De novo PSEN1 mutation (Pro436Gln) in a very early onset posterior variant of Alzheimer’s disease is associated with pyramidal signs

Background Alzheimer’s disease (AD) is a common cause of dementia even in cases with very early onset, and implication of monogenic mutations in the PSEN1, PSEN2, and APP genes must be considered. Strong family history is the rule in autosomal dominant AD associated with mutations in these genes but, in rare cases, de novo mutations can occur. Method Case report of a sporadic AD case with onset in his twenties carrying the Pro436Gln mutation (exon 12, TM‐9 region) in PSEN1. Comparison with a previously reported familial case carrying the same mutation. Result A 32 years old male consulted for a 10 years‐long mild but slowly progressive learning difficulties, apathy and anxiety. There was no family history of neurologic diseases and both parents were cognitively preserved in their early 70s. The previous two years he had developed progressive visual disturbances including impaired reading, recognizing numbers, letters and faces and, more recently, he had experienced troubles with manual praxias. There were no specific complaints regarding episodic memory. Neuropsychological assessment showed severe visual agnosia and mild impairments in memory, speech, and executive functions. Neurologic examination showed brief distal myoclonus in upper limbs, markedly enhanced reflexes in lower limbs, as well as mild spasticiy. Blood tests, EEG, spinal MRI, and SSEP were normal. Brain MRI and FDG‐PET revealed severe parieto‐occipital atrophy/hypoperfusion (fig. 1‐4). AD CSF biomarkers showed decrease in Ab1‐42 and 1‐42/1‐40 ratio, increased pTau and normal total tau. Amyloid‐PET was positive, identifying a high burden of amyloid plaques in posterior cortex. The pathogenic PSEN1 mutation was found in the patient but was absent in his parents. It is remarkable that the phenotype of the previously reported case with this mutation was almost identical as regards onset in the late twenties and associated pyramidalism. Conclusion PSEN1 mutations should be considered in patients with sporadic very early onset dementia, as de novo mutations may occur. AD CSF biomarkers offer valuable diagnostic information in such cases. The specific mutation has a very strong impact in the clinical phenotype. Further, this case is another example that PSEN1 mutations affecting proline residues have the earliest age at onset.