A multiplex pedigree with pathologically confirmed multiple system atrophy and Parkinson's disease with dementia

Alessandra Fanciulli; Fabian Leys; Fabienne Lehner; Victoria Sidoroff; Viktoria C Ruf; Cecilia Raccagni; Philipp Mahlknecht; Demy J S Kuipers; Wilfred F J van IJcken; Heike Stockner; Thomas Musacchio; Jens Volkmann; Camelia Maria Monoranu; Iva Stankovic; Guido Breedveld; Federico Ferraro; Christina Fevga; Otto Windl; Jochen Herms; Stefan Kiechl; Werner Poewe; Klaus Seppi; Nadia Stefanova; Sonja W Scholz; Vincenzo Bonifati; Gregor K Wenning

doi:10.1093/braincomms/fcac175

A multiplex pedigree with pathologically confirmed multiple system atrophy and Parkinson's disease with dementia

Brain Commun. 2022 Jul 4;4(4):fcac175. doi: 10.1093/braincomms/fcac175. eCollection 2022.

Authors

Alessandra Fanciulli¹, Fabian Leys¹, Fabienne Lehner¹, Victoria Sidoroff¹, Viktoria C Ruf², Cecilia Raccagni¹, Philipp Mahlknecht¹, Demy J S Kuipers³, Wilfred F J van IJcken⁴, Heike Stockner¹, Thomas Musacchio⁵, Jens Volkmann⁵, Camelia Maria Monoranu⁶, Iva Stankovic⁷, Guido Breedveld³, Federico Ferraro³, Christina Fevga³, Otto Windl², Jochen Herms², Stefan Kiechl¹, Werner Poewe¹, Klaus Seppi¹, Nadia Stefanova¹, Sonja W Scholz⁸, Vincenzo Bonifati³, Gregor K Wenning¹

Affiliations

¹ Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
² Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany.
³ Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
⁴ Center for Biomics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
⁵ Department of Neurology, University of Würzburg, Würzburg, Germany.
⁶ Department of Neuropathology, Institute of Pathology, University of Würzburg, Würzburg, Germany.
⁷ Neurology Clinic, Clinical Center of Serbia, University of Belgrade, Belgrade, Serbia.
⁸ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.

Abstract

Multiple system atrophy is considered a sporadic disease, but neuropathologically confirmed cases with a family history of parkinsonism have been occasionally described. Here we report a North-Bavarian (colloquially, Lion's tail region) six-generation pedigree, including neuropathologically confirmed multiple system atrophy and Parkinson's disease with dementia. Between 2012 and 2020, we examined all living and consenting family members of age and calculated the risk of prodromal Parkinson's disease in those without overt parkinsonism. The index case and one paternal cousin with Parkinson's disease with dementia died at follow-up and underwent neuropathological examination. Genetic analysis was performed in both and another family member with Parkinson's disease. The index case was a female patient with cerebellar variant multiple system atrophy and a positive maternal and paternal family history for Parkinson's disease and dementia in multiple generations. The families of the index case and her spouse were genealogically related, and one of the spouse's siblings met the criteria for possible prodromal Parkinson's disease. Neuropathological examination confirmed multiple system atrophy in the index case and advanced Lewy body disease, as well as tau pathology in her cousin. A comprehensive analysis of genes known to cause hereditary forms of parkinsonism or multiple system atrophy lookalikes was unremarkable in the index case and the other two affected family members. Here, we report an extensive European pedigree with multiple system atrophy and Parkinson`s disease suggesting a complex underlying α-synucleinopathy as confirmed on neuropathological examination. The exclusion of known genetic causes of parkinsonism or multiple system atrophy lookalikes suggests that variants in additional, still unknown genes, linked to α-synucleinopathy lesions underlie such neurodegenerative clustering.

Keywords: Parkinson’s disease; Parkinson’s disease with dementia; genetics; multiple system atrophy; multiplex pedigree.