Increased risk for recurrent major depression in DYT1 dystonia mutation carriers

Department of Epidemiology of Joseph L. Mailman School of Public Health, Columbia University, New York 10032, USA.
Neurology (Impact Factor: 8.3). 09/2004; 63(4):631-7. DOI: 10.1212/WNL.64.10.1821-a
Source: PubMed

ABSTRACT Prior studies suggest that dystonia is comorbid with affective disorders. This comorbidity could be a reaction to a chronic debilitating disorder or expression of a predisposing gene. The authors took advantage of the identification of a gene for dystonia, DYT1, to test these alternative explanations.
The authors administered a standardized psychiatric interview to members of families with an identified DYT1 mutation. The authors classified family members into three groups: mutation carriers with dystonia (manifesting carriers; n = 96), mutation carriers without dystonia (non-manifesting carriers; n = 60), and noncarriers (n = 65).
The risk for recurrent major depressive disorder was increased in both non-manifesting carriers (RR = 4.95, CI = 1.72 to 14.29) and manifesting carriers (RR = 3.62, CI = 1.00 to 10.53) compared with noncarriers. Mutation carriers also had earlier age at onset of recurrent major depressive disorder than noncarriers. The severity of motor signs was not associated with the likelihood of recurrent depression. Mutation carriers did not have an increased risk for other affective disorders, such as single major depression or bipolar disorder.
Early-onset recurrent major depression is associated with the DYT1 GAG mutation and this association is independent of motor manifestations of dystonia. These findings suggest that early-onset recurrent depression is a clinical expression of the DYT1 gene mutation.

Download full-text


Available from: Rachel Saunders-Pullman, MD, MPH, Nov 13, 2014
  • Source
    • "le , in electrophysiological responses ( Edwards et al . , 2003b ) , temporal processing of sensory stimuli ( Fiorio et al . , 2007 ) , motor sequence learning ( Carbon et al . , 2011 ; Ghilardi et al . , 2003 ) , and sensorimotor cortical activity ( Carbon et al . , 2010 ) , as well as an increase in susceptibility to recurrent major depression ( Heiman et al . , 2004 ) . Second , our results demonstrate that strong neuro - nal activity can alter the synaptic phenotype , and therefore may serve as a ' ' second hit ' ' in DE - torsinA neurons . The low penetrance and phenotypic variabil - ity of DYT1 dystonia imply that genetic polymor - phisms ( Kock et al . , 2006 ; Risch et al . , 2007 ) or envi - "
    [Show abstract] [Hide abstract]
    ABSTRACT: Early-onset generalized dystonia, DYT1, is caused by a mutation in the gene encoding the evolutionarily conserved AAA+ ATPase torsinA. Synaptic abnormalities have been implicated in DYT1 dystonia, but the details of the synaptic pathophysiology are only partially understood. Here, we demonstrate a novel role for torsinA in synaptic vesicle recycling, using cultured hippocampal neurons from a knock-in mouse model of DYT1 dystonia (ΔE-torsinA) and live-cell imaging with styryl FM dyes. Neurons from heterozygous ΔE-torsinA mice released a larger fraction of the total recycling pool (TRP) during a single round of electrical stimulation than did wild-type neurons. Moreover, when the neurons were subjected to prior high activity, the time course of release was shortened. In neurons from homozygous mice, these enhanced exocytosis phenotypes were similar, but in addition the size of the TRP was reduced. Notably, when release was triggered by applying a calcium ionophore rather than electrical stimuli, neither a single nor two ΔE-torsinA alleles affected the time course of release. Thus, the site of action of ΔE-torsinA is at or upstream of the rise in calcium concentration in nerve terminals. Our results suggest that torsinA regulates synaptic vesicle recycling in central neurons. They also indicate that this regulation is influenced by neuronal activity, further supporting the idea that synaptic abnormalities contribute to the pathophysiology of DYT1 dystonia.
    Synapse 05/2012; 66(5):453-64. DOI:10.1002/syn.21534 · 2.43 Impact Factor
  • Source
    • "Nonpharmacological antidepressant treatment has ants exist than were genotyped. On the other hand, the previously claimed association may stem from overestimating the prevalence of recurrent major depression in ∆GAG deletion carriers [2], owing to the relatedness of subjects , a disproportionately small number of "
    [Show abstract] [Hide abstract]
    ABSTRACT: Observations of comorbid depression in subjects with primary dystonia have suggested a dual role for the TOR1A gene in mood disorders and movement disorders. We conducted a systematic search for carriers of the ΔGAG deletion and for other variants in TOR1A exon 5 among 414 Caucasian subjects with recurrent major depression from the Upper Palatinate. Allele frequencies were determined for 27 TOR1A diallelic markers, including two novel synonymous substitutions (L262L and E310E) in the region encoding the torsinA C-terminus, plus four novel variants in the gene's 3'UTR. No carriers of the ΔGAG deletion were observed. When data were compared to previously examined control populations, no significant allelic associations were noted after corrections for multiple testing. The present study adds to the spectrum of TOR1A mutations but provides no evidence of a common genetic predisposition to DYT1 dystonia and recurrent major depression.
    International Journal of Molecular Epidemiology and Genetics 01/2012; 3(1):91-5.
  • Source
    • "Carriers had earlier age at onset of recurrent major depressive disorder than non-carriers and the severity of motor signs was not associated with the likelihood of recurrent depression. Mutation carriers did not have an increased risk for other affective disorders, such as single major depression or bipolar disorder (Heiman et al., 2004). These findings support the hypothesis that recurrent major depression is an independent expression of the DYT1 dystonia mutation and is not necessarily a result of experiencing the disability caused by motor symptoms. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dystonia is typically considered a movement disorder characterized by motor manifestations, primarily involuntary muscle contractions causing twisting movements and abnormal postures. However, growing evidence indicates an important non-motor component to primary dystonia, including abnormalities in sensory and perceptual functions, as well as neuropsychiatric, cognitive and sleep domains. Here, we review this evidence and discuss its clinical and pathophysiological implications.
    Brain 09/2011; 135(Pt 6):1668-81. DOI:10.1093/brain/awr224 · 10.23 Impact Factor
Show more