Cognitive profile and motor phenotype in Mexican patients with familial early onset Alzheimer disease with the p. Ala431Glu variant of the PSEN1 gene

Abstract

AbstractBackgroundGiven the deleterious consequences for patients and families with autosomal dominant AD, it is necessary to identify individuals at risk in preclinical phases, with the objective of include them in clinical intervention trialsMethodWe included 11 DNA samples from patients diagnosed with FAD and 9 DNA samples with of patients with EAD, which were analyzed by clinical exome sequencing in Nextera Next Seq equipment. Results are reported on a case‐by‐case basis for genomics, cognitive, neuropsychiatric, motor, and functional evaluations.ResultWe identify 9 carriers of the pathogenic variant p. Ala431Glu of the PSEN1 gene and in 4 of these patients, more than one uncertain significance variant was identified in the ANO5, TYROBP, ALS2, WASHC5, ABCA7, TOMM40, CLU, ATP7B, USH2A genes. In 5 patients we identify another pathogenic variants in PSEN1 gene. Estimated age at onset (AAO) in carriers of A431E variant was 40.6 ± 3.1 years, while in the Non A431E group was 46 ± 11.6. Patients with E431E variant had the worst performance at the beginning and in his last evaluation in all the cognitive tests. The most striking differences were in MMSE (16.3 ± 6.1 and 9.4 ± 6.2 vs 18.1 ± 2.1 and 11.9 ± 4.7) and PHFV tests (4 ± 5.2 and 1.33 ± 2.2 vs 6.1 ± 0.2 and 2.6 ± 2). The most frequent neuropsychiatric symptoms in A431E group was depression, anxiety and irritability, while in the EAD was apathy. Near to 40% of patients A431E has motor symptoms at baseline, and this percentage increased to 80% in the latest evaluation. This group had a high frequency of stiffness, tremor and spastic gait and in EAD the most consistent symptom was postural tremor. The motor‐symptom profile is presented in Figure 1.ConclusionA high frequency of the Jalisco variant is reported in Mexican patients with FAD. This variant is related to early onset of symptoms, rapid progression, as well as a high frequency of motor symptoms. This makes it necessary to consider their identification of this variant as a first step in the diagnostic algorithm of this type of population. The identification of patients carrying this variant requires correct genetic counseling and makes them candidates to enroll in international clinical trials of pharmacological intervention.