One novel GRN null mutation, two different aphasia phenotypes

Abstract Progranulin gene (GRN) mutations are among the leading causes of Fronto-temporal lobar degeneration (FTLD), a group of neurodegenerative diseases characterized by remarkable clinical heterogeneity. In this paper we report the new GRN 708+4A>T splicing mutation, identified in two siblings of a family with several members affected by cognitive, behavioral and motor disorders. Plasma progranulin dosage and GRN expression analysis, together with in silico prediction studies, supported the pathogenicity of the mutation. Both the patients displayed a clinical syndrome in which language impairment was largely predominant. However, motor speech deficits were the major feature in one case, diagnosed as progressive non fluent aphasia, whereas marked semantic alterations were present in the other, whose clinical phenotype was in favor of a mixed aphasia. The profile of neuroanatomical alterations from imaging studies was in line with the clinical phenotypes. Therefore, also this novel GRN mutation is associated with haploinsufficiency and phenotypic heterogeneity, which are both typical features of progranulinopathies.