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Pathogenic variants in the LRRK2 gene are one of the most commonly identifiable monogenic causes of Parkinson´s disease (PD, PARK-LRRK2). This systematic MDSGene literature review comprehensively summarizes published demographic, clinical, and genetic findings related to LRRK2 variants ( https://www.mdsgene.org/ ). Data on 4660 individuals with 283 different variants were curated. The median age at onset in the PD patients with available information was 56 years, notably, with approximately one-third having PD onset <50 years. Tremor was the most frequently reported initial symptom and more common than reported in other dominantly inherited forms of PD. Of the 211 potentially PD-causing variants, 25 were classified as pathogenic or likely pathogenic, and the remaining 186 (88.2%) were variants of uncertain significance. p.G2019S was the most frequently reported pathogenic variant, followed by p.R1441G and p.R1441C. This systematic review represents the most extensive database on PARK-LRRK2 to date and provides a vital resource to improve precision medicine., Competing Interests: Competing interests: The authors declare no competing interests. C.M. has received honoraria from the Parkinson’s Foundation. C.K. serves as a medical advisor to Centogene and Takeda and previously to Retromer Therapeutics and has received Speakers’ honoraria from Desitin and Bial. K.L. is an Associate Editor at npj Parkinson’s Disease. K.L. was not involved in the journal’s review of, or decisions related to, this manuscript., (© 2025. The Author(s).)

Depending on zygosity and the specific change, different variants in the GBA1 gene can cause Parkinson's disease (PD, PARK-GBA1) with reduced penetrance, act as genetic risk factors for PD or parkinsonism, and/or lead to Gaucher's disease (GD). This MDSGene systematic literature review covers 27,963 patients carrying GBA1 variants from 1082 publications with 794 variants, including 13,342 patients with PD or other forms of parkinsonism. It provides a comprehensive overview of demographic, clinical, and genetic findings from an ethnically diverse sample originating from 82 countries across five continents. The most frequent pathogenic or likely pathogenic variants were "N409S" (aka "N370S"; dominating among Jewish and Whites), and "L483P" (aka "L444P"; dominating among Asians and Hispanics), whereas the most common coding risk variants were "E365K" (E326K), and "T408M" (T369M) (both common among Whites). A novel finding is that early-onset PD patients were predominantly of Asian ethnicity, whereas late-onset PD patients were mainly of White ethnicity. Motor cardinal features were similar between PD patients and other forms of parkinsonism, whereas motor complications and non-motor symptoms were more frequently reported in PD patients carrying "severe" variants than in those with "risk" or "mild" variants. Cognitive decline was reported in most patients after surgical treatment, despite achieving a beneficial motor function response. Most GD patients developing PD harbored the "N409S" variant, were of Ashkenazi Jewish ethnicity, and showed a positive response to chronic levodopa treatment. With this review, we start to fill the gaps regarding genotype-phenotype correlations in GBA1 variant carriers, especially concerning PD. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background and Objectives: In the era of precision medicine, genetic test results have become increasingly relevant in the care of patients with Parkinson disease (PD). While large research consortia are performing widespread research genetic testing to accelerate discoveries, debate continues about whether, and to what extent, the results should be returned to patients. Ethically, it is imperative to keep participants informed, especially when findings are potentially actionable. However, research testing may not hold the same standards required from clinical diagnostic laboratories and hold significant psychosocial implications. The absence of universally recognized protocols complicates the establishment of appropriate guidelines., Methods: Aiming to develop recommendations on return of research results (RoR) practice within the Global Parkinson's Genetics Program (GP2), we conducted a global survey to gain insight on GP2 members' perceptions, practice, readiness, and needs surrounding RoR., Results: GP2 members (n = 191), representing 147 institutions and 60 countries across 6 continents, completed the survey. Access to clinical genetic testing services was significantly higher in high-income countries compared with low- and middle-income countries (96.6% vs 58.4%), where funding was predominantly covered by patients themselves. While 92.7% of the respondents agreed that genetic research results should be returned, levels of agreement were higher for clinically relevant results relating to pathogenic or likely pathogenic variants in genes known to cause PD or other neurodegenerative diseases. Less than 10% offered separate clinically accredited genetic testing before returning genetic research results. A total of 48.7% reported having a specific statement on RoR policy in their ethics consent form, while 53.9% collected data on participants' preferences on RoR prospectively. 24.1% had formal genetic counselling training. Notably, the comfort level in returning incidental genetic findings or returning results to unaffected individuals remains low., Discussion: Given the differences in resources and training for RoR, as well as ethical and regulatory considerations, tailored approaches are required to ensure equitable access to RoR. Several identified strategies to enhance RoR practices include improving informed consent processes, increasing capacity for genetic counselling including providing counselling toolkits for common genetic variants, broadening access to sustainable clinically accredited testing, building logistical infrastructure for RoR processes, and continuing public and health care education efforts on the important role of genetics in PD., Competing Interests: The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: 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 a global scale., Objective: To identify the multi-ancestry spectrum of monogenic PD., Methods: The first systematic approach to embrace monogenic PD worldwide, The Michael J. Fox Foundation Global Monogenic PD Project, contacted authors of publications reporting individuals carrying pathogenic variants in known PD-causing genes. In contrast, the Global Parkinson's Genetics Program's Monogenic Network took a different approach by targeting PD centers underrepresented or not yet represented in the medical literature., Results: In this article, we describe combining both efforts in a merger project resulting in a global monogenic PD cohort with the buildup of a sustainable infrastructure to identify the multi-ancestry spectrum of monogenic PD and enable studies of factors modifying penetrance and expressivity of monogenic PD., Conclusions: This effort demonstrates the value of future research based on team science approaches to generate comprehensive and globally relevant results. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

