P3‐247: GENETIC ANALYSIS OF EARLY‐ONSET DEMENTIA IN CHINA Article Swipe

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Dementia Frontotemporal lobar degeneration Vascular dementia Medicine Leukoencephalopathy Family history C9orf72 Normal pressure hydrocephalus Pediatrics Magnetic resonance imaging Internal medicine Frontotemporal dementia Disease Pathology Radiology

Liling Dong , Chenhui Mao , Ling Qiu , Caiyan Liu , Shanshan Chu , Xinying Huang , Jie Li , Dan Lei , Liying Cui , Qi Xu , Bin Peng , Longze Sha , Jing Gao ·

YOU? · · 2019 · Open Access · · DOI: https://doi.org/10.1016/j.jalz.2019.06.3277 · OA: W2980442337

Early-onset dementias (EOD), which present before 65 years old, have a closer relationship with genetic factors in comparison to late-onset dementias. We aimed to investigate genetic characteristics of EOD. 196 EOD patients were retrospectively and consecutively recruited from Dementia and Leukoencephalopathy Clinic of Peking Union Medical College Hospital from 2012 to 2018. All patients underwent blood test, neuropsychological evaluation and brain magnetic resonance imaging. Some had brain positron emission tomography and cerebrospinal fluid testing of Aβ1-42, t-tau and p-tau. Genetically, whole exome sequencing was performed, as well as targeted screening for HTT and C9orf72 repeat expansion. Some had whole genome sequencing. 93 were males, and 103 were females. The age of onset ranged from 30 to 64 years (53±6.7). The clinical diagnosis included possible Alzheimer's disease (AD) (n=88), frontotemporal lobar degeneration (FTLD) (n=43), dementia with Lewy body (DLB) (n=2), dementia with leukodystrophy (DwL) (n=17), vascular dementia (VaD) (n=15), Creutzfeldt-Jakob disease (CJD) (n=3), Huntington's disease (HTD) (n=1), Parkinson's disease (n=1), normal pressure hydrocephalus (n=2) and unspecified dementia (UnD) (n=24). 37.5% (33/88) AD, 25.6% (11/43) FTLD, 29.4% (5/17) DwL and 26.7% (4/15) VaD cases were ApoE-ε4 carriers. 70.5% (62/88) AD and 46.5% (20/43) FTLD cases had a positive family history of dementia (FHD). Among FHD positive patients, 6.5% (4/62) AD and 30.0% (6/20) FTLD patients showed known causative variations in APP, PSEN1, MAPT, GRN, TBK1 and TARDBP. In addition, 9.7% (6/62) AD and 10.0% (2/20) FTLD showed novel variations in PSEN1 (p.Glu72Lys, p.Trp165Cys, p.His214Arg, p.Gln223Lys), PSEN2 (p.Asn141Ser, p.Met239Thr), OPTN (p.Glu399Gln) and TBK1 (c.359-1G>A). Among those who had a negative or uncertain FHD, none of AD patients showed causative variations. However, 17.4% (4/23) FTLD cases had known causative variations in MAPT, VCP and SQSTM1. Another 17.4% (4/23) FTLD cases showed novel variations in MAPT (p.Thr39Met), TBK1 (p.Thr31fs) and CHMP2B (p.Ser86Cys, p.Cys58Arg).