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Parkinson Disease: HELP
Articles by Christine Klein
Based on 118 articles published since 2010
(Why 118 articles?)
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Between 2010 and 2020, Christine Klein wrote the following 118 articles about Parkinson Disease.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5
1 Editorial Using global team science to identify genetic parkinson's disease worldwide. 2019

Vollstedt, Eva-Juliane / Kasten, Meike / Klein, Christine / Anonymous4411147. ·Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. · Institute of Neurogenetics and Department of Psychiatry, University of Lübeck, Lübeck, Germany. ·Ann Neurol · Pubmed #31155756.

ABSTRACT: -- No abstract --

2 Editorial What would Dr. James Parkinson think today? The role of genetics in Parkinson's disease. 2017

Lill, Christina M / Klein, Christine. ·Institute of Neurogenetics, University of Luebeck, Luebeck, Germany. ·Mov Disord · Pubmed #28836355.

ABSTRACT: -- No abstract --

3 Editorial Genetic risk loci for Parkinson's disease: Moving from state to trait? 2015

Kasten, Meike / Klein, Christine. ·Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. · Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany. ·Mov Disord · Pubmed #25907561.

ABSTRACT: -- No abstract --

4 Editorial MicroRNAs as biomarker of Parkinson disease? Small but mighty. 2015

Marz, Manja / Ferracin, Manuela / Klein, Christine. ·From the Department of Bioinformatics (M.M.), Faculty of Mathematics and Computer Science, Friedrich Schiller University of Jena, Germany · Department of Morphology, Surgery and Experimental Medicine (M.F.), and Laboratory for the Technologies of Advanced Therapies, University of Ferrara, Italy · and Institute of Neurogenetics (C.K.), University of Luebeck, Germany. ·Neurology · Pubmed #25596504.

ABSTRACT: -- No abstract --

5 Review LRRK2 in Parkinson disease: challenges of clinical trials. 2020

Tolosa, Eduardo / Vila, Miquel / Klein, Christine / Rascol, Olivier. ·Parkinson and Movement Disorders Unit, Neurology Service, Hospital Clinic of Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Spain. etolosa@clinic.cat. · Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain. etolosa@clinic.cat. · Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain. · Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute (VHIR), Autonomous University of Barcelona, Barcelona, Spain. · Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain. · Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. · Clinical Investigation Center CIC1436, Departments of Clinical Pharmacology and Neurosciences, NS-Park/FCRIN network and NeuroToul Center of Excellence for Neurodegeneration, INSERM, University Hospital of Toulouse and University of Toulouse, Toulouse, France. ·Nat Rev Neurol · Pubmed #31980808.

ABSTRACT: One of the most common monogenic forms of Parkinson disease (PD) is caused by mutations in the LRRK2 gene that encodes leucine-rich repeat kinase 2 (LRRK2). LRRK2 mutations, and particularly the most common mutation Gly2019Ser, are observed in patients with autosomal dominant PD and in those with apparent sporadic PD, who are clinically indistinguishable from those with idiopathic PD. The discoveries that pathogenic mutations in the LRRK2 gene increase LRRK2 kinase activity and that small-molecule LRRK2 kinase inhibitors can be neuroprotective in preclinical models of PD have placed LRRK2 at the centre of disease modification efforts in PD. Recent investigations also suggest that LRRK2 has a role in the pathogenesis of idiopathic PD and that LRRK2 therapies might, therefore, be beneficial in this common subtype of PD. In this Review, we describe the characteristics of LRRK2-associated PD that are most relevant to the development of LRRK2-targeted therapies and the design and implementation of clinical trials. We highlight strategies for correcting the effects of mutations in the LRRK2 gene, focusing on how to identify which patients are the optimal candidates and how to decide on the timing of such trials. In addition, we discuss challenges in implementing trials of disease-modifying treatment in people who carry LRRK2 mutations.

6 Review MDSGene: Closing Data Gaps in Genotype-Phenotype Correlations of Monogenic Parkinson's Disease. 2018

Klein, Christine / Hattori, Nobutaka / Marras, Connie. ·Institute of Neurogenetics, University of Luebeck, Luebeck, Germany. · Edmond J Safra Program in Parkinson's disease, University Health Network, University of Toronto, Canada. · Department of Neurology, Juntendo University, Bunkyo, Tokyo, Japan. ·J Parkinsons Dis · Pubmed #30584170.

