Understanding monogenic Parkinson's disease at a global scale.

Until recently, about three-quarters of all monogenic Parkinson's disease (PD) studies were performed in European/White ancestry, thereby severely limiting our insights into genotype-phenotype relationships at global scale. The first systematic approach to embrace monogenic PD worldwide, The Michael J. Fox Foundation Global Monogenic PD (MJFF GMPD) Project, contacted authors of publications reporting individuals carrying pathogenic variants in known PD-causing genes. In contrast, the Global Parkinson's Genetics Program's (GP2) Monogenic Network took a different approach by targeting PD centers not yet represented in the medical literature. Here, we describe combining both efforts in a "merger project" resulting in a global monogenic PD cohort with build-up of a sustainable infrastructure to identify the multi-ancestry spectrum of monogenic PD and enable studies of factors modifying penetrance and expression of monogenic PD. This effort demonstrates the value of future research based on team science approaches to generate comprehensive and globally relevant results.

Large-Scale Screening: Phenotypic and Mutational Spectrum in Isolated and Combined Dystonia Genes.

BACKGROUND: Pathogenic variants in several genes have been linked to genetic forms of isolated or combined dystonia. The phenotypic and genetic spectrum and the frequency of pathogenic variants in these genes have not yet been fully elucidated, neither in patients with dystonia nor with other, sometimes co-occurring movement disorders such as Parkinson's disease (PD). OBJECTIVES: To screen >2000 patients with dystonia or PD for rare variants in known dystonia-causing genes. METHODS: We screened 1207 dystonia patients from Germany (DysTract consortium), Spain, and South Korea, and 1036 PD patients from Germany for pathogenic variants using a next-generation sequencing gene panel. The impact on DNA methylation of KMT2B variants was evaluated by analyzing the gene's characteristic episignature. RESULTS: We identified 171 carriers (109 with dystonia [9.0%]; 62 with PD [6.0%]) of 131 rare variants (minor allele frequency <0.005). A total of 52 patients (48 dystonia [4.0%]; four PD [0.4%, all with GCH1 variants]) carried 33 different (likely) pathogenic variants, of which 17 were not previously reported. Pathogenic biallelic variants in PRKRA were not found. Episignature analysis of 48 KMT2B variants revealed that only two of these should be considered (likely) pathogenic. CONCLUSION: This study confirms pathogenic variants in GCH1, GNAL, KMT2B, SGCE, THAP1, and TOR1A as relevant causes in dystonia and expands the mutational spectrum. Of note, likely pathogenic variants only in GCH1 were also found among PD patients. For DYT-KMT2B, the recently described episignature served as a reliable readout to determine the functional effect of newly identified variants. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Longitudinal predictors of health-related quality of life in isolated dystonia.

OBJECTIVE: To determine longitudinal predictors of health-related quality of life (HR-QoL) in an international multicenter cohort of patients with isolated dystonia. METHODS: Out of 603 dystonia patients prospectively enrolled in the Natural History Dystonia Coalition study, 155 were assessed three times within 2 years for HR-QoL, symptoms of depression, generalized anxiety disorder (GAD), and social anxiety disorder (SAD), as well as dystonia severity and dystonic tremor. In addition, the impact of botulinum neurotoxin (BoNT) injections on HR-QoL was evaluated after 1 year. RESULTS: Depressive symptoms at baseline predicted lower HR-QoL on all subscales after 2 years (all p ≤ 0.001). Higher GAD scores at baseline predicted lower HR-QoL related to general health, pain and emotional well-being, whereas higher SAD scores predicted higher pain-related QoL after 2 years (all p ≤ 0.006). Dystonia severity at baseline predicted social functioning (p = 0.002). Neither dystonic tremor, age, or sex predicted HR-QoL at 2 years. Two latent categories were revealed across the three-time points: Category 1 with higher total HR-QoL scores (mean HR-QoL = 74.4% ± 16.1), susceptible to symptoms of depression and SAD, and Category 2 with lower total HR-QoL scores (mean HR-QoL = 45.5% ± 17.6), susceptible to symptoms of GAD. HR-QoL improved over the course of 1 year irrespective of the use of BoNT. CONCLUSION: The longitudinal impact of psychiatric symptoms on HR-QoL emphasizes the importance of incorporating mental health treatment, in particular also the therapy of anxiety disorders, into treatment regimens for dystonia.

