John Parker1, Tahseen Mozaffar2, Ashlynn Messmore3, Joshua L Deignan4, Virginia E Kimonis3, John M Ringman5. 1. Department of Neurology, Keck School of Medicine at USC, United States; Department of Neurology, University of California, Irvine, United States. 2. Department of Neurology, University of California, Irvine, United States. 3. Department of Pediatrics, Division of Genetic and Genomic Medicine, University of California, Irvine, United States. 4. UCLA Molecular Diagnostics Laboratories, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, United States. 5. Department of Neurology, Keck School of Medicine at USC, United States. Electronic address: John.ringman@med.usc.edu.
Abstract
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. Presenilin1 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 γ-secretase activity. γ-secretase is involved in the cleavage of many proteins critical to normal function, including brain development. Therefore, manifestations in persons without normal Presenilin1 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 Presenilin1 variants is compatible with life, though may cause a more aggressive phenotype with younger age of onset and possibly REM behavior disorder.
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. Presenilin1 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 γ-secretase activity. γ-secretase is involved in the cleavage of many proteins critical to normal function, including brain development. Therefore, manifestations in persons without normal Presenilin1 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 Presenilin1 variants is compatible with life, though may cause a more aggressive phenotype with younger age of onset and possibly REM behavior disorder.
Authors: Martin J Dahl; Mara Mather; Markus Werkle-Bergner; Briana L Kennedy; Samuel Guzman; Kyle Hurth; Carol A Miller; Yuchuan Qiao; Yonggang Shi; Helena C Chui; John M Ringman Journal: Neurobiol Aging Date: 2021-12-07 Impact factor: 4.673