Variability of the Clinical Phenotype in an Italian Family with Dementia Associated with an Intronic Deletion in the GRN Gene

Article type: Research Article

Authors: Marcon, Gabriella^{a; b; 1} | Rossi, Giacomina^{a; 1; *} | Giaccone, Giorgio^a | Giovagnoli, Anna Rita^c | Piccoli, Elena^a | Zanini, Sergio^d | Geatti, Onelio^e | Toso, Vito^f | Grisoli, Marina^g | Tagliavini, Fabrizio^a

Affiliations: [a] Division of Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy | [b] DISM, University of Udine, Udine, Italy | [c] Laboratory of Neuropsychology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy | [d] Scientific Institute “E. Medea”, Pasian di Prato, Udine, Italy | [e] Nuclear Medicine Department, University Hospital, Udine, Italy | [f] Neurologist Consultant, Polyclinic Abano Terme, Padua, Italy | [g] Division of Neuroradiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy

Correspondence: [*] Correspondence to: Giacomina Rossi, PhD, Division of Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Celoria 11, 20133 Milano, Italy. Tel.: +39 02 2394 4582; Fax: +39 02 2394 2101; E-mail: grossi@istituto-besta.it.

Note: [1] These authors contributed equally to this work.

Abstract: Mutations in the progranulin gene (GRN) were recently identified as an important cause of familial frontotemporal dementia (FTD). More than 60 pathogenic mutations have been reported up to now and prominent phenotypic variability within and among affected kindreds has been described. We have studied an Italian family with clinical evidence of dementia, and here we report detailed clinical records, imaging, sequential neurological examinations, cognitive assessments, and genetic analysis of three affected members of the same generation. Genetic analysis revealed the presence of the null mutation IVS6 + 5_8delGTGA in GRN, leading to haploinsufficiency, as documented by mRNA analysis. The mutation is associated with wide variation of the clinical phenotype, ranging from FTD to Alzheimer's disease and to a rapidly-progressive dementia. In summary, the patients of this kindred showed highly variable clinical features that do not have a close correspondence with the pattern of the cerebral atrophy. Our data extend the phenotypic spectrum and the complexity of neurodegenerative diseases linked to GRN mutations.

Keywords: Alzheimer's disease, frontotemporal dementia, haploinsufficiency, mutation, phenotype, progranulin

DOI: 10.3233/JAD-2011-110332

Journal: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 583-590, 2011