Young-Onset Alzheimer Dementia Due to a Novel Pathogenic Presenilin 1 Variant Initially Misdiagnosed as Autoimmune Encephalitis

Abstract

Objectives: Pathogenic variants in presenilin 1 (PSEN1) are related to early-onset Alzheimer disease (AD) and may occur as de novo variants. In comparison with sporadic forms, it can present with psychiatric manifestations, seizures, myoclonus, and focal presentation. Because PSEN1 can occur in young patients who lack a family history of neurologic disorders and because these symptoms are also frequent in autoimmune encephalitis (AE), diagnosis may be overlooked. Our aim was to demonstrate the challenge in diagnosing young patients with neurodegenerative diseases that simulate AE.

Methods: We describe a case of a young patient with insidious progressive dementia, myoclonus, seizures, and aphasia, with no family history of dementia, along with signs suggestive of neuroinflammation on brain MRI and CSF examination.

Results: She was initially misdiagnosed as having AE. Further investigation was performed, leading to the discovery of a novel and de novo pathogenic variant in PSEN1.

Discussion: This case demonstrates the importance of considering PSEN1 in young patients with insidious progressive dementia with atypical clinical and neuroimaging features, even in patients without a family history of neurologic disorders. Not adhering to published criteria of possible and probable AE and overinterpretation of subtle inflammatory findings in CSF and MRI contribute to misdiagnosis.

Figure 1. Brain MRI Findings

In an initial MR examination, a coronal T2 image (A) discloses hyperintensity in the left hippocampus together with some enlargement (arrow); presenting gadolinium enhancement in the corresponding axial postcontrast T1 (B) image (arrow). Axial FDG-PET (C) obtained 10 months later demonstrates hypermetabolism of this structure (arrow). After 1 year, follow-up MR and FDG-PET were obtained; a coronal FLAIR image (D) now demonstrates hyperintensity in the right hippocampus (arrow), which is hypermetabolic in the corresponding coronal FDG-PET (E) image (arrow), while the remaining cortex is somewhat hypometabolic. (D) There is also a new hyperintense focus on the right frontal white matter (arrowhead), which presents enhancement in the corresponding axial postcontrast T1 (F) image (arrow). Three-dimensional stereotactic surface projections (3D-SSPs) of the FDG-PET images (G) disclose severe hypometabolism in a sizeable bilateral area comprising the temporoparietal cortex, the precunei, and posterior cingulate gyri (arrows in the lateral and medial projections), with mild to moderate extension to the prefrontal cortex, a pattern closely related to AD-like neurodegeneration. 3D-SSPs of the [¹¹C] PiB-PET/MR exam obtained 1.5 year later (H) disclose widespread deposition of amyloid plaques throughout the cerebral cortex and in the basal ganglia (not shown).