A Clinical Case of Patient Carrying Rare Pathological PSEN1 Gene Mutation (L424V) Demonstrates the Phenotypic Heterogenity of Early Onset Familial AD.

Dementia comprises several neurodegenerative disorders with similar neuropsychiatric features and Alzheimer's disease (AD) is the most common of them. Genetic factors are strongly implicated into its etiology especially for early-onset cases (EOAD) occuring before the age of 65. About 10% of these are inherited in autosomal dominant fashion via pathogenic polymorphisms in three genes- APP, PSEN-1, and PSEN-2. Despite genotypic clarity, however, phenotypic variability exists with different symptom constellations observed in patients with identical mutations. Below, we present a case of a 39-year-old male with a family history for early onset dementia who was referred to our department with anamnesis for abrupt behavioral change 7 months prior to hospitalization-noticeable slowing of speech and reactivity, impaired occupational functioning and irritability, followed by aphasic symptoms and transient episodes of disorientation. He was followed up for 2 years and manifested rapidly progressing cognitive decline with further deterioration of speech, apraxia, acalculia, ataxia, and subsequently bradykinesia and tremor. Based on the clinical and neuroimaging findings (severe cortical atrophy), familial EOAD was suspected and a whole exome sequence (WES) analysis was performed. It identified a heterozygous missense variant Leu424Val (g.71074C > G) in PSEN-1 gene considered to be pathogenic, and only reported once until now in a Spanish patient in 2009. Despite genotype identity however, distinct phenotypic presentations were observed in the two affected subjects, with different neuroimaging findings, and the presence and absence of seizures in the Spanish and Bulgarian case, respectively. Besides, myoclonus and spastic paraparesis considered "typical" EOAD clinical features were absent. Age of symptom onset was consistent with two of the reported mutations affecting 424 codon of PSEN-1 gene and significantly earlier than the other two implying that factors influencing activity of PSEN-1 pathological forms are yet to be clarified. Furthermore, our patient had co-occurring lupus erythematosus (LE) and we suggest that this condition might be etiologically linked to the PSEN-1 mutation. In addition to illustrating the symptomatic heterogeneity of PSEN-1 caused EOAD, our study confirms that in patients presenting with early cognitive deterioration and family history for dementia, WES can be especially informative and should be considered as a first-line examination.