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.

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., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Roy N. Alcalay received consulting fees from Avrobio, Caraway, Ono Therapeutics, GSK, Merck, Sanofi, Janssen and grants from the Michael J. Fox Foundation, DOD, the Parkinson’s Disease Foundation, and the NIH. Melinda Barkhuizen received a PhD scholarship from the National Research Foundation of South Africa (grant numbers 89230 and 98217) and internal funding from the research center where the study was conducted (DST/NWU Preclinical Drug Development Platform, North-West University, South Africa); Ampath Pathology laboratories in South Africa donated services in the form of drawing participant blood for DNA extractions, Several neurologists in South Africa assisted the authors with identifying patients with Parkinson`s disease and referring them to the genotyping study; the North-West University, South Africa provided Ethical oversight and approval of the genotyping project. Vincenzo Bonifati received grants from Stichting Parkinson Fonds (Netherlands) and Alzheimer Nederland, he received honoraria from the International Parkinson and Movement Disorder Society (MDS), for lectures and as Chair of the International Congress Scientific Program Committee (2020-2021), and from Elsevier Ltd. as co-Editor in Chief of the journal Parkinsonism & Related Disorders (2018-current); he is unpaid member of the Stichting Parkinson Fonds (Netherlands). Kathrin Brockmann received grants from the German Federal Ministry of Education and Research (BMBF; PDStrat; FKZ 031L0137B) and from the German Center for Neurodegenerative Diseases (DZNE), consulting fees from Abbvie, Lundbeck, UCB, Zambon, Roche, and honoraria from Abbvie and UCB. Jordi Clarimon is full-time employee at Lundbeck A/S (Denmark). Mario Cornejo-Olivas has subcontracts with Cleveland Clinic and San Marcos Foundation for recruiting participants for the LARGE PD study in Peru. Jean-Christophe Corvol received grants from Sanofi and the Michael J. Fox Foundation, consulting fees from Biogen, UCB, Denali, Idorsia, Prevail therapeutics, Theranexus, and honoraria from Biogen. Joana Damásio received honoraria from Zambon Pharmaceuticals. Anna De Rosa received grants for ROPAD – the Rostock International Parkinson’s Disease Study, sponsored by Centogene and grants from Zambon and AIFA (Italian Agency of Drug), and she is member of the advisory board at BIAL. Joaquim Ferreira received grants from Fundação MSD (Portugal), Novartis, Medtronic, and Abbvie, and lecture fees from Lundbeck, Abbvie, BIAL, Biogen, Sunovion Pharmaceuticals, ONO, Affiris, and Zambon, payment for expert testimony from Novartis, and he participates in advisory boards of Lundbeck, Abbvie, BIAL, Affiris, Sunovion Pharmaceuticals, and Zambon; he is employed by CNS (Campus Néurologico Sénior) and the Medical Faculty of Lisbon. Emilia Gatto received consulting fees from Bago Argentina, honoraria from Bago Argentina,UCB, IPMDS, and Europharm, and participates in advisory boards of Bago Argentina and UCB. Nir Giladi received grants from the Michael J Fox Foundation, The National Parkinson Foundation, The European Union, The Israel Science Foundation Teva, NNE program, Biogen, Ionis, Sieratzki Family Foundation, and The Aufzien Academic Center in Tel-Aviv University; he holds royalties or licenses at Lysosomal Therapeutics (LTI); he received consulting fees from Sionara, NeuroDerm, Pharma2B, Denali, Neuron23, Sanofi-Genzyme, Biogen, and Abbvie; he received honoraria from Abbvie, Sanofi-Genzyme, and the Movement Disorder Society. Nobutaka Hattori received grants from the Japan Society for the Promotion of Science (JSPS; 18H04043, 21H04820, 19K22603), the Japan Agency for Medical Research and Development (AMED; JP20dm0307101, JP20dm0207070, JP20ek0109358, JP19ek0109393, JP19gm0710011, JP19km0405206), Health Labour Sciences Research Grant (20FC1049, H29-FC1-062, H29-FC1-033), and the Japan Science and Technology Agency (JPMJMS2024-5); he participates in advisory boards at Dai-Nippon Sumitomo Pharma, Takeda Pharmaceutical, Kyowa Kirin, TEIJIN PHARMA LIMITED, Novartis Pharma, Ono Pharmaceutical, Biogen Idec Japan, and Kissei Pharmaceutical; he receives consulting fees from Hisamitsu Pharma; he received honoraria from Dai-Nippon Sumitomo Pharma, Takeda Pharmaceutical, Kyowa Kirin, AbbVie