ABSTRACT: Given the rapidly increasing number of reported movement disorder genes and clinical-genetic desciptions of mutation carriers, the International Parkinson's Disease and Movement Disorder Society Gene Database (MDSGene) initiative has been launched in 2016 and grown to become a large international project (http://www.mdsgene.org). MDSGene currently contains >1150 variants described in ∼5700 movement disorder patients in almost 1000 publications including monogenic forms of PD clinically resembling idiopathic (PARK-PINK1, PARK-Parkin, PARK-DJ-1, PARK-SNCA, PARK-VPS35, PARK-LRRK2), as well as of atypical PD (PARK-SYNJ1, PARK-DNAJC6, PARK-ATP13A2, PARK-FBXO7). Inclusion of genes is based on standardized published criteria for determining causation. Clinical and genetic information can be filtered according to demographic, clinical or genetic criteria and summary statistics are automatically generated by the MDSGene online tool. Despite MDSGene's novel approach and features, it also faces several challenges: i) The criteria for designating genes as causative will require further refinement, as well as time and support to replace the faulty list of 'PARKs'. ii) MDSGene has uncovered extensive clinical data gaps. iii) The quickly growing body of clinical and genetic data require a large number of experts worldwide posing logistic challenges. iv) MDSGene currently captures published data only, i.e., a small fraction of the available information on monogenic PD available. Thus, an important future aim is to extend MDSGene to unpublished cases in order to provide the broad data base to the PD community that is necessary to comprehensively inform genetic counseling, therapeutic approaches and clinical trials, as well as basic and clinical research studies in monogenic PD.

7 Review Nonmotor Signs in Genetic Forms of Parkinson's Disease. 2017

Kasten, Meike / Marras, Connie / Klein, Christine. ·University of Lübeck, Lübeck, Germany. · Toronto Western Hospital Morton and Gloria Shulman Movement Disorders Centre and the Edmond J. Safra Program in Parkinson's Disease, University of Toronto, Toronto, Ontario, Canada. · Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. Electronic address: christine.klein@neuro.uni-luebeck.de. ·Int Rev Neurobiol · Pubmed #28802919.

ABSTRACT: Although only a minority (i.e., ~5%) of Parkinson's disease (PD) cases is due to well-defined genetic causes, important clues about the common, "idiopathic" PD (iPD) can be garnered from monogenic model diseases. Nonmotor signs (NMS) are also present in monogenic PD and reviewed in this chapter for the confirmed PD genes SNCA, LRRK2, VPS35, Parkin, PINK1, DJ-1, and the risk factor gene GBA. Within the context of the MDSGene database (www.mdsgene.org), we performed a systematic literature search and extracted information on cognitive decline, depression, psychotic signs and symptoms, autonomic signs and symptoms, anxiety, sleep disorder, and olfactory impairment. Notably, relatively few studies specifically addressed NMS in genetic PD and missing data ranged from 42% to 100%. Diagnostic criteria and examination methods were variable and cases differed widely for age at onset, disease duration, ethnicity, treatment, and comorbidity. Although in comparison to IPD, SNCA duplication carriers have the most similar course of disease, even for duplication carriers the frequencies of dementia, hallucinations, and depression seem higher than in IPD. Supporting the notion that LRRK2-linked PD has a similar course to iPD but is slightly more benign, the frequency of dementia is below that of iPD. For Parkin, the frequency of cognitive decline falls within the range of the general population above the age of 65 years. GBA mutations are associated with a distinct profile of cognitive impairment and a greater prevalence of depression. Despite the current data gaps, NMS should be considered as an important and often treatable concomitant feature of genetic parkinsonism.

8 Review Early-Onset Parkinsonism: Case Report and Review of the Literature. 2017

Al-Rumayyan, Ahmed / Klein, Christine / Alfadhel, Majid. ·King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; Neurology Division, Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia. Electronic address: rumayyana@ksau-hs.edu.sa. · Institute of Neurogenetics, University of Luebeck, Germany. · King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; Genetics Division, Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia. ·Pediatr Neurol · Pubmed #28062148.

ABSTRACT: BACKGROUND: Early-onset parkinsonism can be caused by PTEN-induced putative kinase 1 (PINK1) gene defects and is usually characterized by an age of onset in the fourth decade of life, slow disease progression, resting tremor, rigidity, bradykinesia, postural instability, and levodopa-induced dyskinesia. METHODS: We evaluated a child with early-onset symptoms and performed a literature review for previously reported examples of children aged 18 years or less with PINK1 gene defects. RESULTS: We describe a five-year-old boy with autosomal recessive early-onset parkinsonism caused by a homozygous missense mutation in the PINK1 gene. This is the youngest individual yet reported with early-onset parkinsonism. CONCLUSION: PINK1-type of early-onset parkinsonism can occur in very young patients, and phenotypic expression of PINK1 mutations may depend on age of onset and ethnicity.

