Mosaicism of alpha-synuclein (SNCA) gene rearrangements in 2 unrelated cases of multiple system atrophy with predominant Parkinsonism (MSA-P): A link between Parkinson's disease (PD) and multiple system atrophy?

CALVO, DS; PERANDONES, C; RAINA, GB; GIUGNI, JC; PELLENE, LA; MAIOLA, R; CUEVAS, SM; ROMANO, EA; CAPUTO, M; CORACH, D; VIALE, DL; MATA, IF; ZABETIAN, CP; MICHELI, FE; RADRIZZANI, M

Estocolmo

Congreso; The International Parkinson and Movement Disorder Society?s 18th International Congress of Parkinson's Disease and Movement Disorders; 2014

The International Parkinson and Movement Disorder Society

Objective: To describe the genetic findings and clinical spectrum phenotype of two unrelated cases of Parkinsonism that fulfill the diagnostic criteria of multiple system atrophy with predominant Parkinsonism, associated with mosaicisms of SNCA gene multiplication. Background: Multiple system atrophy (MSA) and Parkinson´s disease (PD) are progressive neurodegenerative disorders characterized neuropathologically by the deposition of abnormally phosphorylated a-syn. In PD, the aggregates are typically found in neurons as Lewy´s bodies, whereas in MSA, a-syn is deposited predominantly in the form of glial cytoplasmic inclusions. These observations suggest that PD and MSA share a common pathogenic mechanism. Although MSA appears to occur sporadically in the community, a number of recent observations have implicated genetic factors in the pathogenesis of the disease. These findings prompted us to screen for multiplications of the SNCA gene in cases of Parkinsonism that met the criteria for MSA. Methods: FISH was performed in lymphocytes and cells from oral mucosae with SNCA BAC RP11-614O7 (151 kb; CHORI) labeled using rhodamine. Samples were considered duplicated/triplicated if they had 3/4 FISH probe signals in greater than 20% of interphase cells scored, out of 100 interphase nuclei examined. Results: In two patients, although FISH was negative for peripheral leucocytes, a high percentage of oral mucosae cells showed duplication of the SNCA gene (74 and 34.8 % respectively). Conclusions: To the best of our knowledge, this is the first report of mosaicism of SNCA rearrangements in patients with MSA. These data are relevant to confirm that genetic factors play a role in the pathogenesis of MSA. Previous studies performed only in peripheral blood have failed to identify a significant association of SNCA rearrangements with MSA. Our findings, together with those we have recently reported in two cases of early onset parkinsonism (EOPD), highlight the need to widen the spectrum of evaluations in patients with MSA-P and EOPD, including FISH in peripheral tissues, before excluding the possibility of SNCA dosage mutations. Understanding the consequences of these rearrangements has the potential to provide a greater insight into the role of SNCA mutations or dysfunction in the pathogenesis of MSA and also PD.