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.

Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations: Experience from the MJFF Global Genetic Parkinson's Disease Project.

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.

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.

Genotype-Phenotype Relations in Primary Familial Brain Calcification: Systematic MDSGene Review.

This systematic MDSGene review covers individuals with confirmed genetic forms of primary familial brain calcification (PFBC) available in the literature. Data on 516 (47% men) individuals, carrying heterozygous variants in SLC20A2 (solute carrier family 20 member 2, 61%), PDGFB (platelet-derived growth factor subunit B, 12%), XPR1 (xenotropic and polytropic retrovirus receptor, 16%), or PDGFRB (platelet-derived growth factor receptor beta, 5%) or biallelic variants in MYORG (myogenesis-regulating glycosidase, 13%) or JAM2 (junctional adhesion molecule 2, 2%), were extracted from 93 articles. Nearly one-third of the mutation carriers were clinically unaffected. Carriers of PDGFRB variants were more likely to be clinically unaffected (~54%), and the penetrance of SLC20A2 and XPR1 variants (<70%) was lower in comparison to the remaining three genes (>85%). Among the 349 clinically affected patients, 27% showed only motor and 31% only nonmotor symptoms/signs, whereas the remaining 42% had a combination thereof. While parkinsonism and speech disturbance were the most frequently reported motor manifestations, cognitive deficits, headache, and depression were the major nonmotor symptoms/signs. The basal ganglia were always calcified, and the cerebellum, thalamus, and white matter contained calcifications in 58%, 53%, and 43%, respectively, of individuals. In autosomal-dominant PFBC, mutation severity influenced the number of calcified brain areas, which in turn correlated with the clinical status, whereby the risk of developing symptoms/signs more than doubled for each additional region with calcifications. Our systematic analysis provides the most comprehensive insight into genetic, clinical, and neuroimaging features of known PFBC forms, to date. In addition, it puts forth the penetrance estimates and newly discovered genotype-phenotype relations that will improve counseling of individuals with mutations in PFBC genes. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genotype-Phenotype Relations for the Atypical Parkinsonism Genes: MDSGene Systematic Review.

This Movement Disorder Society Genetic mutation database Systematic Review focuses on monogenic atypical parkinsonism with mutations in the ATP13A2, DCTN1, DNAJC6, FBXO7, SYNJ1, and VPS13C genes. We screened 673 citations and extracted genotypic and phenotypic data for 140 patients (73 families) from 77 publications. In an exploratory fashion, we applied an automated classification procedure via an ensemble of bootstrap-aggregated ("bagged") decision trees to distinguish these 6 forms of monogenic atypical parkinsonism and found a high accuracy of 86.5% (95%CI, 86.3%-86.7%) based on the following 10 clinical variables: age at onset, spasticity and pyramidal signs, hypoventilation, decreased body weight, minimyoclonus, vertical gaze palsy, autonomic symptoms, other nonmotor symptoms, levodopa response quantification, and cognitive decline. Comparing monogenic atypical with monogenic typical parkinsonism using 2063 data sets from Movement Disorder Society Genetic mutation database on patients with SNCA, LRRK2, VPS35, Parkin, PINK1, and DJ-1 mutations, the age at onset was earlier in monogenic atypical parkinsonism (24 vs 40 years; P = 1.2647 × 10-12) and levodopa response less favorable than in patients with monogenic typical presentations (49% vs 93%). In addition, we compared monogenic to nonmonogenic atypical parkinsonism using data from 362 patients with progressive supranuclear gaze palsy, corticobasal degeneration, multiple system atrophy, or frontotemporal lobar degeneration. Although these conditions share many clinical features with the monogenic atypical forms, they can typically be distinguished based on their later median age at onset (64 years; IQR, 57-70 years). In conclusion, age at onset, presence of specific signs, and degree of levodopa response inform differential diagnostic considerations and genetic testing indications in atypical forms of parkinsonism. © 2021 International Parkinson and Movement Disorder Society.

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.

Expanding Data Collection for the MDSGene Database: X-linked Dystonia-Parkinsonism as Use Case Example.

MDSGene is an online database on movement disorders that collates genetic and clinical knowledge using a standardized published literature abstraction strategy. This review is dedicated to X-linked dystonia-parkinsonism (XDP). We screened 233 citations and curated phenotypic and genotypic data for 414 cases. To reduce data missingness, we (1) contacted authors and engaged the research community to provide additional clinical and genetic information, and (2) revisited previously unpublished data from a cohort of XDP patients seen at our institution. Using these approaches, we expanded the cohort to 577 cases and increased information available for important clinical and genetic features such as age at onset, initial manifestation, predominant motor symptoms, functional impairments, and repeat size information. We established the use of mining unpublished data to expand the MDSGene workflow and present an up-to-date description of the phenomenology of XDP using an extensive collection of previously reported and unreported data. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genotype-phenotype relations for the Parkinson's disease genes SNCA, LRRK2, VPS35: MDSGene systematic review.

