A PROSPECTIVE NEUROGENETIC STUDY ON EARLY-ONSET DEMENTIA IN PATIENTS WITH UNCLEAR INITIAL DIAGNOSIS OF DEGENERATIVE DEMENTIA

Abstract

Genetic research studies on early-onset dementia (EOD) have shown that only patients fulfilling strict standard diagnostic are included in genetic studies. Patients in the early stages of the disease, have sometimes unclear symptoms which are insufficient to specify a clinical diagnosis. Those patients are therefore systematically excluded from standard dementia research studies. We hypothesized that the very early-onset ages and/or a positive family history of degenerative dementia in those excluded EOD patients are strong indicators of a potential underlying genetic cause. We designed a prospective study on 212 Belgian EOD patients. Patients had diverse degenerative forms of dementia, including heterogeneous clinical phenotype, multiple differential diagnosis or mild cognitive impairment. The aim of the study was to assess the genetic contribution of the major dementia genes in the EOD patient group, verifying if we could genetically explain some of those patients. We applied MASTR assay target enrichment, repeat-primed PCR to detect C9orf72 G4C2 repeat expansions and cDNA sequencing transcript analysis. The screening revealed a total of 15 mutations in 16 patients, including two carriers of two mutations. Among those, we identified 6 known pathogenic mutations in 8 patients (3.8%). We also detected two premature stop codon variants in PSEN2 (p.Gly359Leufs*74) and LRRK2 (p.Leu2063fs*). The cDNA sequence analysis revealed a residual expression of the mutated transcript in both, leading to a possible production of a truncated protein. We were able to explain 8 (3.8%) of the 212 clinical undefined EOD patients underscoring the significance of genetic testing in diagnosis of patients with uncertain initial symptoms. Longitudinal follow-up of the patient carriers by neurologists might help to make a differential diagnosis clinical phenotype.