RESUMEN
In the last few years, the SORL1 gene has been strongly implicated in the development of Alzheimer's disease (AD). We performed whole-exome sequencing on 37 patients with early-onset dementia or family history suggestive of autosomal dominant dementia. Data analysis was based on a custom panel that included 46 genes related to AD and dementia. SORL1 variants were present in a high proportion of patients with candidate variants (15%, 3/20). We expand the clinical manifestations associated with the SORL1 gene by reporting detailed clinical and neuroimaging findings of six unrelated patients with AD and SORL1 mutations. We also present for the first time a patient with the homozygous truncating variant c.364C>T (p.R122*) in SORL1, who also had severe cerebral amyloid angiopathy. Furthermore, we report neuropathological findings and immunochemistry assays from one patient with the splicing variant c.4519+5G>A in the SORL1 gene, in which AD was confirmed by neuropathological examination. Our results highlight the heterogeneity of clinical presentation and familial dementia background of SORL1-associated AD and suggest that SORL1 might be contributing to AD development as a risk factor gene rather than as a major autosomal dominant gene.
Asunto(s)
Enfermedad de Alzheimer , Demencia , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Predisposición Genética a la Enfermedad , Humanos , Proteínas Relacionadas con Receptor de LDL/genética , Proteínas de Transporte de Membrana/genética , NeuroimagenRESUMEN
Hereditary cerebral amyloid angiopathies (CAA) are rare disorders of early onset and severe course. We describe a 47-year-old patient with Iowa-type amyloid precursor protein (APP) mutation-related hereditary CAA that manifested with concomitant lobar hemorrhage and venous sinus thrombosis. To analyze the cerebral amyloid-ß burden, an amyloid-PET was performed, demonstrating low cortical retention except for the calcarine cortex. High amyloid retention was also found in the thalamus and pallidum. The co-occurrence of CAA and venous thrombosis has not been previously reported in Iowa CAA and its mechanism is yet to be elucidated. Low cortical florbetapir-PET uptake does not rule out CAA in young patients, who may benefit from genetic testing to reach diagnosis when suspicion is strong.