This comprehensive MDSGene review is devoted to the three autosomal-dominant PD forms: PARK-SNCA, PARK-LRRK2, and PARK-VPS35. It follows MDSGene's standardized data extraction protocol, screened a total of 2,972 citations, and is based on fully curated phenotypic and genotypic data on 937 patients with dominantly inherited PD attributed to 44 different mutations in SNCA, LRRK2, or VPS35. All of these data are also available in an easily searchable online database (www.mdsgene.org), which additionally provides descriptive summary statistics on phenotypic and genetic data. Despite the high degree of missingness of phenotypic features and unsystematic reporting of genotype data in the original literature, the present review recapitulates many of the previously described findings including later onset of disease (median age at onset: ∼49 years) compared to recessive forms of PD of an overall excellent treatment response. Our systematic review validates previous reports showing that SNCA mutation carriers have a younger age at onset compared to LRRK2 and VPS35 (P < 0.001). SNCA mutation carriers often have additional psychiatric symptoms, and although not exclusive to only LRRK2 or VPS35 mutation carriers, LRRK2 mutation carriers have a typical form of PD, and, lastly, VPS35 mutation carriers have good response to l-dopa. © 2018 International Parkinson and Movement Disorder Society.

Motor protein binding and mitochondrial transport are altered by pathogenic TUBB4A variants.

Mutations in TUBB4A have been identified to cause a wide phenotypic spectrum of diseases ranging from hereditary generalized dystonia with whispering dysphonia (DYT-TUBB4A) and hereditary spastic paraplegia (HSP) to leukodystrophy hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). TUBB4A encodes the brain-specific ß-tubulin isotype, ß-tubulin 4A. To elucidate the pathogenic mechanisms conferred by TUBB4A mutations leading to the different phenotypes, we functionally characterized three pathogenic TUBB4A variants (c.4C>G,p.R2G; c.745G>A,p.D249N; c.811G>A, p.A271T) as representatives of the mutational and disease spectrum) in human neuroblastoma cells and human induced pluripotent stem cell (iPSC)-derived neurons. We showed that mRNA stability was not affected by any of the TUBB4A variants. Although two mutations (p.R2G and p.D249N) are located at the α/ß-tubulin interdimer interface, we confirmed incorporation of all TUBB4A mutants into the microtubule network. However, we showed that the mutations p.D249N and p.A271T interfered with motor protein binding to microtubules and impaired neurite outgrowth and microtubule dynamics. Finally, TUBB4A mutations, as well as heterozygous knockout of TUBB4A, disrupted mitochondrial transport in iPSC-derived neurons. Taken together, our findings suggest that functional impairment of microtubule-associated transport is a shared pathogenic mechanism by which the TUBB4A mutations studied here cause a spectrum of diseases.

Genotype-Phenotype Relations for the Parkinson's Disease Genes Parkin, PINK1, DJ1: MDSGene Systematic Review.

This first comprehensive MDSGene review is devoted to the 3 autosomal recessive Parkinson's disease forms: PARK-Parkin, PARK-PINK1, and PARK-DJ1. It followed MDSGene's standardized data extraction protocol and screened a total of 3652 citations and is based on fully curated phenotypic and genotypic data on >1100 patients with recessively inherited PD because of 221 different disease-causing mutations in Parkin, PINK1, or DJ1. All these data are also available in an easily searchable online database (www.mdsgene.org), which also provides descriptive summary statistics on phenotypic and genetic data. Despite the high degree of missingness of phenotypic features and unsystematic reporting of genotype data in the original literature, the present review recapitulates many of the previously described findings including early onset (median age at onset of ∼30 years for carriers of at least 2 mutations in any of the 3 genes) of an overall clinically typical form of PD with excellent treatment response, dystonia and dyskinesia being relatively common and cognitive decline relatively uncommon. However, when comparing actual data with common expert knowledge in previously published reviews, we detected several discrepancies. We conclude that systematic reporting of phenotypes is a pressing need in light of increasingly available molecular genetic testing and the emergence of first gene-specific therapies entering clinical trials. © 2018 International Parkinson and Movement Disorder Society.