Band 34, Heft 2

X-linked dystonia-parkinsonism (XDP) is a neurodegenerative movement disorder that primarily affects adult Filipino men. It is caused by a founder retrotransposon insertion in TAF1 that contains a hexanucleotide repeat, the number of which differs among the patients and correlates with the age at disease onset (AAO) and other clinical parameters. A recent work has identified additional genetic modifiers of age-associated penetrance in XDP, bringing to light the DNA mismatch repair genes MSH3 and PMS2 . Despite X-linked recessive inheritance, a minor subset of patients are female, manifesting the disease via various mechanisms such as homozygosity, imbalanced X-chromosome inactivation, or aneuploidy. Here, we summarize and discuss clinical and genetic aspects of XDP, with a focus on variable disease expressivity as a consequence of subtle genetic differences within a seemingly homogenous population of patients.

Mutations in Leucine-rich repeat kinase 2 ( LRRK2 ) are the most frequent cause of dominantly inherited Parkinson’s disease (PD). LRRK2 mutations, among which p.G2019S is the most frequent, are inherited with reduced penetrance. Interestingly, the disease risk associated with LRRK2 G2019S can vary dramatically depending on the ethnic background of the carrier. While this would suggest a genetic component in the definition of LRRK2 -PD penetrance, only few variants have been shown to modify the age at onset of patients harbouring LRRK2 mutations, and the exact cellular pathways controlling the transition from a healthy to a diseased state currently remain elusive. In light of this knowledge gap, recent studies also explored environmental and lifestyle factors as potential modifiers of LRRK2 -PD. In this article, we (i) describe the clinical characteristics of LRRK2 mutation carriers, (ii) review known genes linked to LRRK2 -PD onset and (iii) summarize the cellular functions of LRRK2 with particular emphasis on potential penetrance-related molecular mechanisms. This section covers LRRK2 ’s involvement in Rab GTPase and immune signalling as well as in the regulation of mitochondrial homeostasis and dynamics. Additionally, we explored the literature with regard to (iv) lifestyle and (v) environmental factors that may influence the penetrance of LRRK2 mutations, with a view towards further exposomics studies. Finally, based on this comprehensive overview, we propose potential future in vivo , in vitro and in silico studies that could provide a better understanding of the processes triggering PD in individuals with LRRK2 mutations.

The etiology and progression of Parkinson’s Disease (PD), the second most prevalent neurological disorder, have been widely investigated for several decades; however, a cure is still lacking. Despite the development of several neurotoxins and animal models to study this rather heterogeneous disease, a complete recapitulation of the neurophysiology and neuropathology of PD has not been fully achieved. One underlying cause for this could be that mutations in PD-associated genes have reduced penetrance. Therefore, the quest for novel PD models is required where a double hit approach needs to be evoked – a combination of genetic alterations and environmental factors need to be accounted for in one unique model simultaneously.

Movement disorders comprise a clinically, pathologically, and genetically heterogeneous group of diseases associated with the phenomenon of reduced penetrance. Penetrance refers to the likelihood that a clinical condition will occur when a particular genotype is present. Elucidating the cause of reduced penetrance may contribute to more personalized medicine by identifying genetic factors that may prevent individuals from developing disease. Therefore, patient material becomes an irreplaceable resource in this approach. It is needed to identify genetic modifiers of the disease in the first place and to subsequently elucidate underlying mechanisms in endogenous human cell models that provide the entire genetic background.

Pathogenic variants in THAP1 can cause dystonia with a penetrance of about 50 %. The underlying mechanisms are unknown and can be considered as means of endogenous disease protection. Since THAP1 encodes a transcription factor, drivers of this variability putatively act at the transcriptome level. Several transcriptome studies tried to elucidate THAP1 function in diverse cellular and mouse models, including mutation carrier-derived cells and iPSC-derived neurons, unveiling various differentially expressed genes and affected pathways. These include nervous system development, dopamine signalling, myelination, or cell-cell adhesion. A network diffusion analysis revealed mRNA splicing, mitochondria, DNA repair, and metabolism as significant pathways that may represent potential targets for therapeutic interventions.

Background Parkinson‘s disease (PD) is known to be associated with non-genetic factors. To infer causality, Mendelian randomization (MR) studies are increasingly used. Here, genetic variants are used as instrumental variables for the risk factor but have no direct effect on PD themselves. Methods We performed a systematic literature review on MR studies for PD. Studies were identified searching the PubMed database. Upon data extraction, we evaluated the methodological quality and summarized the evidence. Results Twelve articles were included. Most studies showed “good” methodological quality, but most did not report proper power estimations. Twelve analyses yielded nominally significant effects. Conclusions Our systematic review shows that most MR studies were well performed and allow to identify causal exposures, which may inform further studies on the prevention and early intervention of PD.

Reduced penetrance is an important but underreported aspect in monogenic diseases. It refers to the phenomenon that carriers of pathogenic variants do not manifest with an overt disease. Clinical expressivity, on the other hand, describes the degree to which certain disease characteristics are present. In this article, we discuss the implications of reduced penetrance on genetic testing and counseling, outline how penetrance can be estimated in rare diseases using large cohorts and review the ethical, legal and social implications of studying non-manifesting carriers of pathogenic mutations. We highlight the interplay between reduced penetrance and the prodromal phase of a neurodegenerative disorder through the example of monogenic Parkinson’s disease and discuss the therapeutic implications.