Objective: To screen for the presence of C9ORF72 repeat expansions in patients affected by atypical parkinsonism syndromes and PD complicated by psychosis or dementia, and in unrelated age- and sex-matched healthy controls.

Background: Large expansions of the non-coding GGGGCC-repeat (more than 30) in the first intron of the C9ORF72 gene have been demonstrated to cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent papers have investigated the possible pathogenic role of hexanucleotide expansions with intermediate repetition ranging between 20 and 29 repeats. Some studies supported its pathogenicity within a phenotypic spectrum ranging from typical PD, atypical Parkinsonian syndromes, FTD with/without parkinsonism, and ALS with/without parkinsonism or with/without dementia.

Methods: We enrolled 93 consecutive unrelated patients (48 M, 45 F) with atypical parkinsonism syndromes and PD complicated by psychosis or dementia. Atypical Parkinsonian syndromes were further divided into two groups: one with patients who met the criteria for the classic forms of atypical parkinsonism (MSA, LBD, PSP, CBD); and patients who did not meet the above criteria, named non-classical atypical parkinsonism with or without dementia. Also unrelated age- and sex-matched healthy Sardinian control individuals were investigated and included in this study.

Results: No patient was detected with pathogenic (=>30) C9ORF72 repeat expansions. Intermediate 20-29 repeats expansions were detected in 5 female patients (5.4%). Four of them presented clinical features of non-classical atypical parkinsonism while the remaining patient presented clinical features of typical PD complicated by psychosis. Among 121 control subjects, none presented long or short expansion for the C9ORF72 gene. Intermediate-length expansions were significantly more frequent in cases than in controls (p < 0.034).

Conclusions: It has been hypothesized that the intermediate expansions of the C9ORF72 mutation might express different pathological conditions. We retain that hexanucleotide expansions of C9ORF72 gene with intermediate repetitions, should be considered as pathogenic and can give rise to variable clinical phenotypes ranging from complicated PD to atypical parkinsonism syndromes.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/c9orf72-intermediate-repeat-copies-as-a-rare-genetic-cause-of-atypical-parkinsonian-syndromes-or-parkinsons-disease-complicated-by-psychosis-in-a-sardinian-population/