (psychology) , essential tremor , neuroscience , psychology , psychiatry , psychotherapist
Cervical dystonia (CD) may be accompanied by a bilateral postural tremor of the arms. The mechanisms leading to dystonia and tremor are not clear; aberrant neuroplasticity may, however, play a role. The brainderived neurotrophic factor (BDNF, OMIM #113505) is involved in neuroplasticity modulation. A functional polymorphism Val66Met (rs6265) in BDNF has been described. Two small association studies have investigated the Val66Met polymorphism in CD, with contradicting results. In order to adequately clarify the role of the Val66Met polymorphism in CD, we investigated this variant in a large, clinically well-defined Dutch CD cohort. All CD patients (n 1⁄4 472) were examined by a movement disorders specialist. A subgroup of CD patients exhibited postural arm tremor, previously termed ‘‘tremor associated with dystonia.’’ An ageand sex-matched control group (711 subjects, not available for examination) was recruited from the Dutch National Blood Bank. All details regarding patient inclusion, genotyping, and data analysis can be found in the Supporting Information. The clinical characteristics of the CD cohort are listed in Table 1. The frequency of the 66Met-allele was 0.21 in the CD group and 0.20 in the unaffected group (P 1⁄4 .60, odds ratio [OR], 1.05; Fisher’s exact test). In addition, no genotype association was found (P 1⁄4 .67). To assess the genetic modifier effects of this polymorphism as they relate to CD, we defined phenotypic subgroups based on postural arm tremor and the spread of symptoms (Table 1). We compared the genotype frequencies of Val66Met between subgroups (Table 1) and found that Met66Met was not associated with an increased risk of segmental spread of dystonia (OR for Met66Met, 0.46; 95% confidence interval [CI], 0.13–1.59; P 1⁄4 .22), nor did it influence the age at onset (AaO, P 1⁄4 .98). Interestingly, we did find a significantly higher frequency of bilateral postural arm tremor in CD patients with the BDNF Met66Met polymorphism (53%), compared to 35% in Val66Met and 29% in Val66Val carriers (P 1⁄4 .02; OR, 2.52; 95% CI, 1.10–5.76). This result could not be attributed to AaO, disease duration, age at examination, or sex (adjusted ORs: 2.60, 2.51, 2.85, and 2.77, respectively). The effect is only present in the homozygous Met66Met and not in theVal66Met group (OR, 1.28; 95% CI, 0.84–1.95; P 1⁄4 .23). The literature tells us that subjects carrying the Met-allele lack training-dependent increases in the motor evoked potential (MEP) amplitude, show a reduced motor map reorganization and a differential response to repetitive transcranial magnetic stimulation (rTMS) plasticity induction protocols. Replication of the association between Met66Met and postural arm tremor in CD will require over 400 CD patients with arm tremor to reach 80% power to detect an equal effect as seen in the present study (OR 2.50 or higher). With a prevalence of arm tremor in CD of approximately 32%, a CD cohort of at least 1250 patients is required. Our findings suggest that the BDNF polymorphism is associated with arm tremor in CD. Further research is needed to investigate whether this effect is only present in CD patients or if BDNF is also a risk factor for other tremor syndromes, such as essential tremor.