A Novel Presenilin-1 Mutation (Leu226Val) In Early Onset Alzheimer’s Disease With Parkinsonism

Abstract

Alzheimer's disease (AD) represents the most common cause of dementia, accounting for 60% of cognitive disorders worldwide. AD is defined as early-onset (EOAD) when the clinical onset occurs before the age of 65, and it presents a higher frequency of familial clustering than the late-onset subtype.To date, variants in three causative genes such as presenilin 1 (PSEN-1), presenilin 2 (PSEN-2), and amyloid precursor protein (APP) have been identified as responsible for familial AD with Mendelian inheritance and almost complete penetrance. Overall, they account for less than 1% of all AD cases, although the prevalence peaks at about 20% in familiar EOAD. 1 PSEN-1, encoding a subunit of γ-secretase with a proteolytic activity on APP, is the main cause of monogenic AD. Thanks to the increasing availability of next-generation sequencing (NGS) panels, over 300 mutations in PSEN-1 have been discovered [https://www.alzforum.org/mutations/psen-1, accessed in March 2023), leading to a broad phenotypic variability.In 2020, a 50-years-old right-handed Caucasian man presented with a progressive and insidious onset of episodic memory deficits, reduced working ability, and neglect in his self-care.One year later, bradykinesia and left-hand action tremor appeared. Due to these symptoms, he underwent a DAT-SCAN (123I-Ioflupane) SPECT assessment, which revealed reduced uptake in the right basal ganglia. Consequently, he initiated dopaminergic treatment with L-dopa, titrated up to 200 mg/day, resulting in slight efficacy on the bradykinesia features.Two years later, the patient was admitted to our Neurology unit due to the persistence of extrapyramidal and cognitive features. His personal medical history was unremarkable and the patient did not suffer from any comorbidities. However, the assessment of his familial medical history revealed that his father had been diagnosed with cognitive impairment at about 50 years of age, and his brother had committed suicide at the age of 50.The initial clinical examination revealed a slight action tremor in the left hand, ipsilateral bradykinesia, along with plastic hypertonia and impaired visuospatial abilities. No anosmia, REM sleep behavior disorder, and dysautonomic signs were observed.