期刊
NEUROSCIENCE LETTERS
卷 699, 期 -, 页码 195-198出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2019.01.047
关键词
PSEN1; Homozygote; Alzheimer's disease; Spastic paraparesis; A431E; Autosomal dominant; REM behavior disorder
资金
- NIH [U01 AG-051218, P50 AG-005142, P50 AG-016573]
Objective: We report a 35 year-old male with childhood learning disability and early onset dementia who is homozygous for the A431E variant in the PSEN1 gene. Presenilin 1 mutations are associated with autosomal dominant Alzheimer's dementia with young and somewhat stereotyped onset. Such variants may cause Alzheimer's dementia through aberrant processing of amyloid precursor protein through effects on gamma-secretase activity. gamma-secretase is involved in the cleavage of many proteins critical to normal function, including brain development. Therefore, manifestations in persons without normal Presenilin 1 function is of interest. Methods: Clinical evaluation including family history, examination, brain MRI, and genetic analysis. Results: Our patient had mild developmental delay, chronic nighttime behavioral disturbance, and onset of progressive cognitive deficits at age 33. Clinical evaluation demonstrated spastic paraparesis and pseudobulbar affect. Brain MRI revealed cerebral atrophy disproportionate to age. Chronic microhemorrhages within bilateral occipital, temporal, and right frontal lobes were seen. Sanger sequencing confirmed homozygosity for the A431E variant in PSEN1, which is a known pathogenic variant causing autosomal dominant Alzheimer's dementia. Conclusions: Our report demonstrates that homozygosity for pathogenic Presenilin 1 variants is compatible with life, though may cause a more aggressive phenotype with younger age of onset and possibly REM behavior disorder.
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