Abstract
Mutations in PSEN1 are responsible for familial Alzheimer’s disease (FAD) inherited as autosomal dominant trait, but also de novo mutations have been rarely reported in sporadic early-onset dementia cases. Parkinsonism in FAD has been mainly described in advanced disease stages. We characterized a patient presenting with early-onset dystonia-parkinsonism later complicated by dementia and myoclonus. Brain MRI showed signs of iron accumulation in the basal ganglia mimicking neurodegeneration with brain iron accumulation (NBIA) as well as fronto-temporal atrophy. Whole exome sequencing revealed a novel PSEN1 mutation and segregation within the family demonstrated the mutation arose de novo.
We suggest considering PSEN1 mutations in cases of dystonia-parkinsonism with positive DAT-Scan, later complicated by progressive cognitive decline and cortical myoclonus even without a dominant family history.
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Acknowledgements
We acknowledge the “Cell lines and DNA Bank of Paediatric Movement Disorders and Mitochondrial diseases” of the Telethon Network of Genetic Biobanks (project no. GTB09003) and the Eurobiobank Network. This work received financial support from the Fondazione Pierfranco e Luisa Mariani, Milan and TIRCON project (FP7/2007-2013, HEALTH-F2-2011, #277984 to VT and HP). CFB was partially supported by the Italian Ministry of Health grant GR-2009-1594645. TBH work was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (grant no. FKZ 01ZX1405C).
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All Authors have been involved in critical revision and authorization of the draft manuscript.
MC, MP, VT: conceived the study, analysed the results, and drafted the manuscript. LV, BG, TBH, AI, HP: performed exome sequencing and genetic investigation. AEE, AC, AV, CFB, SP, PB, LR: provided clinical details and followed the patient.
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Subject’s consent was obtained according to the Declaration of Helsinki: BMJ 1991; 302, 1194. In addition, we obtained institutional review board–approved informed consent from patient for videotape and its publication. Health professionals and patient’s mother also gave their consent for videotape and publication.
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Video 1
segment 1 (age 26): absent arm swings with dystonic posturing of the right arm, mild bradykinesia on tapping; segment 2 (age 29): freezing of gait, lower limb dystonia (tip-toe walking), axial dystonia and loss of postural reflexes, severe bilateral bradykinesia, hypomimia, severe dysarthria and hypophonic speech, mild levodopa-induced dyskinesias are present at rest; segment 3 (age 33): severe akinetic-rigid parkinsonism, anarthria, stimulus-sensitive myoclonic jerks in the upper limbs on posture, pyramidal signs in the lower limbs, frontal release signs (grasping, Myerson’s sign). (MP4 44,217 kb)
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Carecchio, M., Picillo, M., Valletta, L. et al. Rare causes of early-onset dystonia-parkinsonism with cognitive impairment: a de novo PSEN-1 mutation. Neurogenetics 18, 175–178 (2017). https://doi.org/10.1007/s10048-017-0518-4
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DOI: https://doi.org/10.1007/s10048-017-0518-4