9 Review iPS models of Parkin and PINK1. 2015

Rakovic, Aleksandar / Seibler, Philip / Klein, Christine. ·*Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. ·Biochem Soc Trans · Pubmed #25849934.

ABSTRACT: Parkinson disease (PD) is a degenerative disorder of the central nervous system resulting from depletion of dopaminergic neurons and currently remains incurable despite enormous international research efforts. The development of induced pluripotent stem cell (iPSC) technology opened up the unique possibility of studying disease mechanisms in human tissue that was otherwise not accessible, such as the brain. Of particular interest are the monogenetic forms of PD as they closely resemble the more common 'idiopathic' PD and, through the mutated protein, provide a clear research target in iPSC-derived neurons. Recessively inherited Parkin and PTEN-induced putative kinase 1 (PINK1) mutations have been investigated in this context and the present review describes the first insights gained from studies in iPSC-derived dopaminergic neurons, which comprise abnormalities in mitochondrial and dopamine homoeostasis, microtubular stability and axonal outgrowth. These new models of PD have a high translational potential that includes the identification of druggable targets, testing of known and novel therapeutic agents in the disease-relevant tissue using well-defined read-outs and potential regenerative approaches.

10 Review Stimulation of electron transport as potential novel therapy in Parkinson's disease with mitochondrial dysfunction. 2015

Vos, Melissa / Verstreken, Patrik / Klein, Christine. ·*Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. · †VIB Center for the Biology of Disease, Leuven, Belgium. ·Biochem Soc Trans · Pubmed #25849929.

ABSTRACT: Parkinson's disease (PD) is a neurodegenerative motor disorder characterized by the loss of dopaminergic neurons. This loss of dopaminergic neurons is the pathological hallmark of the disease that results in the characteristic motor syndrome. Restoration of dopamine levels is the basis of current therapy; however, this does not tackle the cause of the disease. While the aetiology of PD remains mostly elusive, mitochondrial dysfunction has been linked to (at least) part of the PD cases. In this review we discuss recent findings in Drosophila melanogaster showing that stimulation of the electron transport chain is beneficial for PD fly models showing Complex I defects and discuss the possible clinical applications of these findings.

11 Review Next-generation phenotyping using the parkin example: time to catch up with genetics. 2013

Grünewald, Anne / Kasten, Meike / Ziegler, Andreas / Klein, Christine. ·Insitute of Neurogenetics, University of Lübeck, Lübeck, Germany. ·JAMA Neurol · Pubmed #23835509.

ABSTRACT: IMPORTANCE: Two decades of intense research have led to important insights into the pathophysiology of neurodegenerative diseases, with limited direct clinical impact. While next-generation sequencing has emerged as a powerful research tool, we hypothesized that systematic exploitation of phenotypic data are lagging behind genetic advances. OBJECTIVES: To use the 15-year experience with parkin-associated Parkinson disease (PD) to evaluate type, quality, and quantity of genetic and phenotypic data and to elucidate clinical or genetic features impacting genetic testing and counseling. EVIDENCE REVIEW: We searched MEDLINE: (1998-2012) using the term parkin AND mutation for English publications about proved parkin-associated PD and at least minimal, individual clinical information excluding digenic cases, and redundant articles. This approach identified 877 articles, of which 196 described patients with PD with confirmed parkin mutations and 127 articles fulfilled our inclusion criteria. Information was extracted using predefined criteria and a consensus approach for questionable details. To evaluate study method differences, we devised a quality score representing the completeness of clinical, demographic, and genetic information. FINDINGS: In the data about 1184 patients, the quality score increased steadily and was driven exclusively by improvements in genetic analyses. By contrast, demographic and clinical content stagnated. The mean age at onset was 9 years lower in index patients with 2 mutant parkin alleles than in heterozygotes. Genotype-phenotype correlation was observed for the number of mutated alleles and dystonia. By contrast, dementia was rare in all parkin-mutation carriers (<3%), despite long disease duration. CONCLUSIONS AND RELEVANCE: Notwithstanding large gaps in phenotypic information content, we identified dystonia and the absence of dementia as "red flags" to be incorporated in counseling guidelines. We propose mandatory minimal criteria for genotype-phenotype studies to facilitate the next breakthrough-following genetics-toward more personalized medicine for genetic conditions, extending well beyond the parkin example.

