Premutation Alleles Associated With Parkinson Disease and Essential Tremor
- Hao Deng, PhD;
- Weidong Le, MD, PhD;
- Joseph Jankovic, MD
- KEYWORDS:
- ESSENTIAL TREMOR
- FRAGILE X SYNDROME
- MUTATION
- PARKINSON DISEASE
- TRINUCLEOTIDE REPEAT EXPANSION
To the Editor: There is evidence that older male carriers of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene are at high risk of developing the fragile X–associated tremor/ataxia syndrome1 and spinocerebellar ataxia.2 Since the phenotypes associated with these disorders overlap with those of Parkinson disease (PD) and essential tremor, we sought to determine the prevalence of FMR1 premutation alleles in men with these movement disorders.
Methods
From our DNA bank we conducted FMR1 premutation analysis in 216 men with idiopathic PD excluding atypical cases (mean age at symptom onset, 56.3 [SD, 12.2] years) and in 196 male patients with typical essential tremor (mean age at symptom onset, 53.7 [SD, 14.3] years). Genomic DNA was isolated from peripheral blood and amplification of DNA was carried out using the GC-RICH polymerase chain reaction System (Roche Diagnostics, Indianapolis, Ind). The CGG repeats were detected on 6% denatured polyacrylamide gel, and nucleotide sequencing was performed by an automated DNA sequencer (ABI PRISM 3100) from purified polymerase chain reaction products. Written informed consent, approved by the Baylor College of Medicine institutional review board, was obtained from all participants.
Results
Using sampling from a binomial distribution, the expected frequency of premutation of FMR1 was less than 2% in PD and essential tremor with 95% confidence. We did not detect CGG premutation in any of the 412 X chromosomes of patients with PD and essential tremor. There were 31 distinct alleles, ranging from 13 to 51 CGG repeats. Four of 216 patients (1.9%) with PD and 3 of 196 patients (1.5%) with essential tremor had alleles with CGG repeats falling within the “gray zone” of 45 to 54 CGG repeats as defined by the American College of Medical Genetics,3 with maximum CGG repeats of 51 found in 1 patient with PD and 47 found in 1 patient with essential tremor. Patients in this range cannot be differentiated from others by clinical features, and the frequency of 45 to 54 CGG repeats in these patients is not different from that in normal controls.4 We also confirmed a premutation (55 CGG repeats) in a 38-year-old African American patient with parkinsonism and dementia from a Huntington disease–like 2 (HDL2) pedigree,5 the first report of coexistence of the premutation of FMR1 with the lowest end and trinucleotide repeats expansion (57 CTG/CAG repeats) of JPH3 (HDL2) in the same patient, while a family member with full mutation of FMR1 and trinucleotide expansion of JPH3 showed no symptom of parkinsonism.
Comment
Premutation of the FMR1 gene in men is associated with various movement disorders, including tremor, ataxia, and parkinsonism, that have clinical features overlapping with PD and essential tremor.1, 6 We sought premutations in men with PD and in those with essential tremor to determine whether these 2 disorders are pathogenetically related to this genetic abnormality, but we found no FMR1 premutation in our population of patients with PD and essential tremor. This is consistent with other reports indicating lack of FMR1 premutation in patients with essential tremor,7-8 atypical parkinsonism, and ataxias.8 Thus, premutation of FMR1 probably plays little or no role in the pathogenesis of idiopathic PD or essential tremor. Furthermore, it is unlikely that this genetic abnormality accounts for the male preponderance in patients with PD.9
Access to Data: All of the authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analyses.
Funding /Support: This work was supported by National Institute of Neurological Disorders and Stroke grant 043567.
Role of the Sponsor: The National Institute of Neurological Disorders and Stroke had no role in the design and conduct of the study; the collection, interpretation, and analysis of the data; the preparation of the data; or the preparation, review, or approval of the manuscript.
