Novel homozygous nonsense mutation in SORL1 gene presenting as dementia and cerebral amyloid angiopathy: Genetics/genetic factors of Alzheimer's disease

Background The SORL1 gene encodes a type‐I transmembrane protein termed sortilin‐related receptor (SorLA). SorLA regulates the intracellular transport and processing of the amyloid precursor protein in neurons, and therefore, it has been implicated in the pathogenesis of Alzheimer’s disease (AD). Several SORL1 mutations have been described as a risk factor for AD, especially rare missense and non‐coding variants. To date, there are no reports of nonsense SORL1 mutations in homozygosis. Also, the relationship between cerebral amyloid angiopathy (CAA) and SORL1 mutations is not well established. Method Case report. Results A 62‐year‐old man was referred to our department complaining of a 3‐year history of apathy, memory complaints and spatial difficulties. His family history was remarkable for early onset dementia in his father and behavioural problems in his mother starting at the age of 80. Neuropsychological testing showed moderate episodic memory impairment, mild ideomotor apraxia and mild dysexecutive symptoms. The MRI showed marked global atrophy, superficial siderosis and multiple cortico‐subcortical microhemorrhages, fulfilling Boston criteria for probable CAA. Genetic testing using whole exome revealed the variant c.364C>T (p.R122*) in SORL1 gene (NM_003105.5) in homozygosis. In addition, APOE genotype was 3/3. Conclusion we describe a novel SORL1 mutation associated with AD. This is the first human report of a SORL1 nonsense mutation in homozygosis. SORL1 could play a role in the development of CAA.