Autosomal dominant early onset Alzheimer's disease in the Mexican state of Jalisco: High frequency of the mutation PSEN1 c.1292C>A and phenotypic profile of patients

Abstract

Mutations in three genes (APP, PSEN1, and PSEN2) are the main cause of the autosomal dominant early‐onset Alzheimer's disease (AD‐EOAD). In PSEN1, the A431E (c.1292C>A, rs63750083) mutation is suspected to have exerted a founder effect in the State of Jalisco, Mexico. In Guadalajara, Jalisco, Mexico, this mutation was found in 46 index cases evaluated for AD‐EOAD. In our genealogical analysis, 301 affected relatives of the mutation carriers were identified, 195 of whom were already deceased at the time of interview. Moreover, 560 descendants had a 50% risk of carrying the mutation, and 348 were potentially at risk. A systematic phenotyping was performed in 39 patients. The mean onset age was 42.5 ± 3.9 years, and no significant difference in onset age was observed between the male and female patients. Furthermore, a substantial clinical heterogeneity and high frequencies of spastic paraparesis, language disorders, and neuropsychiatric symptoms were observed. To our knowledge, the investigated families represent the second biggest population carrying a PSEN1 mutation in Latin America, offering a unique opportunity to study the genetic basis of Alzheimer's disease. Addressing AD‐EOAD warrants an integral approach involving a deep understanding of its clinical behavior, as well as counseling protocols and prevention studies.

PSEN1 c.1292C<A Variant and Early-Onset Alzheimer’s Disease: A Scoping Review

“…Evidence regarding phenotypic variability is not conclusive. Joshi et al (2012) identified atypical features in carriers of variants associated with FAD, and these features were also reported by other authors: Pseudobulbar effect was identified also in the case of Parker et al (2019); myoclonus was presented in one of the families identified by Yescas et al (2006); gait abnormality was identified as a first symptom (Dumois-Petersen et al, 2020); and headaches were reported in the case of an A431E carrier (Alakkas et al, 2020), but the prevalence and intensity of the headaches could not be inquired; in addition, headaches were present in 67% of carriers in the study by Ringman et al (2008a) and allowed for differentiating carriers and non-carriers of variants in both PSEN1 and APP in a sample composed mainly of families with a history of A431E. Could these symptoms be part of a continuum or manifest at any moment is a topic of study and could be addressed in upcoming longitudinal studies.…”

“…In the preclinical stage, two of the studies were conducted on PSEN variant carriers ( Ringman et al, 2004 , 2007a ) and 12 on subjects with a history or carriers of EOAD-associated variants Ringman et al, 2008a , b , 2011 , 2012b , d , e ; Golob et al, 2009 ; Medina et al, 2011 , 2021 ; Braskie et al, 2013 ; Petok et al, 2018 ; Joe et al, 2019 ). In the clinical phase, three of the studies were conducted in A431E carriers ( Parker et al, 2019 ; Alakkas et al, 2020 ; Dumois-Petersen et al, 2020 ), and two of the studies were conducted in PSEN variant carriers ( Joshi et al, 2012 ; Soosman et al, 2016 ). Three studies were conducted on A431E carriers in both preclinical and clinical stages ( Murrell et al, 2006 ; Yescas et al, 2006 ; Santos-Mandujano et al, 2020 ), “three in PSEN variant carriers ( Rogaeva et al, 2001 ; Ringman et al, 2005 ; Leverenz et al, 2006 ), and eight in subjects with a history or carriers of EOAD-associated variants ( Ringman et al, 2007b , 2010 , 2012a , c ; Apostolova et al, 2011 ; Braskie et al, 2012 ; Lee et al, 2013 ; Singer et al, 2021 ).…”

“…In 2006, a study hypothesized the founding effect of this variant in the Altos de Jalisco area ( Yescas et al, 2006 ), a letter to the editor, further added 15 independent families to this finding ( Murrell et al, 2006 ). Phenotypic variability reported in the studies, such as SP ( Murrell et al, 2006 ; Yescas et al, 2006 ; Parker et al, 2019 ; Dumois-Petersen et al, 2020 ), motor impairment, visuospatial deficits, olfactory dysfunctions, such as hyposmia and anosmia, as well as respiratory difficulties and visual impairment ( Santos-Mandujano et al, 2020 ), language disorders ( Dumois-Petersen et al, 2020 ), neuropsychiatric symptoms ( Alakkas et al, 2020 ; Dumois-Petersen et al, 2020 ), atrophy disproportionate to age ( Parker et al, 2019 ; Alakkas et al, 2020 ; Santos-Mandujano et al, 2020 ), chronic microhemorrhages within bilateral occipital, temporal, and right frontal lobes and pseudobulbar affect ( Parker et al, 2019 ), and periventricular white matter hyperintensities ( Santos-Mandujano et al, 2020 ), were reported. Two of these studies are case reports ( Parker et al, 2019 ; Alakkas et al, 2020 ), one of them describing a case of a homozygous person ( Parker et al, 2019 ).…”

“…While the pathophysiology is similar, there are differences in the AD phenotype (Ringman et al, 2014). Among the variants in PSEN1, A431E is one of the primary three due to the number of carriers, which varies from 381 to 301 (Dumois-Petersen et al, 2020;Llibre-Guerra et al, 2021), and Compare global and localized fractional anisotropy measures in WM between FAD mutation carriers and non-carriers in the preclinical and presymptomatic stages of the disease.…”

“…A431E is one of the three variants in PSEN1 with the highest number of affected individuals in Latin America ( Dumois-Petersen et al, 2020 ; Llibre-Guerra et al, 2021 ). The estimated population varies from 381 ( Llibre-Guerra et al, 2021 ) to 301 ( Dumois-Petersen et al, 2020 ), while the number of people at risk ranges from 463 ( Llibre-Guerra et al, 2021 ) to 560 ( Dumois-Petersen et al, 2020 ). Therefore, an increase in A431E carriers is expected, as diagnostic studies and evaluations are still being held mostly by our group.…”