Elucidating causative gene variants in hereditary Parkinson's disease in the Global Parkinson's Genetics Program (GP2).

The Monogenic Network of the Global Parkinson's Genetics Program (GP2) aims to create an efficient infrastructure to accelerate the identification of novel genetic causes of Parkinson's disease (PD) and to improve our understanding of already identified genetic causes, such as reduced penetrance and variable clinical expressivity of known disease-causing variants. We aim to perform short- and long-read whole-genome sequencing for up to 10,000 patients with parkinsonism. Important features of this project are global involvement and focusing on historically underrepresented populations.

Characterizing the temporal discrimination threshold in musician's dystonia.

The temporal discrimination threshold (TDT) has been established as a biomarker of impaired temporal processing and endophenotype in various forms of focal dystonia patients, such as cervical dystonia, writer's cramp or blepharospasm. The role of TDT in musician's dystonia (MD) in contrast is less clear with preceding studies reporting inconclusive results. We therefore compared TDT between MD patients, healthy musicians and non-musician controls using a previously described visual, tactile, and visual-tactile paradigm. Additionally, we compared TDT of the dystonic and non-dystonic hand and fingers in MD patients and further characterized the biomarker regarding its potential influencing factors, i.e. musical activity, disease variables, and personality profiles. Repeated measures ANOVA and additional Bayesian analyses revealed lower TDT in healthy musicians compared to non-musicians. However, TDTs in MD patients did not differ from both healthy musicians and non-musicians, although pairwise Bayesian t-tests indicated weak evidence for group differences in both comparisons. Analyses of dystonic and non-dystonic hands and fingers revealed no differences. While in healthy musicians, age of first instrumental practice negatively correlated with visual-tactile TDTs, TDTs in MD patients did not correlate with measures of musical activity, disease variables or personality profiles. In conclusion, TDTs in MD patients cannot reliably be distinguished from healthy musicians and non-musicians and are neither influenced by dystonic manifestation, musical activity, disease variables nor personality profiles. Unlike other isolated focal dystonias, TDT seems not to be a reliable biomarker in MD.

Motor learning deficits in cervical dystonia point to defective basal ganglia circuitry.

Dystonia is conceptualized as a network disorder involving basal ganglia, thalamus, sensorimotor cortex and the cerebellum. The cerebellum has been implicated in dystonia pathophysiology, but studies testing cerebellar function in dystonia patients have provided equivocal results. This study aimed to further elucidate motor network deficits in cervical dystonia with special interest in the role of the cerebellum. To this end we investigated motor learning tasks, that differ in their dependence on cerebellar and basal ganglia functioning. In 18 cervical dystonia patients and 18 age matched healthy controls we measured implicit motor sequence learning using a 12-item serial reaction time task mostly targeting basal ganglia circuitry and motor adaptation and eyeblink conditioning as markers of cerebellar functioning. ANOVA showed that motor sequence learning was overall impaired in cervical dystonia (p = 0.01). Moreover, unlike healthy controls, patients did not show a learning effect in the first part of the experiment. Visuomotor adaptation and eyeblink conditioning were normal. In conclusion, these data lend support to the notion that motor learning deficits in cervical dystonia relate to basal ganglia-thalamo-cortical loops rather than being a result of defective cerebellar circuitry.

Quality of life in isolated dystonia: non-motor manifestations matter.

