Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6802892 | Neurobiology of Aging | 2018 | 26 Pages |
Abstract
In a prospective study of dementia in Flanders (Belgium), we observed a substantial fraction of early-onset dementia patients who did not fulfill the criteria for a specific dementia subtype, leaving the patients without a precise clinical diagnosis. We selected 211 of these patients for genetic testing of causal genes linked to neurodegenerative brain diseases. In this group, the onset or inclusion age was 59.9 ± 8.2 years and 27.4% had a positive family history. We used a panel of 16 major genes linked to Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, Parkinson's disease, and prion diseases. In addition, we tested for the presence of a pathogenic C9orf72 repeat expansion. We identified 13 rare variants in 15 patients, including a carrier of variants in 2 different genes. Six patients (2.84%), carried a mutation in a Mendelian causal gene, that is, APP, MAPT, SOD1, TBK1, and C9orf72. In the other 7 patients, 7 variants were of uncertain significance, including a frameshift mutation in PSEN2, p.G359Lfs*74, in 2 patients sharing a common haplotype, and in LRRK2, p.L2063fs*. Expression studies showed reduced PSEN2 and a near complete loss of LRRK2, in lymphoblast cells or brain material of these patients. Overall, our study underscores the relevance of genetic testing of known causal genes in early-onset patients with symptomatology of neurodegenerative dementia but an unclear clinical diagnosis. A positive genetic result can help to obtain a precise diagnosis as well as a better understanding of the presence of multiple affected relatives in the family.
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Biochemistry, Genetics and Molecular Biology
Ageing
Authors
Federica Perrone, Rita Cacace, Sara Van Mossevelde, Tobi Van den Bossche, Peter P. De Deyn, Patrick Cras, Sebastiaan Engelborghs, Julie van der Zee, Christine Van Broeckhoven,