Early onset familial Alzheimer Disease with spastic paraparesis, dysarthria, and seizures and N135S mutation in PSEN1.
OBJECTIVE
Early onset familial Alzheimer disease (EOFAD) can be caused by mutations in genes for amyloid precursor protein, presenilin 1 (PSEN1), or presenilin 2 (PSEN2). There is considerable phenotypic variability in EOFAD, including some patients with spastic paraparesis. The objective is to describe clinical and neuropathologic features of a family with a PSEN1 mutation that has been reported previously, without autopsy confirmation, in a single Greek family whose affected members presented with memory loss in their 30s, as well as variable limb spasticity and seizures.


METHODS
We prospectively evaluated 2 children (son and daughter) with EOFAD and reviewed medical records on their mother. Archival material from the autopsy of the mother was reviewed and postmortem studies were performed on the brain of the daughter.


RESULTS
All 3 individuals in this family had disease onset in their 30s, with cognitive deficits in multiple domains, including memory, language, and attention, as well as less common features such as spastic dysarthria, limb spasticity, and seizures. At autopsy both the mother and her daughter had pathologic findings of Alzheimer disease, and histologic evidence of corticospinal tract degeneration. Genetic studies revealed a mutation in PSEN1 leading to an asparagine to serine substitution at amino acid residue 135 (N135S) in presenilin 1.


CONCLUSIONS
This is the first description of neuropathologic findings in EOFAD owing to N135S PSEN1 mutation. The clinical phenotype was remarkable for spastic dysarthria, limb spasticity, and seizures, in addition to more typical features of EOFAD.
Rudzinski
Leslie A
LA
Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA. rudzinski.leslie@mayo.edu
Fletcher
Rita M
RM
Dickson
Dennis W
DW
Crook
Richard
R
Hutton
Michael L
ML
Adamson
Jennifer
J
Graff-Radford
Neill R
NR
D000328:Adult; D017668:Age of Onset; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D004252:DNA Mutational Analysis; D004401:Dysarthria / Q000209:etiology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation; D009410:Nerve Degeneration / Q000209:etiology / Q000473:pathology; D020336:Paraparesis, Spastic / Q000209:etiology; D010375:Pedigree; D016133:Polymerase Chain Reaction; D053764:Presenilin-1 / Q000235:genetics*; D011712:Pyramidal Tracts / Q000473:pathology; D012640:Seizures / Q000209:etiology
C508853:PSEN1 protein, human; D053764:Presenilin-1