12 Review Lysosomal impairment in Parkinson's disease. 2013

Dehay, Benjamin / Martinez-Vicente, Marta / Caldwell, Guy A / Caldwell, Kim A / Yue, Zhenyue / Cookson, Mark R / Klein, Christine / Vila, Miquel / Bezard, Erwan. ·Institute of Neurodegenerative Diseases, University of Bordeaux Segalen, Centre National de Recherche Scientifique Unité Mixte de Recherche 5293, Bordeaux, France. benjamin.dehay@u-bordeaux2.fr ·Mov Disord · Pubmed #23580333.

ABSTRACT: Impairment of autophagy-lysosomal pathways (ALPs) is increasingly regarded as a major pathogenic event in neurodegenerative diseases, including Parkinson's disease (PD). ALP alterations are observed in sporadic PD brains and in toxic and genetic rodent models of PD-related neurodegeneration. In addition, PD-linked mutations and post-translational modifications of α-synuclein impair its own lysosomal-mediated degradation, thereby contributing to its accumulation and aggregation. Furthermore, other PD-related genes, such as leucine-rich repeat kinase-2 (LRRK2), parkin, and phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), have been mechanistically linked to alterations in ALPs. Conversely, mutations in lysosomal-related genes, such as glucocerebrosidase (GBA) and lysosomal type 5 P-type ATPase (ATP13A2), have been linked to PD. New data offer mechanistic molecular evidence for such a connection, unraveling a causal link between lysosomal impairment, α-synuclein accumulation, and neurotoxicity. First, PD-related GBA deficiency/mutations initiate a positive feedback loop in which reduced lysosomal function leads to α-synuclein accumulation, which, in turn, further decreases lysosomal GBA activity by impairing the trafficking of GBA from the endoplasmic reticulum-Golgi to lysosomes, leading to neurodegeneration. Second, PD-related mutations/deficiency in the ATP13A2 gene lead to a general lysosomal impairment characterized by lysosomal membrane instability, impaired lysosomal acidification, decreased processing of lysosomal enzymes, reduced degradation of lysosomal substrates, and diminished clearance of autophagosomes, collectively contributing to α-synuclein accumulation and cell death. According to these new findings, primary lysosomal defects could potentially account for Lewy body formation and neurodegeneration in PD, laying the groundwork for the prospective development of new neuroprotective/disease-modifying therapeutic strategies aimed at restoring lysosomal levels and function.

13 Review Genetics of Parkinson disease and other movement disorders. 2012

Kumar, Kishore R / Lohmann, Katja / Klein, Christine. ·Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lübeck, Lübeck, Germany. ·Curr Opin Neurol · Pubmed #22772876.

ABSTRACT: PURPOSE OF REVIEW: We will review the recent advances in the genetics of Parkinson disease and other movement disorders such as dystonia, essential tremor and restless legs syndrome (RLS). RECENT FINDINGS: Mutations in VPS35 were identified as a novel cause of autosomal dominant Parkinson disease using exome sequencing. Next generation sequencing (NGS) was also used to identify PRRT2 mutations as a cause of paroxysmal kinesigenic dyskinesia (DYT10). Using a different technique, that is linkage analysis, mutations in EIF4G1 were implicated as a cause of Parkinson disease and mutations in SLC20A2 as a cause of familial idiopathic basal ganglia calcification. Furthermore, genome-wide association studies (GWAS) and meta-analyses have confirmed known risk genes and identified new risk loci in Parkinson disease, RLS and essential tremor. New models to study genetic forms of Parkinson disease, such as stem cell-derived neurons, have helped to elucidate disease-relevant molecular pathways, such as the molecular link between Gaucher disease and Parkinson disease. SUMMARY: New genes have been implicated in Parkinson disease and other movement disorders through the use of NGS. The identification of risk variants has been facilitated by GWAS and meta-analyses. Furthermore, new models are being developed to study the molecular mechanisms involved in the pathogenesis of these diseases.

14 Review Fixing the broken system of genetic locus symbols: Parkinson disease and dystonia as examples. 2012

Marras, Connie / Lohmann, Katja / Lang, Anthony / Klein, Christine. ·Toronto Western Hospital Morton and Gloria Shulman Movement Disorders Centre and the Edmond J. Safra Program in Parkinson’s Disease, University of Toronto, Toronto, Canada. cmarras@uhnresearch.ca ·Neurology · Pubmed #22454269.

