Objective: To report a new presenilin-1 (PSEN 1) missense variant (p.Pro88Arg) characterized by initial Progressive Supranuclear Palsy (PSP) like phenotype.

Background: Pathogenic variants in the PSEN1gene are currently reported in familial autosomal dominant early-onset Alzheimer’s disease. Atypical presentations have also been reported including extrapyramidal features but rarely with PSP phenotype.

Method: We report on a 54-year-old female of Moroccan origin with a rapidly progressive parkinsonism, postural instability with falls, frontal dementia and supranuclear gaze palsy, first suspecting the diagnosis of PSP. Family history found an early-onset dementia with walking disorder in her mother (died at 60 years of age) and psychiatric disorders in her son. One year later she was referred to the ALS reference center: on clinical examination, she presented with spastic paraparesis with pyramidal syndrome and dystonia of the foot in bilateral equine varus, bilateral and symmetrical extra pyramidal syndrome with akinesia and rigidity, supranuclear gaze palsy and frontal syndrome with grasping reflex. One year later, she had epileptic seizures and died at 55 years of age.

Results: The family history and rapid evolution first suggested a metabolic inherited disease. Blood test, ophthalmologic evaluation, medullar MRI and nerve conduction studies were unremarkable excluding infectious, auto immune, paraneoplastic, metabolic etiologies (Niemann-Pick C, Gaucher’s disease, long chain fatty acid, vitamin level, serum and urine copper). Neuropsychological testing was impossible. Brain MRI (figure 1) evidenced bilateral temporal and parietal atrophy on T1-weighted images and predominantly posterior and peri ventricular white matter hyper intensities on T2-weighted images. DAT-scan was normal. CSF biomarker showed isolated alteration of amyloid metabolism with low amyloid beta 42 level and amyloid beta 42/40 ratio. Total Tau, phosphorylated Tau and ratio tau/ phosphorylated tau were normal. 14.3.3 level was normal. Singleton exome sequencing disclosed a causative heterozygous PSEN1 missense variant (p.Pro88Arg).

Conclusion: This case shows the diagnostic difficulties of familial Alzheimer’s disease presenting with atypical phenotype and the interest of exome sequencing in the diagnosis of atypical neurodegenerative diseases.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/new-presenilin-1-missense-variant-p-pro88arg-characterized-by-initial-progressive-supranuclear-palsy-like-phenotype/