Elsevier

Neurobiology of Aging

Volume 49, January 2017, Pages 216.e7-216.e13
Neurobiology of Aging

Genetic report abstract
Clinical, imaging, pathological, and biochemical characterization of a novel presenilin 1 mutation (N135Y) causing Alzheimer's disease

https://doi.org/10.1016/j.neurobiolaging.2016.09.020Get rights and content

Abstract

We present 2 cases of early-onset Alzheimer's disease due to a novel N135Y mutation in PSEN1. The proband presented with memory and other cognitive symptoms at age 32. Detailed clinical characterization revealed initial deficits in memory with associated dysarthria, progressing to involve executive dysfunction, spastic gait, and episodic confusion with polyspike discharges on long-term electroencephalography. Amyloid- and FDG-PET scans showed typical results of Alzheimer's disease. By history, the proband's father had developed cognitive symptoms at age 42 and died at age 48. Neuropathological evaluation confirmed Alzheimer's disease, with moderate to severe amyloid angiopathy. Skeletal muscle showed type 2 fiber–predominant atrophy with pale central clearing. Genetic testing of the proband revealed an N135Y missense mutation in PSEN1. This mutation was predicted to be pathogenic by in silico analysis. Biochemical analysis confirmed that the mutation caused an increased Aβ42/Aβ40 ratio, consistent with other PSEN1 mutations and with a loss of presenilin function.

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).

References (37)

  • D. Xia et al.

    Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer's disease

    Neuron

    (2015)
  • I.A. Adzhubei et al.

    A method and server for predicting damaging missense mutations

    Nat. Methods

    (2010)
  • H. Braak et al.

    Neuropathological stageing of Alzheimer-related changes

    Acta Neuropathol.

    (1991)
  • L. Chávez-Gutiérrez et al.

    The mechanism of γ-Secretase dysfunction in familial Alzheimer disease

    EMBO J.

    (2012)
  • Y. Choi et al.

    Predicting the functional effect of amino acid substitutions and indels

    PLoS One

    (2012)
  • R. Crook et al.

    Early-onset Alzheimer's disease with a presenilin-1 mutation at the site corresponding to the Volga German presenilin-2 mutation

    Ann. Neurol.

    (1997)
  • B. De Strooper

    Loss-of-function presenilin mutations in Alzheimer disease. Talking point on the role of presenilin mutations in Alzheimer disease

    EMBO Rep.

    (2007)
  • K. Duff et al.

    Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1

    Nature

    (1996)
  • Cited by (7)

    • Cerebral Small Vessel Disease in Sporadic and Familial Alzheimer Disease

      2021, American Journal of Pathology
      Citation Excerpt :

      The most common type of CAA is Aβ angiopathy, which is reported to be as high as 90% in AD.105 The majority of pathologically verified familial AD subjects exhibit CAA.47,56,106–153 The first case in Argentina with marked vascular pathology including CAA carried the APP Ala171Thr mutation.154

    • Leveraging hallmark Alzheimer's molecular targets using phytoconstituents: Current perspective and emerging trends

      2021, Biomedicine and Pharmacotherapy
      Citation Excerpt :

      Thus, the impending AD treatment would be based on a multidrug and multi-target approach like chemotherapy. Still, it is unsure how these probable drug treatments will be syndicated with the relevant subgroups and even the order of their selection [221]. Such trends would include non-amyloid approaches, essentially altering the therapeutic scene.

    • Using big data methods to understand Alzheimer’s disease

      2021, Alzheimer’s Disease: Understanding Biomarkers, Big Data, and Therapy
    • Presenilin-1 mutation is associated with a hippocampus defect in alzheimer's disease: Meta-Analysis for neuroimaging research

      2020, Clinical Neurology and Neurosurgery
      Citation Excerpt :

      As shown in the forest plots (Fig. 2), combining the five studies using continuous hippocampal volume and providing weighted mean differences (n = 37 PSEN1+ subjects and n = 98 PSEN1- subjects) yielded a statistically significant association between the PSEN1 mutation and decreased hippocampal volume: pooled standardized mean difference = −3.3 (95 % CI − 5.36 to −1.24) (I2 = 93.8 %, Cochran’s Q = 64.43, p < 0.0001); test for overall effect: Z = 3.14, p = 0.002. The study found a statistically significant correlation between PSEN1 mutation and hippocampal atrophy. [10,17,19–21]. In order to investigate whether PSEN1 independently results in hippocampal volume changes, three studies (with no significant differences in MMSE values) were selected for further meta-analysis (Fig. 3).

    • Identification of a novel PSEN1 Gly111Val missense mutation in a Chinese pedigree with early-onset Alzheimer's disease

      2020, Neurobiology of Aging
      Citation Excerpt :

      There was a trend of Aβ42 to increase, but not significantly. This finding is in agreement with previous studies of other PSEN1 mutations, such as PSEN1 Ala79Val, PSEN1 Asn135Tyr, PSEN1 Met139Val, and PSEN1 Leu166Pro (Kumar-Singh et al., 2006; Li et al., 2016; Natelson Love et al., 2017; Shioi et al., 2007). PS1 is the catalytic center of γ-secretase.

    View all citing articles on Scopus
    View full text