ABSTRACT: Originally, locus symbols (e.g., DYT1) were introduced to specify chromosomal regions that had been linked to a familial disorder with a yet unknown gene. Symbols were systematically assigned in a numerical series to designate mapped loci for a specific phenotype or group of phenotypes. Since the system of designating and using locus symbols was originally established, both our knowledge and our techniques of gene discovery have evolved substantially. The current system has problems that are sources of confusion, perpetuate misinformation, and misrepresent the system as a useful reference tool for a list of inherited disorders of a particular phenotypic class. These include erroneously assigned loci, duplicated loci, missing symbols, missing loci, unconfirmed loci in a consecutively numbered system, combining causative genes and risk factor genes in the same list, and discordance between phenotype and list assignment. In this article, we describe these problems and their impact, and propose solutions. The system could be significantly improved by creating distinct lists for clinical and research purposes, creating more informative locus symbols, distinguishing disease-causing mutations from risk factors, raising the threshold of evidence prior to assigning a locus symbol, paying strict attention to the predominant phenotype when assigning symbols lists, and having a formal system for reviewing and continually revising the list that includes input from both clinical and genetics experts.

15 Review Genetics of Parkinson's disease. 2012

Klein, Christine / Westenberger, Ana. ·Section of Clinical and Molecular Neurogenetics at the Department of Neurology, University of Lübeck, Lübeck, Germany. christine.klein@neuro.uni-luebeck.de ·Cold Spring Harb Perspect Med · Pubmed #22315721.

ABSTRACT: Fifteen years of genetic research in Parkinson's disease (PD) have led to the identification of several monogenic forms of the disorder and of numerous genetic risk factors increasing the risk to develop PD. Monogenic forms, caused by a single mutation in a dominantly or recessively inherited gene, are well-established, albeit relatively rare types of PD. They collectively account for about 30% of the familial and 3%-5% of the sporadic cases. In this article, we will summarize the current knowledge and understanding of the molecular genetics of PD. In brief, we will review familial forms of PD, basic genetic principles of inheritance (and their exceptions in PD), followed by current methods for the identification of PD genes and risk factors, and implications for genetic testing.

16 Review Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis. 2011

van Es, Michael A / Schelhaas, Helenius J / van Vught, Paul W J / Ticozzi, Nicola / Andersen, Peter M / Groen, Ewout J N / Schulte, Claudia / Blauw, Hylke M / Koppers, Max / Diekstra, Frank P / Fumoto, Katsumi / LeClerc, Ashley Lyn / Keagle, Pamela / Bloem, Bastiaan R / Scheffer, Hans / van Nuenen, Bart F L / van Blitterswijk, Marka / van Rheenen, Wouter / Wills, Anne-Marie / Lowe, Patrick P / Hu, Guo-fu / Yu, Wenhao / Kishikawa, Hiroko / Wu, David / Folkerth, Rebecca D / Mariani, Claudio / Goldwurm, Stefano / Pezzoli, Gianni / Van Damme, Philip / Lemmens, Robin / Dahlberg, Caroline / Birve, Anna / Fernández-Santiago, Rubén / Waibel, Stefan / Klein, Christine / Weber, Markus / van der Kooi, Anneke J / de Visser, Marianne / Verbaan, Dagmar / van Hilten, Jacobus J / Heutink, Peter / Hennekam, Eric A M / Cuppen, Edwin / Berg, Daniela / Brown, Robert H / Silani, Vincenzo / Gasser, Thomas / Ludolph, Albert C / Robberecht, Wim / Ophoff, Roel A / Veldink, Jan H / Pasterkamp, R Jeroen / de Bakker, Paul I W / Landers, John E / van de Warrenburg, Bart P / van den Berg, Leonard H. ·Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands. ·Ann Neurol · Pubmed #22190368.

ABSTRACT: OBJECTIVE: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD. METHODS: We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios. RESULTS: Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 × 10(-6) for ALS and p = 4.3 × 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD. INTERPRETATION: The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD.

17 Review The curious case of phenocopies in families with genetic Parkinson's disease. 2011

Klein, Christine / Chuang, Rosalind / Marras, Connie / Lang, Anthony E. ·Morton and Gloria Shulman Movement Disorders Center and the Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. ·Mov Disord · Pubmed #21735483.