OBJECTIVE: To evaluate the relationship between health-related quality of life (HR-QoL) and both physical and psychiatric factors in a large, international, multicentre cohort of patients with isolated dystonia, the Dystonia Coalition. METHODS: Natural history data from 603 patients with isolated dystonia (median age 57 years (IQR: 48 to 64 years), 67.0% women) were prospectively acquired and analysed. HR-QoL (RAND 36-Item Health Survey), severity of depressive symptoms, generalised anxiety (Hospital Anxiety and Depression Scale) and social anxiety (Liebowitz Social Anxiety Scale) were assessed. Dystonia severity (Burke-Fahn-Marsden Dystonia Rating Scale) and dystonic tremor were examined. Statistical predictors of HR-QoL were calculated using saturated path analysis. RESULTS: Reduced HR-QoL was strongly associated with the degree of depressive symptoms and generalised and social anxiety (8/8 RAND 36 subscales, p≤0.001). Increased dystonia severity was associated with worse physical functioning, physical and emotional role functioning and social functioning (all p≤0.001). The presence of tremor correlated with worse physical functioning and pain (all p≤0.006). Younger age was associated with reduced emotional well-being and vitality (all p≤0.006). There were no HR-QoL differences between sexes. CONCLUSION: HR-QoL in isolated dystonia is strongly associated with psychiatric and physical features. While current standard of care focus on motor aspects of dystonia, comprehensive care should address both physical and mental aspects of health.

Genotype-Phenotype Relations for Isolated Dystonia Genes: MDSGene Systematic Review.

This comprehensive MDSGene review is devoted to 7 genes - TOR1A, THAP1, GNAL, ANO3, PRKRA, KMT2B, and HPCA - mutations in which may cause isolated dystonia. It followed MDSGene's standardized data extraction protocol and screened a total of ~1200 citations. Phenotypic and genotypic data on ~1200 patients with 254 different mutations were curated and analyzed. There were differences regarding age at onset, site of onset, and distribution of symptoms across mutation carriers in all 7 genes. Although carriers of TOR1A, THAP1, PRKRA, KMT2B, or HPCA mutations mostly showed childhood and adolescent onset, patients with GNAL and ANO3 mutations often developed first symptoms in adulthood. GNAL and KMT2B mutation carriers frequently have 1 predominant site of onset, that is, the neck (GNAL) or the lower limbs (KMT2B), whereas site of onset in DYT-TOR1A, DYT-THAP1, DYT-ANO3, DYT-PRKRA, and DYT-HPCA was broader. However, in most DYT-THAP1 and DYT-ANO3 patients, dystonia first manifested in the upper half of the body (upper limb, neck, and craniofacial/laryngeal), whereas onset in DYT-TOR1A, DYT-PRKRA and DYT-HPCA was frequently observed in an extremity, including both upper and lower ones. For ANO3, a segmental/multifocal distribution was typical, whereas TOR1A, PRKRA, KMT2B, and HPCA mutation carriers commonly developed generalized dystonia. THAP1 mutation carriers presented with focal, segmental/multifocal, or generalized dystonia in almost equal proportions. GNAL mutation carriers rarely showed generalization. This review provides a comprehensive overview of the current knowledge of hereditary isolated dystonia. The data are also available in an online database (http://www.mdsgene.org), which additionally offers descriptive summary statistics. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dystonia and Tremor: A Cross-Sectional Study of the Dystonia Coalition Cohort.

OBJECTIVE: To assess the clinical manifestations and predictors of different types of tremors in individuals with different types of isolated dystonia. METHODS: Clinical manifestations of tremor were assessed in a multicenter, international cross-sectional, cohort study of 2,362 individuals with all types of isolated dystonia (focal, segmental, multifocal, and generalized) recruited through the Dystonia Coalition. RESULTS: Methodical and standardized assessments of all participants in this cohort revealed the overall prevalence of any type of tremor was 53.3%. The prevalence of dystonic tremor varied from 36.9% to 48.4%, depending on criteria used to define it. To identify the factors associated with tremors in dystonia, the data were analyzed by generalized linear modeling and cluster analyses. Generalized linear modeling indicated 2 of the strongest factors associated with tremor included body region affected by dystonia and recruitment center. Tremor was also associated with severity of dystonia and duration of dystonia, but not with sex or race. The cluster analysis distinguished 8 subgroups within the whole cohort; defined largely by body region with dystonia, and secondarily by other clinical characteristics. CONCLUSION: The large number of cases evaluated by an international team of movement disorder experts facilitated the dissection of several important factors that influence the apparent prevalence and phenomenology of tremor in dystonia. These results are valuable for understanding the many differences reported in prior studies, and for guiding future studies of the nosology of tremor and dystonia.

