Abstract
Background: Early onset dementias have variable clinical presentations and
are often difficult to diagnose. We established a family pedigree that demonstrated
consistent recurrence of very early onset dementia in successive generations.
Objective and Method: In order to refine the diagnosis in this family, we
sequenced the exomes of two affected family members and relied on discrete filtering to
identify disease genes and the corresponding causal variants.
Results: Among the 720 nonsynonymous single nucleotide polymorphisms (SNPs)
shared by two affected members, we found a C to T transition that gives rise to a
Thr147Ile missense substitution in the presenilin 1 (PS1) protein. The presence of this
same mutation in a French early-onset Alzheimer’s disease family, other affected members
of the family, and the predicted high pathogenicity of the substitution strongly suggest
that it is the causal variant. In addition to exceptionally young age of onset, we also
observed significant limb spasticity and early loss of speech, concurrent with progression
of dementia in affected family members. These findings extend the clinical presentation
associated with the Thr147Ile variant. Lastly, one member with the Thr147Ile variant was
treated with the PKC epsilon activator, bryostatin, in a compassionate use trial after
successful FDA review. Initial improvements with this treatment were unexpectedly clear,
including return of some speech, increased attentional focus, ability to swallow, and some
apparent decrease in limb spasticity.
Conclusions: Our findings confirm the role of the PS1 Thr147Ile substitution
in Alzheimer’s disease and expand the clinical phenotype to include expressive aphasia and
very early onset of dementia.