ABSTRACT: Monogenic forms of Parkinson's disease account for ∼3% of all "idiopathic" Parkinson's disease. With reduced penetrance in dominant forms and manifesting heterozygotes in recessive forms of Parkinson's disease, it has been well recognized that inheritance patterns do not always follow classic Mendelian genetics. A novel twist to the puzzle is the presence of phenocopies (i.e., family members with the same clinical syndrome as the mutation carriers, but lacking the familial mutation). We reviewed all pedigrees published between 1997 and 2009 with α-synuclein, leucine-rich repeat kinase 2, Parkin, or PTEN-induced kinase 1 mutations with at least 2 affected individuals and known genetic status for the possible presence of phenocopies. Of 537 patients with clinical Parkinson's disease in 160 families meeting our inclusion criteria, 27 patients (5.0%) from 23 families (14.4%) were phenocopies. Phenocopies represented 3.8% of all blood relatives reported in the pedigrees containing phenocopies and an estimated 1.3% of all blood relatives in all pedigrees included. Both of these rates exceeded age-specific prevalences of Parkinson's disease. In 4 families, the phenocopy was explained by another known mutation: In 2 pedigrees, a monogenic cause was likely; in another 2, secondary parkinsonism was suspected; and in the remaining 15 families, "sporadic Parkinson's disease" was suggested as the cause of disease in the phenocopy. The unexpectedly high number of phenocopies of mostly unknown origin within families with a seemingly known etiology of Parkinson's disease adds another level of complexity to genetic research of Parkinson's disease, as well as to the interpretation of genetic testing results in the clinical diagnostic setting.

18 Review Translational research in neurology and neuroscience 2011: movement disorders. 2011

Klein, Christine / Krainc, Dimitri / Schlossmacher, Michael G / Lang, Anthony E. ·Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lübeck, Lübeck, Germany. ·Arch Neurol · Pubmed #21320985.

ABSTRACT: We provide an update on the state of translational research in movement disorders, using examples of Huntington disease, Parkinson disease, and dystonia. While substantial progress in our understanding of these disorders has been achieved, development of neuroprotective treatments remains an unrealized goal. Here we highlight some of the emerging research areas that show the most promise for translational research in Huntington disease, Parkinson disease, and dystonia. Aetiology and pathogenesis, biomarker directions, and causal treatment opportunities are discussed for each disease, followed by a brief discussion drawing attention to important translational initiatives.

19 Review Nonmotor symptoms in genetic Parkinson disease. 2010

Kasten, Meike / Kertelge, Lena / Brüggemann, Norbert / van der Vegt, Joyce / Schmidt, Alexander / Tadic, Vera / Buhmann, Carsten / Steinlechner, Susanne / Behrens, Maria Isabel / Ramirez, Alfredo / Binkofski, Ferdinand / Siebner, Hartwig / Raspe, Heiner / Hagenah, Johann / Lencer, Rebekka / Klein, Christine. ·Department of Neurology, University of Lübeck, Lübeck, Germany. ·Arch Neurol · Pubmed #20558386.

ABSTRACT: OBJECTIVES: To review current knowledge on nonmotor symptoms (NMS), particularly psychiatric features, in genetic Parkinson disease (PD) and to provide original data for genetic and idiopathic PD. DATA SOURCES: A MEDLINE search using Parkinson and known PD genes focused on the presence of depression, anxiety, hallucinations, and dementia was performed. Original data from 82 outpatients with idiopathic (n = 55) and genetic (n = 27) PD were obtained. STUDY SELECTION: All studies including information on NMS and patients with genetic PD. DATA EXTRACTION: Study methods and clinical and genetic information were summarized. DATA SYNTHESIS: The literature search yielded 1855 citations; 305 included genetic information on PD patients, of which 119 also contained information on any type of NMS (990 cases). Availability of information varied by gene and type of NMS; studies differed by recruitment and examination method. Literature search and original data showed high frequencies of the following NMS: depression, 8% to 37% (literature) and 33% to 40% (our data); anxiety, 7% to 37% (literature) and 10% to 22% (our data); hallucinations, 3% to 23% (literature) and 23% to 29% (our data); and dementia, 5% to 26% (literature), absent in our own data. CONCLUSIONS: Data on NMS in genetic PD are limited. Specific data needs include a systematic approach to NMS assessment reporting permitting comparability of studies. Overall, the frequency of NMS in genetic PD does not appear to be higher and may even be lower than in idiopathic PD. Nonmotor symptoms have a high impact on the patients' quality of life and caregiver burden and should be considered important and often treatable concomitant features of genetic PD.

20 Clinical Trial Genetic risk factors in Parkinson's disease: single gene effects and interactions of genotypes. 2012

Göbel, Anna / Macklin, Eric A / Winkler, Susen / Betensky, Rebecca A / Klein, Christine / Lohmann, Katja / Simon, David K. · ·J Neurol · Pubmed #22878430.

