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

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.

An update on multiple system atrophy

“…The molecular basis of MSA remains unknown; it is primarily considered a sporadic disease with no clear environmental or genetic risk factors identified. However, notable exceptions exist, particularly in certain familial cases with confirmed MSA pathology and autosomal dominant or recessive inheritance pattern observed in European and Asian pedigrees [4]. One puzzling genetic finding in MSA involves functionally impaired variants of the COQ2 gene.…”

Family History for Neurodegeneration in Multiple System Atrophy: Does it Indicate Susceptibility?

“…1 A family history (FH) for parkinsonism or other neurodegenerative disorders may in fact occur in people with MSA, but the contribution of genetic factors to MSA pathogenesis is not fully understood to date. 3,4 Here we retrospectively assessed the frequency rates of FH for parkinsonism, dementia, tremor, ataxia, or motor neuron disease within first-to-third-degree relatives of people included in the Innsbruck MSA Registry (n = 144), and compared them with historical MSA cohorts (cumulative n = 1173), Innsbruck-based PD cases (n = 226), and published population-based controls (cumulative n = 20,784). A detailed methodological description is provided in Supplementary Document 1.…”

“…Pathogenic loss-of-function and missense mutations in SORL1 have been postulated to affect APP shuttling between the trans-Golgi network and early endosomes, leading to disease. 4 Interestingly, several studies have also found rare SORL1 mutations in patients with Alzheimer's disease with concomitant LBD, suggesting that SORL1 may be a pleiotropic risk gene. [4][5][6] Here, we assessed the possible association of SORL1 variants with risk for LBD.…”

“…4 Interestingly, several studies have also found rare SORL1 mutations in patients with Alzheimer's disease with concomitant LBD, suggesting that SORL1 may be a pleiotropic risk gene. [4][5][6] Here, we assessed the possible association of SORL1 variants with risk for LBD.…”

“… 1 A family history (FH) for parkinsonism or other neurodegenerative disorders may in fact occur in people with MSA, but the contribution of genetic factors to MSA pathogenesis is not fully understood to date. 3 , 4 …”