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.

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

Graphical Abstract

Figure 1

Map of Bavaria indicating the pedigree’s origin. Created with Microsoft PowerPoint 2016 using files from Wikimedia Commons that are available under the Creative Commons CC0 1.0 Universal Public Domain Dedication (Bavaria Blank Map on Wikimedia Commons. Accessed 02 February 2022. https://commons.wikimedia.org/wiki/File:Bayern_Blank_map.svg) and from the Bavarian Government, which has released its Coat of Arms into the public domain (Coat of Arms of Bavaria on Wikimedia Commons. Accessed 02 February 2022. https://commons.wikimedia.org/wiki/File:Coat_of_arms_of_Bavaria.svg).

Figure 2

Family tree of a Bavarian multiplex pedigree with pathologically confirmed multiple system atrophy and Parkinson’s disease with dementia. The percentages within the symbols indicate the calculated probability of prodromal Parkinson’s disease in the examined family members without clinically evident parkinsonism. MSA = multiple system atrophy; PD = Parkinson’s disease; PDD = Parkinson’s disease with dementia.

Figure 3

Neuropathological examination of the index case IV₂₂ with definite multiple system atrophy. Substantial loss of Purkinje cells in the cerebellar cortex (A; haematoxylin & eosin) and marked demyelination (I; Kluver-Barrera), with reactive astro- (J; GFAP immunohistochemistry) and microgliosis (K; Iba-1 immunohistochemistry) of the cerebellar white matter. Severe neuronal loss, demyelination and reactive gliosis in the pons and inferior olive (B–C; haematoxylin & eosin), but not putamen (D; haematoxylin & eosin). High amounts of α-synuclein-positive glial cytoplasmic inclusions in the cerebellar white matter (E; α-synuclein immunohistochemistry) and pons (F; α-synuclein immunohistochemistry), with additional neuronal cytoplasmic inclusions there (F; arrowhead, inset; α-synuclein immunohistochemistry). Low to moderate amounts of glial cytoplasmic inclusions in the inferior olive (G; α-synuclein immunohistochemistry) and putamen (H; α-synuclein immunohistochemistry). α-synuclein inclusions in oligodendrocytes (O; α-synuclein/Olig2 double immunofluorescence), but not in astrocytes (L; α-synuclein/GFAP double immunofluorescence) or microglia cells (P; α-synuclein/Iba-1 double immunofluorescence) at double immunofluorescence. Early Alzheimer-associated changes with neurofibrillary tangles and neuropil threads in the (trans)-entorhinal cortex (M; AT8 immunohistochemistry). Early argyrophylic grain disease changes with pretangles and argyrophilic grains (arrowheads) in the hippocampus (CA1/2) (N; AT8 immunohistochemistry). Scale bars: A-H, 50 µm; I, 100 µm; J-P, 20 µm. GFAP = glial fibrillary acidic protein; Iba-1 = ionized calcium-binding adapter molecule 1; Olig2 = oligodendrocyte transcription factor.

Figure 4

Neuropathological examination of the family member IV₂₅ deceased to Parkinson’s disease with dementia. Lewy bodies and Lewy neurites strongly positive for α-synuclein detected in the substantia nigra (A, E; haematoxylin & eosin, α-synuclein immunohistochemistry), locus coeruleus (B and F; haematoxylin & eosin, α-synuclein immunohistochemistry) and neocortex (C and G; haematoxylin & eosin, α-synuclein immunohistochemistry), among other regions. Preserved myelination of the cerebral white matter (Kluver-Barrera, D). α-synuclein inclusions in numerous glial cells with fine, tiny processes (G; arrows, inset; α-synuclein immunohistochemistry) in the cortex, but not in the white matter (H; α-synuclein immunohistochemistry). α-synuclein-positive inclusions in astrocytes (K; α-synuclein/GFAP double immunofluorescence) and microglia cells (L; α-synuclein/Iba-1 double immunofluorescence), but not in oligodendrocytes (P; α-synuclein/Olig2 double immunofluorescence) next to Lewy bodies (arrowheads in K, L and P) at double immunofluorescence staining. Reactive astro- and microgliosis in the substantia nigra (I and J; GFAP and Iba-1 immunohistochemistry, respectively). Advanced Alzheimer’s disease pathology with neurofibrillary tangles, neuritic plaques, neuropil threads (M; AT8 immunohistochemistry). Advanced argyrophilic grain disease changes with pretangles and numerous argyrophilic grains (N arrowheads; AT8 immunohistochemistry). High amounts of thorn-shaped astrocytes at periventricular sites (O; AT8 immunohistochemistry). Scale bars: A–C, E–G, I, J, M, N: 20 µm; D, H, O: 100µm; L: 50 µm. GFAP = glial fibrillary acidic protein; Iba-1 = ionized calcium-binding adapter molecule 1; Olig2 = oligodendrocyte transcription factor.