ABSTRACT: -- No abstract --

21 Article Rare Variants in Specific Lysosomal Genes Are Associated with Parkinson's Disease. 2020

Hopfner, Franziska / Mueller, Stefanie H / Szymczak, Silke / Junge, Olaf / Tittmann, Lukas / May, Sandra / Lohmann, Katja / Grallert, Harald / Lieb, Wolfgang / Strauch, Konstantin / Müller-Nurasyid, Martina / Berger, Klaus / Schormair, Barbara / Winkelmann, Juliane / Mollenhauer, Brit / Trenkwalder, Claudia / Maetzler, Walter / Berg, Daniela / Kasten, Meike / Klein, Christine / Höglinger, Günter U / Gasser, Thomas / Deuschl, Günther / Franke, André / Krawczak, Michael / Dempfle, Astrid / Kuhlenbäumer, Gregor. ·Department of Neurology, Universitätsklinikum Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany. · Department of Neurology, Hannover Medical School, Hannover, Germany. · Institute of Health Informatics, University College London, London, United Kingdom. · Institute of Medical Informatics and Statistics, Kiel University, University Hospital Schleswig-Holstein, Kiel, Germany. · Institute of Epidemiology, University of Kiel, Kiel, Germany. · Institute of Clinical Molecular Biology, Kiel University, University Hospital Schleswig-Holstein, Kiel, Germany. · Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. · Institute of Epidemiology II, German Research Center for Environmental Health, Helmholtz Zentrum München, Neuherberg, Germany. · Research Unit of Molecular Epidemiology, German Research Center for Environmental Health, Helmholtz Zentrum München, Neuherberg, Germany. · German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany. · Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. · Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University, Munich, Germany. · Department of Medicine I, Ludwig-Maximilians-Universität, Munich, Germany. · DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany. · Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany. · Institute of Neurogenomics, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health, Neuherberg, Germany. · Institute of Human Genetics, Faculty of Medicine, Technical University Munich, Munich, Germany. · Munich Cluster for Systems Neurology (SyNergy), München, Deutschland. · Paracelsus-Elena-Klinik Kassel, Kassel, Germany. · Department of Neurology, University Medical Center Göttingen, Göttingen, Germany. · Clinic for Neurosurgery, University Medical Centre, Georg August University Göttingen, Göttingen, Germany. · Paracelsus-Elena Hospital, Kassel, Germany. · Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany. · Technical University of Munich, School of Medicine, Department of Neurology, Munich, Germany. · German Center for Neurodegenerative Diseases, Munich, Germany. · Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases, University Clinic Tuebingen, Tuebingen, Germany. ·Mov Disord · Pubmed #32267580.

ABSTRACT: OBJECTIVE: Impaired lysosomal degradation of α-synuclein and other cellular constituents may play an important role in Parkinson's disease (PD). Rare genetic variants in the glucocerebrosidase (GBA) gene were consistently associated with PD. Here we examine the association between rare variants in lysosomal candidate genes and PD. METHODS: We investigated the association between PD and rare genetic variants in 23 lysosomal candidate genes in 4096 patients with PD and an equal number of controls using pooled targeted next-generation DNA sequencing. Genewise association of rare variants in cases or controls was analyzed using the optimized sequence kernel association test with Bonferroni correction for the 23 tested genes. RESULTS: We confirm the association of rare variants in GBA with PD and report novel associations for rare variants in ATP13A2, LAMP1, TMEM175, and VPS13C. CONCLUSION: Rare variants in selected lysosomal genes, first and foremost GBA, are associated with PD. Rare variants in ATP13A2 and VPC13C previously linked to monogenic PD and more common variants in TMEM175 and VPS13C previously linked to sporadic PD in genome-wide association studies are associated with PD. © 2020 International Parkinson and Movement Disorder Society.

22 Article The Role of Rare Coding Variants in Parkinson's Disease GWAS Loci. 2019

Germer, Elisabeth Luisa / Imhoff, Sophie / Vilariño-Güell, Carles / Kasten, Meike / Seibler, Philip / Brüggemann, Norbert / Anonymous1071050 / Klein, Christine / Trinh, Joanne. ·Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. · Department of Medical Genetics, Centre for Applied Neurogenetics, University of British Columbia, Vancouver, BC, Canada. ·Front Neurol · Pubmed #31920912.

ABSTRACT:

23 Article 'Atypical' Parkinson's disease - genetic. 2019

Weissbach, Anne / Wittke, Christina / Kasten, Meike / Klein, Christine. ·Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. · Institute of Neurogenetics, University of Lübeck, Lübeck, Germany; Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany. ·Int Rev Neurobiol · Pubmed #31779813.