Risk of spread in adult-onset isolated focal dystonia: a prospective international cohort study.

OBJECTIVE: Isolated focal dystonia can spread to muscles beyond the initially affected body region, but risk of spread has not been evaluated in a prospective manner. Furthermore, body regions at risk for spread and the clinical factors associated with spread risk are not well characterised. We sought here to prospectively characterise risk of spread in recently diagnosed adult-onset isolated focal dystonia patients. METHODS: Patients enrolled in the Dystonia Coalition with isolated dystonia affecting only the neck, upper face, hand or larynx at onset of symptoms were included. Timing of follow-up visits was based on a sliding scale depending on symptom onset and ranged from 1 to 4 years. Descriptive statistics, Kaplan-Meier survival curves and Cox proportional hazard regression models were used to assess clinical characteristics associated with dystonia spread. RESULTS: 487 enrolled participants (68.3% women; mean age: 55.6±12.2 years) met our inclusion/exclusion criteria. Spread was observed in 50% of blepharospasm, 8% of cervical dystonia, 17% of hand dystonia and 16% of laryngeal dystonia cases. Most common regions for first spread were the oromandibular region (42.2%) and neck (22.4%) for blepharospasm, hand (3.5%) for cervical dystonia and neck for hand (12.8%) and laryngeal (15.8%) dystonia. Increased spread risk was associated with a positive family history (HR=2.18, p=0.012) and self-reported alcohol responsiveness (HR=2.59, p=0.009). CONCLUSIONS: Initial body region affected in isolated focal dystonia has differential risk and patterns of spread. Genetic factors likely influence the risk of spread. These findings can aid clinical prognostication and inform future investigations into potential disease-modifying treatments.

Temporal discrimination threshold and blink reflex recovery cycle in cervical dystonia - two sides of the same coin?

INTRODUCTION: Elevated temporal discrimination thresholds (TDT) have been found in cervical dystonia (CD) and unaffected first-degree relatives, indicating autosomal dominant inheritance with reduced penetrance, serving as an endophenotype and being indicative of abnormal inhibitory processing within the brainstem-basal ganglia circuits. The blink reflex R2 recovery cycle (BRRC) is also a measure of excitability of brainstem-basal ganglia circuits, and inconsistent findings are reported in CD. The aim was to investigate TDT and BRRC in CD and evaluate its reliability as an endophenotype. METHODS: 29 patients with isolated cervical dystonia (mean age: 56.1 ±â€¯14.3, female n = 18) and 29 age- and gender-matched healthy controls (mean age: 56.0 ±â€¯14.2, female n = 18) were evaluated using a TDT-paradigm, performed as previously described by testing visual, tactile and visual-tactile temporal discrimination thresholds, and the BRRC, investigated with electrical and air puff stimulation. RESULTS: Mean visual-tactile (p = 0.001) and visual TDTs (p = 0.015) differed between CD and controls; tactile TDTs revealed no group differences (p = 0.232). No between group differences were found for BRRC using either electrical or air puff stimulation (p = 0.117). There was no correlation between the elevation of TDTs and the degree of BRRC-inhibition in CD. CONCLUSION: Our findings support the hypothesis that the TDT is an endophenotype in CD. BRRC testing did not demonstrate disinhibition of brainstem-basal ganglia circuits in CD. In contrast to TDT, the BRRC seems not to represent an endophenotype in cervical dystonia.

Spinocerebellar Ataxia Type 28-Phenotypic and Molecular Characterization of a Family with Heterozygous and Compound-Heterozygous Mutations in AFG3L2.

