A patient with posterior cortical atrophy possesses a novel mutation in the presenilin 1 gene

Abstract

Posterior cortical atrophy is a dementia syndrome with symptoms of cortical visual dysfunction, associated with amyloid plaques and neurofibrillary tangles predominantly affecting visual association cortex. Most patients diagnosed with posterior cortical atrophy will finally develop a typical Alzheimer's disease. However, there are a variety of neuropathological processes, which could lead towards a clinical presentation of posterior cortical atrophy. Mutations in the presenilin 1 gene, affecting the function of γ-secretase, are the most common genetic cause of familial, early-onset Alzheimer's disease. Here we present a patient with a clinical diagnosis of posterior cortical atrophy who harbors a novel Presenilin 1 mutation (I211M). In silico analysis predicts that the mutation could influence the interaction between presenilin 1 and presenilin1 enhancer-2 protein, a protein partner within the γ-secretase complex. These findings along with published literature support the inclusion of posterior cortical atrophy on the Alzheimer's disease spectrum.

Figure 1. Analysis of visuospatial dysfunction of the patient.

Patient's drawings in the context of drawings by a patient with semantic dementia. (SD) scoring 19 in MMSE were presented. A) flowers drawn by the patients from memory: A1) PCA patient, A2) SD patient; B) model, C) patients' copy: C1) PCA patient, C2) SD patient. Copying pictures and drawing to command indicated severe optic ataxia and partial simultanognosia. The test was performed at first neuropsychological assessment. During the second assessment (six months later) the patient was unable to draw even simple patterns and presented with complete simultanognosia.

Figure 2. Results of MRI and SPECT examinations of the proband.

Magnetic Resonance Imaging revealed marked cortical and subcortical atrophy within both occipital and parietal lobes bilaterally. The atrophy was less pronounced in the frontal and temporal lobes, and the hippocampal structures of the temporal lobes were mostly preserved. Single Photon Emission Computed Tomography demonstrated severe hypoperfusion within the parietal, occipital and temporal lobes bilaterally.

Figure 3. Results of MRI and SPECT examination of a control subject.

Magnetic Resonance Imaging and Single Photon Emission Computed Tomography demonstrating the normal scans of a control, age-matched patient with no signs of any neurodegenerative disorder.

Figure 4. In silico modeling of presenilin 1 and PEN-2 protein interaction.

A model of a complex of PS1 TM4-TM5 (in blue) and PEN-2 TM1 (in yellow) were shown. Only the residues discussed in the text are depicted and colored: I211 and Q223 in orange other residues in cyan. Hydrogen bonds are visualized as dashed yellow cylinders. The residues N204 and N33 form a hydrogen bond, while R220 and E40 form a salt bridge at extracellular side of the presenilin 1.