In their recent article, Dr Raux and colleagues1 report eight new presenilin‐1 (PSEN1) mutations in autosomal dominant early onset Alzheimer's disease (AD), four of which are said to be at codons not previously reported as mutant in AD (codons 214, 386, 391, and 424).
In our review of PSEN1 mutations,2 we identified a previous report from Poland3 of a mutation (L424R) at codon 424, with earlier age at onset (30–35 years) than in the French pedigree (38–42 years). Of the novel mutations at codons previously reported mutant in AD (codons 105, 116, 143, and 206),1 two (T116I and G206S) produce predicted amino acid substitutions already reported. In an Italian patient with the T116I mutation, with age at onset of 45 years, there was no family history of AD and this was thought to represent a de novo mutation.4 The G206S mutation has been reported but without clinical details.5
It is important to compare the clinical phenotypes of families sharing the same mutation, to ascertain whether phenotypes are mutation specific, or whether there is clinical heterogeneity. If the latter, then this is a first step in looking for the sources of heterogeneity, both genetic and epigenetic.2
Footnotes
Competing interests: there are no competing interests
References
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