Summary Background Mutations in THAP1 were recently identified as the cause of DYT6 primary dystonia; a founder mutation was detected in Amish–Mennonite families, and a different mutation was ...identified in another family of European descent. To assess more broadly the role of this gene, we screened for mutations in families that included one family member who had early-onset, non-focal primary dystonia. Methods We identified 36 non- DYT1 multiplex families in which at least one person had non-focal involvement at an age of onset that was younger than 22 years. All three coding exons of THAP1 were sequenced, and the clinical features of individuals with mutations were compared with those of individuals who were negative for mutations in THAP1 . Genotype–phenotype differences were also assessed. Findings Of 36 families, nine (25%) had members with mutations in THAP1 , and most were of German, Irish, or Italian ancestry. One family had the Amish–Mennonite founder mutation, whereas the other eight families each had novel, potentially truncating or missense mutations. The clinical features of the families with mutations conformed to the previously described DYT6 phenotype; however, age at onset was extended from 38 years to 49 years. Compared with non-carriers, mutation carriers were younger at onset and their dystonia was more likely to begin in brachial, rather than cervical, muscles, become generalised, and include speech involvement. Genotype–phenotype differences were not found. Interpretation Mutations in THAP1 underlie a substantial proportion of early-onset primary dystonia in non- DYT1 families. The clinical features that are characteristic of affected individuals who have mutations in THAP1 include limb and cranial muscle involvement, and speech is often affected. Funding Dystonia Medical Research Foundation; Bachmann–Strauss Dystonia and Parkinson Foundation; National Institute of Neurological Disorders and Stroke; Aaron Aronov Family Foundation.
We report the discovery of a mutation in the THAP1 gene in three Amish-Mennonite families with mixed-onset primary torsion dystonia (also known as DYT6 dystonia). Another mutation in a German family ...with primary torsion dystonia suggests that THAP1 mutations also cause dystonia in other ancestry groups. We demonstrate that the missense mutation impairs DNA binding, suggesting that transcriptional dysregulation may contribute to the phenotype of DYT6 dystonia.
Abstract Mutations in GBA1 are a well-established risk factor for Parkinson disease (PD). GBA-associated PD (GBA-PD) may have a higher burden of nonmotor symptoms than idiopathic PD (IPD). We sought ...to characterize the relationship between GBA-PD and neuropsychiatric symptoms. Subjects were screened for common GBA1 mutations. GBA-PD (n = 31) and non-carrier (IPD; n = 55) scores were compared on the Unified Parkinson Disease Rating Scale (UPDRS), Montreal Cognitive Assessment (MoCA), Beck Depression Inventory (BDI), and the State-Trait Anxiety Index (STAI). In univariate comparisons, GBA-PD had a greater prevalence of depression (33.3%) versus IPD (13.2%) (p < 0.05). In regression models controlling for age, sex, disease duration, motor disability, and MoCA score, GBA-PD had an increased odds of depression (OR 3.66, 95% CI 1.13
–
11.8) (p = 0.03). Post-hoc analysis stratified by sex showed that, among men, GBA-PD had a higher burden of trait anxiety and depression than IPD; this finding was sustained in multivariate models. Among women, GBA-PD did not confer greater psychiatric morbidity than IPD. These results suggest that GBA1 mutations confer greater risk of neuropsychiatric morbidity in PD, and that sex may affect this association.
Mutations and variants in the glucocerebrosidase (
) gene are among the most common genetic risk factors for the development of Parkinson's disease (PD). Yet, penetrance is markedly reduced, and less ...is known about the burden of carrying a single mutation among those without diagnosed PD. Motor, cognitive, psychiatric, and olfactory functioning were assessed in 30 heterozygous
mutation carriers without PD (the majority of whom had mild
mutations) and 49 non-carriers without PD. Study focus was on domains affected in
mutation carriers with PD, as well as those previously shown to be abnormal in
mutation carriers without PD.
mutation carriers showed poorer performance on the Stroop interference measure of executive functioning when controlling for age. There were no group differences in verbal memory, Montreal Cognitive Assessment (MoCA), overall motor score, or presence of REM sleep behavior disorder or depression. Although total olfaction scores did not differ,
mutation carriers with hyposmia had lower global cognition scores than those without hyposmia. As anticipated by the low penetrance of
mutations, these findings suggest that pre-manifest non-motor or motor features of PD may not present in most
mutation carriers. However, there is support that there may be a subtle difference in executive functioning among some non-manifesting heterozygous
mutation carriers, and, combined with olfaction, this may warrant additional scrutiny as a potential biomarker for pre-manifest and pre-clinical
related PD.
It has been difficult to link synaptic modification to overt behavioral changes. Rodent models of DYT1 dystonia, a motor disorder caused by a single gene mutation, demonstrate increased long-term ...potentiation and decreased long-term depression in corticostriatal synapses. Computationally, such asymmetric learning predicts risk taking in probabilistic tasks. Here we demonstrate abnormal risk taking in DYT1 dystonia patients, which is correlated with disease severity, thereby supporting striatal plasticity in shaping choice behavior in humans.
There is a paucity of genetic characterization in people with Parkinson's disease (PD) of Latino and Afro-Caribbean descent. Screening LRRK2 and GBA variants in 32 New Yorkers of Puerto Rican ...ethnicity with PD and in 119 non-Hispanic-non-Jewish European PD cases revealed that Puerto Rican participants were more likely to harbor the LRRK2-p.G2019S variant (15.6% vs. 4.2%, respectively). Additionally, whole exome sequencing of twelve Puerto Rican and Dominican PD participants was performed as an exploratory study.
The Montreal Cognitive Assessment (MoCA), an instrument widely used for cognitive screening in Parkinson's disease (PD), is validated in Hebrew and English. However, it remains unknown whether the ...scores are comparable.
The MoCA was analyzed in 483 Ashkenazi Jewish PD patients in Tel-Aviv and New York who had MoCA ≥21. Each section of the MoCA was compared between English and Hebrew. Linear regression models were used to test the association between MoCA performance and language.
Total MoCA scores were lower in Hebrew than in English (25.4 versus 26.1; P = 0.007), even after adjustment for age, sex, PD duration, genotype, levodopa equivalent dose, the Unified Parkinson's Disease Rating Scale (UPDRS-III), and Geriatric Depression Scale score in a linear model (P < 0.001). However, when language sections were removed from the total, scores were similar between the languages (Hebrew 23.7 versus English 23.4, P = 0.111).
The language section of the MoCA may be more difficult in Hebrew. The comparability of MoCA in different languages requires further evaluation.
•Total MoCA scores were lower in Hebrew-speaking than in English-speaking Parkinson's patients.•The language section in the Hebrew version of the MoCA may be more difficult.•Merging data from cognitive testing performed in different languages requires caution.
The DYT1 dystonia mutation is associated with an abnormal metabolic brain network characterized by hypermetabolism of the basal ganglia, supplementary motor area, and the cerebellum. In this study, ...we quantified the activity of this network in carriers of other dystonia mutations to determine whether this functional abnormality is linked to genotype. The findings suggest that the DYT1 metabolic topography is not genotype specific and may be present in carriers of other dystonia mutations.
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