Page 49 - Demo

Parkinsonism in GNDs472Research implicationsPhenotypic heterogeneity may be significant in GNDs given incomplete penetrance of genetic variants, variable expression, and pleiotropy,121and may be particularly relevant in those GNDs involving multiple genes, such as is the case in 22q11.2 deletion syndrome. Detailed phenotype analysis (‘deep-phenotyping’) is crucial to further our knowledge on the complex relationships between genetics, pathophysiological mechanisms, environmental factors and the phenotypic characteristics of parkinsonism in GNDs. International collaborative research is needed, to overcome the issue of the limited number of patients with individually rare conditions. In addition to routine assessments including careful history taking that focusses on parkinsonian/neurological features and comorbid conditions of the genetic variant, and structured physical examinations (e.g. MDSUPDRS), this should include careful family history taking. Periodic video assessments may also be considered. Despite the challenges, GNDs are often diagnosed at an early age, long before the onset of motor and non-motor Parkinson’s disease related symptoms, facilitating early-stage research of parkinsonism. In addition to human studies, recognizing GNDs makes it possible to use cell and animal models, available for many GNDs, to expand the possibilities of studying the pathophysiologic mechanisms, identify potential biomarkers and design rational interventions.30, 90 Diseasespecific intervention strategies have been suggested in several human and animal models of GNDs and clearly demonstrate the benefits of these kind of studies.85, 122With an increased life expectancy for many GNDs, future research should also focus on overlap between GNDs and other neurodegenerative disorders, e.g., major neurocognitive disorder, in order to understand shared underlying mechanisms and improve clinical care. Strengths and LimitationsThe strengths of this systematic review include the pre-registration of the protocol, the comprehensive search strategy, and the extensive data extraction on key characteristics of parkinsonism and its proposed pathophysiologic mechanisms. Several limitations should also be mentioned. The data need to be considered in view of the retrospective