GK, Nippon Boehringer Ingelheim, Otsuka Pharmaceutical, Novartis Pharma, Bristol-Myers Squibb, Ono Pharmaceutical, FP Pharmaceutical, Eisai, Kissei Pharmaceutical, Nihon Medi-physics, and Daiichi Sankyo; he received payment for expert testimony from Mitsubishi Tanabe Pharma; he received support for attending meeting from Takeda Pharmaceutical, and Kyowa Kirin; he has 17 patents planned or pending and 5 issued; he is Team Leader at the Neurodegenerative Disorders Collaborative Laboratory, RIKEN Center for Brain Science; he holds equity stock (8%) of PARKINSON Laboratories Co. Ltd., unrelated to the submitted work. Silvia Jesús has received grants from “Consejería de Salud y Familias” PI-0459-2018, “acción B Clínicos-Investigdores” B-0007-2019 and from the “instituto de Salud Carlos III” PI-18/01898; she received honoraria from Abbvie, Bial, Merz, UCB, Italfarmaco, Zambon and Server. Valtteri Kaasinen received grants from Turku University Foundation, Päivikki and Sakari Sohlberg Foundation, and the Finnish Cultural Foundation; he received consulting fees from Nordic Infucare, Abbvie, and Adamant Health; he received honoraria from Nordic Infucare and Abbvie; he received Support for attending meetings and/or travel from Nordic Infucare; he participates on a Data Safety Monitoring Board or Advisory Board at Nordic Infucare and Abbvie; he is board member of the Finnish Neurological Society. Christine Klein received royalties from Oxford University Press; she received consulting fees from Centogene and Retromer Therapeutics; she received payment or honoraria from Desitin Pharma; she received support to attend meetings from the Movement Disorder Society; she participates on a Data Safety Monitoring Board or Advisory Board at the Else Kroener Fresenius Foundation. Peter Klivenyi received honoraria from Abbvie and Medtronic. Vladimir Kostic received Grant 17590 from the Ministry of Education, Science and Technological Development of Serbia; he received honoraria from Novartis and Boehringer Ingelheim. Shen-Yang Lim received the following grants, (i) Stipend - Global Parkinson’s Genetics Program (GP2) Working Group Co-Lead Award, from the Michael J. Fox Foundation, (ii) Michael J. Fox Foundation (Grant 18305: "Identifying leucocyte and urine biomarkers in PD patients with LRRK2 G2385R variant"). George Mellick received grants from the National Health and Medical Research Foundation, Australia (APP1151854, APP1084560). Lukasz Milanowski received grants from the Polish National Agency for Academic Exchange Iwanowska’s Fellowship PPN/IWA/2018/1/00006/U/00001/01, the APDA, the Foundation for Polish Science (FNP) and the Haworth Family Professorship in Neurodegenerative Diseases Fund. Pablo mir received grants from the Spanish Ministry of Science and Innovation (RTC2019-007150-1), the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER, PI19/01576), and the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PE-0210-2018); he received payment or honoraria for lectures from Abbvie, Abbott, and Zambon; he received Support for attending meetings and travel from Abbvie. Shalini Padmanabhan is employed by the Michael J. Fox Foundation. Andreas Puschmann received grants from Region Skåne, Sweden, Skåne University Hospital, Sweden, The Swedish Parkinson Academy, The Swedish Parkinson Foundation (Parkinsonfonden), MultiPark – a strategic research environment at Lund University, and Bundy Academy, Sweden; he received honoraria from Elsevier (Associate editor for Parkinsonism and Related Disorders), from the International Parkinson and Movement Disorder Society (MDS), and from the International Association of Parkinsonism and Related Disorders; he received support for travels from the International Association of Parkinsonism and Related Disorders; he is board member of the International Association of Parkinsonism and Related Disorders. Mariana Spitz received funding from Centogene for the ROPAD study; she received support for travels from Roche. Justin Solle is employed by the Michel J. Fox Foundation. Oksana Suchowersky received grants from Roche and WaveLifeSciences; she holds royalties or licenses at UpToDate; she received consulting fees from Abbvie and Sunovion; she received honoraria from the World Parkinson Conference; she participates in advisory boards at Alexion; she is board member of the Parkinson Society Alberta. Pichet Termsarasab received book