Research in neurodegenerative diseases: C9orf72 repeat expansion (GGGGCC) in a series of Portuguese FTLD individuals
Maria Rosário Almeida, Isabel Santana, Beatriz Santiago (FMUC, CNC)
Frontotemporal lobar degeneration (FTLD) is a neurodegenerative condition characterized by extensive clinical, pathological and genetic heterogeneity. Positive family history is observed in 25-50% of the cases with an autosomal dominant inheritance. In some FTLD families, mutations in MAPT and PGRN genes have been identified and were associated to tau and TDP43 pathology, respectively. Interestingly, some relatives of these families also developed MND with TDP43 pathology. Recently a pathological hexanucleotide repeat expansion in C9orf72 on chromosome 9p21 has been identified as the major cause of these FTLD/MND forms. Therefore in the present work we aimed to assess the frequency of the C9orf72 repeat expansion (GGGGCC) in a series of Portuguese FTLD individuals and their associated phenotypic characteristics.

Eighty three patients with clinical diagnosis of FTLD assisted in the Dementia outpatient clinic of CHUC or with genetic investigation at the CNC have been enrolled in the study. Of these, 42 sporadic FTLD and 37 familial and 4 with concomitant FTLD and MND patients were tested for the C9orf72 hexanucleotide repeat expansion in the framework of the Early-Onset Dementia (EOD)-Consortium. The expansion has been identified in 7 patients, one (2%) of 42 sporadic FTLD, four (18%) of 37 familial FTLD and two (50%) of 4 with FTLD/MND. All these patients have been previously tested for MAPT and PGRN genes with no mutations found. As a result, the pathogenic expansion in C9orf72 was present in a significant proportion of cases, unexplained by the available recognized genetic causative defects. Although few patients with FTLD and MND were analyzed, the expansion accounts for half of the cases and 18% of familial FTLD. Detailed phenotypic evaluation of the seven C9orf72 expansion carriers revealed a high clinical heterogeneity, intra and inter-familial. The location of this expansion within C9orf72 intronic region suggests the pathogenic involvement of the mutant RNA in the underlying FTLD mechanism.

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