Parkinson’s disease patients with heterozygous GBA-mutation: longitudinal phenotyping of motor and non-motor symptoms – more rapid progression compared to Parkinson’s disease patients without GBA-mutation

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dc.contributor.advisor Berg, Daniela (Prof. Dr. med.)
dc.contributor.author Kober, Sylvia Deborah geb. Pflederer
dc.date.accessioned 2021-01-29T09:08:18Z
dc.date.available 2021-01-29T09:08:18Z
dc.date.issued 2021-01-29
dc.identifier.other 1746012110 de_DE
dc.identifier.uri http://hdl.handle.net/10900/112226
dc.identifier.uri http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-1122261 de_DE
dc.identifier.uri http://dx.doi.org/10.15496/publikation-53602
dc.description.abstract The following comprises a short summary of this clinical observation study including the objective, the applied methods and results as well as the discussion. A common disease such as Parkinson's disease, which is now understood as a systemic disease and goes far beyond pure motor disturbance, is clearly associated with the rare lysosomal disorder Gaucher’s disease. At first glance, GD has little in common with the second most frequent neurodegenerative disease worldwide. Nevertheless, the genetic origin of this compound is based on mutations in the GBA gene that lead to an increased risk of PD. Profound acknowledgement of prodromal and clinical symptoms of PDGBA as well as of the progression characteristics of this PD subgroup is of essential importance. Otherwise, one will not be able at all to detect subjects with the most relevant risk factor for PD and – as the next step – these subjects at risk for PD might not be included in clinical and experimental trials. This, however, is the only way to hopefully expand and deepen the current understanding of the underlying mechanisms on how GBA mutations exactly contribute to PD pathology. Based on these required investigations, the development of promising therapeutic options, that go far beyond the present symptomatic level, are conceivable and are expected to slow down or even stop PD progression in the future. Therefore, a clinical phenotyping of GBA patients was performed in this study. It revealed that the PDGBA group presented not significantly different from the PDIdiopathic group at the beginning of the 3-year period regarding motor and non-motor performance. However, at time of the examination in 2013, the PDGBA group was affected more severely than the comparison group: motor and cognitive impairment had worsened more rapidly. Moreover, higher doses of dopaminergic drugs were required, and H&Y disease stages reflected a faster progression of PDGBA to one PD-milestone that can be life-changing for PD patients: the endpoint of postural instability. Further, higher mortality rates for PDGBA patients were demonstrated in this study. Epigenetic and environmental factors may seem to play a relevant role in this subgroup of PD, as well as complex gene-gene interactions. Theories, attempting to explain the underlying pathology, range from the causal linkage of common diseases with common genetic variants (CDCV hypothesis) to the currently more probable assumption that common diseases, such as Parkinson's disease, are caused by a variety of singular and separately rare variants (CDRV). At the cellular level, moreover, several approaches are pursued, including the pathological interaction of GCase and α-syn, the impairment of lysosomal clearance, dysfunctional lipid metabolism, disturbances in the area of the proteasome as well as deficits in mitochondrial function. The primary background of this prospective study was to contribute to a better understanding of this neurodegenerative disease by phenotypically characterizing the subtype PDGBA. This is of crucial importance for following steps as to be able to make a diagnosis at a preferably early disease stage and thus, to prevent disease-associated and irreversibly neuronal cell loss by means of future disease-modifying, targeted therapies. Currently, promising therapeutic studies are in progress with the aim of increasing GCase activity or alternatively, minimizing its pathogenic substrate glucosylceramide. en
dc.language.iso de de_DE
dc.language.iso en de_DE
dc.publisher Universität Tübingen de_DE
dc.rights ubt-podok de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=de de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=en en
dc.subject.classification Parkinson-Krankheit de_DE
dc.subject.ddc 610 de_DE
dc.subject.other Parkinson’s disease en
dc.subject.other GBA en
dc.subject.other phenotyping en
dc.title Parkinson’s disease patients with heterozygous GBA-mutation: longitudinal phenotyping of motor and non-motor symptoms – more rapid progression compared to Parkinson’s disease patients without GBA-mutation en
dc.type PhDThesis de_DE
dcterms.dateAccepted 2020-10-22
utue.publikation.fachbereich Medizin de_DE
utue.publikation.fakultaet 4 Medizinische Fakultät de_DE

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