Genetic report abstractClinical, imaging, pathological, and biochemical characterization of a novel presenilin 1 mutation (N135Y) causing Alzheimer's disease
Introduction
Mutations of the presenilin 1 (PSEN1) gene on chromosome 14 account for 76.4% of the known cases of autosomal dominant Alzheimer's disease (ADAD; Ryman et al., 2014, Shea et al., 2015). They cause a more aggressive form of ADAD than PSEN2 mutations and APP mutations/duplications, with earlier age of onset (43.3 ± 8 years) and possibly a shorter duration until death (Shea et al., 2015). Clinically, those with PSEN1 mutations may exhibit more prominent aphasia, myoclonus, seizures, spasticity, or cerebellar dysfunction (Miller and Boeve, 2009, Shea et al., 2015).
The PSEN1 gene is located on chromosome 14 and consists of 13 exons encoding multiple protein isoforms through alternative mRNA splicing (Miller and Boeve, 2009). The resulting PS1 protein has 467 amino acids with 9 transmembrane (TM) domains. A systematic review of ADAD suggests a distinction between PSEN1 mutations before and after codon 200 (Shea et al., 2015). Patients with PSEN1 mutations on the amino side of codon 200 have slightly earlier onset and are more likely to be affected by seizures and myoclonus than those with mutations on the carboxy side of codon 200. Patients with PSEN1 mutations after codon 200 are more likely to be affected by visuospatial impairment and spastic paraparesis (Shea et al., 2015). However, this distinction has not been observed among participants in the Dominantly Inherited Alzheimer's Network (DIAN; Tang et al., in press). Pathologically, amyloid plaques, neurofibrillary tangles, and amyloid angiopathy are common (Miller and Boeve, 2009).
The PS1 protein is a critical component of γ-secretase, a protease required for β-amyloid formation from amyloid precursor protein (APP; De Strooper, 2003). PS1 forms a protein complex with 3 other proteins within neuronal membranes: nicastrin, anterior pharynx-defective 1 (Aph1) and presenilin enhancer 2 (Pen2). The complex has aspartyl protease activity and cleaves APP within the TM domain, liberating the C-terminal fragment of APP. It is the final enzymatic step in the production of Aβ40 and Aβ42 (Miller and Boeve, 2009). In vitro studies suggest that pathogenic mutations within PSEN1 increase the ratio of Aβ42, which is more amyloidogenic, to Aβ40 (Duff et al., 1996, Kumar-Singh et al., 2006, Scheuner et al., 1996). More than 220 mutations in the PSEN1 gene have been identified (Shea et al., 2015). Here, we describe the features of ADAD caused by a PSEN1 mutation that has not been previously reported.
Section snippets
Genetic testing
Genetic testing was performed by Athena Diagnostics (Worcester, MA, USA), with screening for sequence variants in APP, PSEN1, PSEN2, and for duplication of APP.
MRI
As part of the DIAN (NIA # U19 AG032438, R. J. Bateman, PI) the participant received a high-resolution (1.1 × 1.1 × 1.2-mm voxel) T1-weighted MPRAGE series acquired in the sagittal direction on a 3T scanner. This structural MRI acquisition was performed using the Alzheimer's disease Neuroimaging Initiative (ADNI) protocol (Jack et al.,
Case 1: clinical and imaging characterization
A 36-year-old right-handed white woman presented to the Memory Disorders Clinic at the University of Alabama at Birmingham with the chief complaint of forgetfulness. Her husband provided the history and stated that he had noticed the insidious onset of memory problems about 4 years earlier. At that time, he felt that she was forgetting “little things,” or would retrieve only parts of memories for recent events, but performed better when her memory was supported with cues. There was gradual
Discussion
This is the first report of the clinical syndrome associated with a N135Y mutation in the PSEN1 gene. The cases we identified developed AD in their 30s–40s associated with spasticity, hippocampal hyperexcitability, and epileptiform discharges. Differences in age at onset of 10 years among individuals with the same mutation are not common, but do occur (Ryman et al., 2014), and may result from the contribution of other genes to overall dementia risk (Lalli et al., 2015). Due to the limited
Disclosure statement
The authors have no conflicts of interest to disclose related to this article.
Acknowledgements
This research was supported by the National Institutes of Health (R01NS075487, U19AG032438, and U-01-AG042791), the National Institute on Aging (U19 AG032438), and the Veterans Administration (E6553W).
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