royalties from Elsevier and Springer Nature Switzerland; he received honoraria for manuscript writing from MedLink Neurology and for lectures from Viatris. Bart van de Warrenburg received grants from Radboudumc, ZonMW, Hersenstichting, Gossweiler Foundation, and the Michael J Fox Foundation; he holds royalties or licenses at BSL Springer Nature; he received consulting fees from uniQure; he received honoraria from UKM Medical Center Kuala Lumpur; he participates in Medical advisory board of patient organizations (unpaid); he is unpaid member of Steering committees or executive boards of various research consortia; he received a wearable sensor set by Brugling Fund/Hersenstichting. Caroline H. Williams-Gray collaborates with Astra-Zeneca on the microbiome in Parkinson’s disease; she received consultancy fees from Modus Outcomes and Evidera, Inc./GlaxoSmithKline; she received honoraria from Profile Pharma Limited. Eva-Juliane Vollstedt, Harutyun Madoev, Anna Aasly, Azlina Ahmad-Annuar, Bashayer Al-Mubarak, Victoria Alvarez, Ignacio Amorin, Grazia Annesi, David Arkadir, Soraya Bardien, Roger A. Barker, A. Nazli Basak, Agnita Boon, Laura Brighina, Andrea Carmine Belin, Jonathan Carr, Leonor Correia Guedes, David Crosiers, Parimal Das, Patricia de Carvalho Aguiar, Jolanta Dorszewska, Sibel Ertan, Rosangela Ferese, Gençer Genç, Pilar Gómez-Garre, Hasmet Hanagasi, Faycal Hentati, Dorota Hoffman-Zacharska, Sergey N. Illarioshkin, Joseph Jankovic, Anneke Kievit, Dariusz Koziorowski, Andrea A. Kühn, Anthony E. Lang, Chin-Hsien Lin, Katja Lohmann, Vladana Markovic, Mika Henrik Martikainen, Marcelo Merello, Özgür Öztop-Çakmak, Márcia Mattos Gonçalves Pimentel, Teeratorn Pulkes, Ekaterina Rogaeva, Esther M. Sammler, Maria Skaalum Petersen, Matej Skorvanek, Ai Huey Tan, Avner Thaler, Vitor Tumas, Enza Maria Valente, Ruey-Mei Wu, Baorong Zhang, and Alexander Zimprich report no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Vollstedt et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Most episodic ataxias (EA) are autosomal dominantly inherited and characterized by recurrent attacks of ataxia and other paroxysmal and non-paroxysmal features. EA is often caused by pathogenic variants in the CACNA1A, KCNA1, PDHA1, and SLC1A3 genes, listed as paroxysmal movement disorders (PxMD) by the MDS Task Force on the Nomenclature of Genetic Movement Disorders. Little is known about the genotype-phenotype correlation of the different genetic EA forms., Methods: We performed a systematic review of the literature to identify individuals affected by an episodic movement disorder harboring pathogenic variants in one of the four genes. We applied the standardized MDSGene literature search and data extraction protocol to summarize the clinical and genetic features. All data are available via the MDSGene protocol and platform on the MDSGene website (https://www.mdsgene.org/)., Results: Information on 717 patients (CACNA1A: 491, KCNA1: 125, PDHA1: 90, and SLC1A3: 11) carrying 287 different pathogenic variants from 229 papers was identified and summarized. We show the profound phenotypic variability and overlap leading to the absence of frank genotype-phenotype correlation aside from a few key 'red flags'., Conclusion: Given this overlap, a broad approach to genetic testing using a panel or whole exome or genome approach is most practical in most circumstances., (© 2023 European Academy of Neurology.)

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., (© 2023. The Author(s).)

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., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

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., (© 2021 International Parkinson and Movement Disorder Society.)

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., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

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., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

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., (© 2018 International Parkinson and Movement Disorder Society.)

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 β-tubulin isotype, β-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/β-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., (© 2018 Wiley Periodicals, Inc.)

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., (© 2018 International Parkinson and Movement Disorder Society.)