ABSTRACT: Genetic atypical Parkinson's disease (PD) describes monogenic forms of PD that resemble idiopathic PD but feature prominent atypical clinical signs and symptoms and can be sub-grouped into i) atypical monogenic forms caused by mutations in the ATP13A2, DNAJC6, FBXO7, SYNJ1, VPS13C, and DCTN genes; ii) monogenic PD more closely resembling idiopathic PD, but associated with atypical features in at least a subset of cases (SNCA-, LRRK2-, VPS35-, Parkin-, PINK1-, and DJ-1-linked PD; iii) carriers of mutations in genes that are usually associated with other movement disorders but may present with parkinsonism, such as dopa-responsive dystonia. Some atypical features are shared by almost all forms, such as an overall early age at onset. Other clinical signs are present in carriers of mutations across several different genes, such as for example, early cognitive decline. Finally, several clinical features can serve as red flags for specific forms of atypical PD including a supranuclear gaze palsy in ATP13A2 mutation carriers or hypoventilation linked to mutations in the DCTN1 gene.

24 Article Generation and characterization of human-derived iPSC lines from three pairs of monozygotic twins discordant for Parkinson's disease. 2019

Dulovic-Mahlow, Marija / Lukomska, Agnieszka / Diaw, Sokhna Haissatou / Balck, Alexander / Borsche, Max / Grütz, Karen / Lenz, Insa / Rudolph, Franziska / Lohmann, Katja / Klein, Christine / Seibler, Philip. ·Institute of Neurogenetics, University of Luebeck, Luebeck, Germany. ·Stem Cell Res · Pubmed #31706098.

ABSTRACT: Despite a genetic component in the development of Parkinson's disease (PD), monozygotic twin pairs often display discordance for PD. Here, we describe the generation of six human induced pluripotent stem cell (iPSC) lines from dermal fibroblasts of three pairs of monozygotic twins discordant for PD. We used non-integrating Sendai virus and the iPSC lines were comprehensively characterized. These lines provide a valuable resource for studying molecular differences between the affected and unaffected monozygotic twin and their response to genetic and non-genetic factors that might be involved in the development of PD.

25 Article Impaired serine metabolism complements LRRK2-G2019S pathogenicity in PD patients. 2019

Nickels, Sarah Louise / Walter, Jonas / Bolognin, Silvia / Gérard, Deborah / Jaeger, Christian / Qing, Xiaobing / Tisserand, Johan / Jarazo, Javier / Hemmer, Kathrin / Harms, Amy / Halder, Rashi / Lucarelli, Philippe / Berger, Emanuel / Antony, Paul M A / Glaab, Enrico / Hankemeier, Thomas / Klein, Christine / Sauter, Thomas / Sinkkonen, Lasse / Schwamborn, Jens Christian. ·Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367, Belvaux, Luxembourg; Life Sciences Research Unit (LSRU), Systems Biology Group, University of Luxembourg, L-4367, Belvaux, Luxembourg; Integrated Biobank of Luxembourg (IBBL), Luxembourg Institute of Health, L-3555, Dudelange, Luxembourg. · Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367, Belvaux, Luxembourg. · Life Sciences Research Unit (LSRU), Systems Biology Group, University of Luxembourg, L-4367, Belvaux, Luxembourg. · Leiden Academic Centre for Drug Research (LACDR), Analytical Biosciences, Leiden University, NL-2333, CC Leiden, Netherlands. · Institute of Neurogenetics, University of Lübeck, D-23538, Lübeck, Germany. · Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367, Belvaux, Luxembourg. Electronic address: jens.schwamborn@uni.lu. ·Parkinsonism Relat Disord · Pubmed #31621607.

ABSTRACT: Parkinson's disease (PD) is a multifactorial disorder with complex etiology. The most prevalent PD associated mutation, LRRK2-G2019S is linked to familial and sporadic cases. Based on the multitude of genetic predispositions in PD and the incomplete penetrance of LRRK2-G2019S, we hypothesize that modifiers in the patients' genetic background act as susceptibility factors for developing PD. To assess LRRK2-G2019S modifiers, we used human induced pluripotent stem cell-derived neuroepithelial stem cells (NESCs). Isogenic controls distinguish between LRRK2-G2019S dependent and independent cellular phenotypes. LRRK2-G2019S patient and healthy mutagenized lines showed altered NESC self-renewal and viability, as well as impaired serine metabolism. In patient cells, phenotypes were only partly LRRK2-G2019S dependent, suggesting a significant contribution of the genetic background. In this context we identified the gene serine racemase (SRR) as a novel patient-specific, developmental, genetic modifier contributing to the aberrant phenotypes. Its enzymatic product, d-serine, rescued altered cellular phenotypes. Susceptibility factors in the genetic background, such as SRR, could be new targets for early PD diagnosis and treatment.

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