While heterozygous mutations in the AFG3L2 gene have been linked to spinocerebellar ataxia 28 (SCA28), homozygous mutations in the same gene can cause spastic ataxia 5 (SPAX5). AFG3L2 encodes a mitochondrial ATP-dependent metalloprotease. We here report a SCA28 patient with biallelic AFG3L2 variants and his heterozygous mother. The patient and his mother underwent a detailed neurological examination and fibroblast lines were established. The effect of the two missense variants on mitochondria was assessed by form factor analysis and quantification of mitochondrial proteins (TOMM70, complex V). The 39-year-old index patient presented with a slowly progressive cerebellar gait disorder for 19 years, bilateral ptosis, and dysarthria. A cranial MRI showed mild cerebellar atrophy. He carried two compound-heterozygous, rare, missense variants (c.1847A>G [p.Y616C], c.2167G>A [p.V723M]) in AFG3L2, while his mother was heterozygous for the first change that had previously been described in SPAX5. Altered mitochondrial morphology and interconnectivity, together with reduced protein levels of TOMM70 and complex V (ATPase), suggest mitochondrial structural defects in the patient's fibroblasts. No significant abnormalities were found in his mother's fibroblast cultures albeit all measurements were slightly below the control level. We here present a SCA28 patient with compound-heterozygous AFG3L2 variants and demonstrate mitochondrial abnormalities in skin fibroblast cultures from this patient. Thus, AFG3L2 variants should be considered in both slowly progressive ataxias and phenotypes with clinical features reminiscent of mitochondrial disease. Of note, ptosis was present in both mutation carriers and may serve as a red flag in the diagnosis of SCA28.

Role of ANO3 mutations in dystonia: A large-scale mutational screening study.

BACKGROUND: The role of ANO3 variants as a monogenic cause of dystonia is still under debate because of its relatively high frequency also in controls. OBJECTIVE: To screen >1000 patients with movement disorders for rare ANO3 variants. METHODS: We searched for rare ANO3 variants in 729 dystonia and 294 Parkinson's disease (PD) patients using a gene panel. Variants were validated by Sanger sequencing. For one variant carrier, family members were available for segregation analysis. RESULTS: Nine carriers (seven with dystonia [1.0%], two with PD [0.7%]) of seven different rare, protein-changing variants were identified. None of these variants has been previously reported in dystonia patients. Two of the variants in dystonia patients were found recurrently: p.Arg328Cys was detected in two Korean and p.Arg969Gln in two German patients. The frequency of these two variants in our sample seemed to be higher as in ethnically matched samples from the Genome Aggregation Database (GnomAD). Further, we identified a patient with early-onset, generalized dystonia with a de-novo variant in ANO3 (p.Val561Glu). Of note, she benefitted from deep brain stimulation. CONCLUSION: This study confirms the relatively high frequency of rare, protein-changing ANO3 variants in both dystonia and non-dystonia patients indicating that not all variants contribute to the disease. Thus, disease relevance of novel variants remains difficult to interpret and functional studies are warranted for a better understanding of the role of ANO3 variants in dystonia. In contrast, de-novo variants in childhood-onset, generalized dystonia seem to represent an as yet underestimated phenotypic expression of changes in ANO3.

Predictors of alcohol responsiveness in dystonia.

OBJECTIVE: To determine predictors of alcohol responsiveness in a large cohort of patients with dystonia. METHODS: A total of 2,159 participants with dystonia were prospectively enrolled in the cross-sectional Dystonia Coalition multicenter study. Patients with secondary, combined, or confirmed genetic dystonia (total n = 164) or unknown alcohol responsiveness (n = 737) were excluded. Patients answered a standardized questionnaire and were clinically examined using a standardized video protocol and the Burke-Fahn-Marsden Dystonia Rating Scale. Alcohol responsiveness was determined by patients' self-report. RESULTS: A total of 1,258 patients with isolated dystonia (mean age: 59.5 ± 12.2 years; 898 women) met the inclusion criteria; 369 patients (29.3%) reported improvement of dystonia after alcohol consumption. Alcohol responsiveness was not related to sex (p = 0.742), age (p = 0.715), or severity of dystonia (p = 0.623). Age at onset was lower in patients who responded to alcohol (p < 0.001). Alcohol responsiveness differed across dystonia subgroups (multifocal/generalized > segmental [p = 0.014]; cervical and laryngeal > cranial and limb [p < 0.001]) and was related to a positive family history of movement disorders (p = 0.001), and presence of tremor (p < 0.001). CONCLUSION: The association of alcohol responsiveness with a positive family history for movement disorders, generalized dystonia, and an earlier age at onset suggests that patients with dystonia who have an underlying genetic contribution may be more likely to respond beneficially to alcohol. The fact that dystonic tremor may respond to alcohol is in keeping with the observation that the intake of GABAergic drugs may have a beneficial effect in a proportion of patients.

