Mutation frequency of PRKAR1B and the major familial dementia genes in a Dutch early onset dementia cohort.
Level 4 - case-series / case-control
Cross-sectional genetic screening of a clinical case cohort
PubMed 25108559 · doi:10.1007/s00415-014-7456-y
What was done
DNA from 303 Dutch patients with early-onset dementia (onset before age 70)—comprising 229 patients clinically diagnosed with Alzheimer's disease (AD) and 74 clinically diagnosed with frontotemporal dementia (FTD)—underwent targeted mutation analysis for PSEN1, APP, MAPT, GRN, C9orf72, and PRKAR1B.
What was found
In AD patients, mutation frequencies were: PSEN1 (3.5%), APP (0.4%), C9orf72 repeat expansions (0.4%), MAPT (0.4%), and GRN (0.4%). In FTD patients, mutation frequencies were: C9orf72 repeat expansions (9.9%), GRN (2.7%), MAPT (1.4%), and 0% for both PSEN1 and APP. No pathogenic mutations were detected in PRKAR1B in either cohort.
Why it matters
This study defines the prevalence of known familial dementia mutations in the Netherlands and shows that PRKAR1B is unlikely to be a common cause of early-onset AD or FTD.
Limits
The study is restricted to a single Dutch cohort and relies entirely on clinical diagnoses without neuropathological confirmation. The FTD sample size is modest (n = 74), which limits the precision of frequency estimates for rare variants.
Cited by
- supports Familial Alzheimer's disease accounts for less than 5% of Alzheimer's cases, and APP mutations represent less than 1% of Alzheimer's disease cases in humans.