Psychiatric associations of adult-onset focal dystonia phenotypes.

BACKGROUND: Depression and anxiety frequently accompany the motor manifestations of isolated adult-onset focal dystonias. Whether the body region affected when this type of dystonia first presents is associated with the severity of these neuropsychiatric symptoms is unknown. OBJECTIVES: The aim of this study was to determine whether depression, anxiety and social anxiety vary by dystonia onset site and evaluate whether pain and dystonia severity account for any differences. METHODS: Patients with isolated focal dystonia evaluated within 5 years from symptom onset, enrolled in the Natural History Project of the Dystonia Coalition, were included in the analysis. Individual onset sites were grouped into five body regions: cervical, laryngeal, limb, lower cranial and upper cranial. Neuropsychiatric symptoms were rated using the Beck Depression Inventory, Hospital Anxiety and Depression Scale and Liebowitz Social Anxiety Scale. Pain was estimated using the 36-Item Short Form Survey. RESULTS: Four hundred and seventy-eight subjects met our inclusion criteria. High levels of depression, anxiety and social anxiety occurred in all groups; however, the severity of anxiety and social anxiety symptoms varied by onset site group. The most pronounced differences were higher anxiety in cervical and laryngeal, lower anxiety in upper cranial and higher social anxiety in laryngeal. Increases in pain were associated with worse neuropsychiatric symptom scores within all groups. Higher anxiety and social anxiety in laryngeal and lower anxiety in upper cranial persisted after correcting for pain and dystonia severity. CONCLUSION: Anxiety and social anxiety severity vary by onset site of focal dystonia, and this variation is not explained by differences in pain and dystonia severity.

Clinical and genetic features of cervical dystonia in a large multicenter cohort.

OBJECTIVE: To characterize the clinical and genetic features of cervical dystonia (CD). METHODS: Participants enrolled in the Dystonia Coalition biorepository (NCT01373424) with initial manifestation as CD were included in this study (n = 1,000). Data intake included demographics, family history, and the Global Dystonia Rating Scale. Participants were screened for sequence variants (SVs) in GNAL, THAP1, and Exon 5 of TOR1A. RESULTS: The majority of participants were Caucasian (95%) and female (75%). The mean age at onset and disease duration were 45.5 ± 13.6 and 14.6 ± 11.8 years, respectively. At the time of assessment, 68.5% had involvement limited to the neck, shoulder(s), and proximal arm(s), whereas 47.4% had dystonia limited to the neck. The remaining 31.5% of the individuals exhibited more extensive anatomical spread. A head tremor was noted in 62% of the patients. Head tremor and laryngeal dystonia were more common in females. Psychiatric comorbidities, mainly depression and anxiety, were reported by 32% of the participants and were more common in females. Family histories of dystonia, parkinsonian disorder, and tremor were present in 14%, 11%, and 29% of the patients, respectively. Pathogenic or likely pathogenic SVs in THAP1, TOR1A, and GNAL were identified in 8 participants (0.8%). Two individuals harbored novel missense SVs in Exon 5 of TOR1A. Synonymous and noncoding SVs in THAP1 and GNAL were identified in 4% of the cohort. CONCLUSIONS: Head tremor, laryngeal dystonia, and psychiatric comorbidities are more common in female participants with CD. Coding and noncoding variants in GNAL, THAP1, and TOR1A make small contributions to the pathogenesis of CD.