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Poster Presentations P3:
members and additional family members will be sequenced to see if the mutation is pathogenic. Both the insertion- and deletion-mutations result in a frameshift and premature stop codon. Previous reports suggest that this leads to nonsense mediated RNA decay of the transcripts and thus haploinsufficiency. We will further investigate the effect of the mutations by protein and RNA studies as well as immunohistochemical studies of brain tissue. The finding of mutations in the GRN gene in FTD patients can help us understand how FTD develops and to develop treatments for the disease. P3-279
A NOVEL PROGRANULIN MUTATION IN A LARGE FRONTOTEMPORAL DEMENTIA CALABRIAN KINDRED
Francesca Frangipane1, Rosanna Colao1, Maria Mirabelli1, Gianfranco Puccio1, Livia Bernardi1, Carmine Tomaino1, Maria Anfossi1, Maura Gallo1, Silvana Geracitano1, Raffaele Maletta1, Nicoletta Smirne1, Joshua Elder2, Toshitaka Kawarai3, Christine Sato3, Silvia Pradella4, Yosuke Wakutani3, Andrew Kertesz5, Peter St. George Hyslop3, John Hardy2, Ekaterina Rogaeva3, Parastoo Momeni2, Amalia Cecilia Bruni1, 1Centro Regionale di Neurogenetica, Lamezia Terme, Italy; 2Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA; 3Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, Toronto, ON, Canada; 4Department of Neurology and Psychiatry, Universita` di Firenze, Firenze, Italy; 5Department of Clinical Neurological Sciences, St. Joseph’s Health Centre, University of Western Ontario, London, ON, Canada. Contact e-mail:
[email protected] Background: Frontotemporal dementia (FTD) in several 17q21-linked families was recently explained by truncating mutations in the progranulin gene (GRN). Objective of this study is to determine the frequency of GRN mutations in a cohort of Caucasian FTD patients without mutations in known FTD genes. Methods: GRN was sequenced in a series of 78 independent FTD patients including 23 familial subjects. A different Calabrian dataset (109 normal controls and 96 FTD patients) was used to establish the frequency of the GRN mutation Results: A novel truncating GRN mutation (c.1145insA) was detected in a proband of an extended consanguineous Calabrian kindred. Segregation analysis of 70 family members revealed 19 heterozygous mutation carriers including 9 patients affected by FTD. The absence of homozygous carriers in highly consanguineous kindred may indicate that the loss of both GRN alleles might lead to embryonic lethality. An extremely variable age-atonset in the mutation carriers (more than five decades apart) is not explained by APOE genotypes or the H1/H2 MAPT haplotypes. Intriguingly, the mutation was excluded in four FTD patients belonging to branches with an autosomal dominant mode of inheritance of FTD, suggesting that another novel FTD gene accounts for the disease in the phenocopies. It is difficult to clinically distinguish phenocopies from GRN mutation carriers, except that language in mutation carriers was more severely compromised. Conclusions: The current results imply further genetic heterogeneity of FTD, since we detected only one GRN-linked family (⬃1%). The value of discovering large kindred includes the possibility of a longitudinal study of GRN mutation carriers. P3-280
ALZHEIMER’S DISEASE-LIKE CLINICAL PHENOTYPE IN A FAMILY WITH FTDP-17 CAUSED BY A MAPT R406W MUTATION
Suzanne G. Lindquist1, Ida E. Holm2, Marianne Schwartz3, Ian Law4, Jette Stokholm1, Mustafa Batbayli3, Gunhild Waldemar1, Jørgen E. Nielsen1, 1Memory Disorders Research Group, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; 2Department of Pathology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark; 3Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; 4Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. Contact e-mail:
[email protected]
Background: Inherited frontotemporal dementia is most often caused by mutations in one of the two genes; the microtubule associated protein tau (MAPT) gene or the progranulin (PGRN) gene, both localized on chromosome 17. We report clinical, molecular, neuroimaging and neuropathological features of a Danish family with autosomal dominant inherited dementia, a clinical phenotype resembling Alzheimer’s disease and a pathogenic mutation (R406W) in the MAPT gene. Methods: Presymptomatic and affected family members underwent multidisciplinary (clinical, molecular, neuroimaging and neuropathological) examinations. Results: Treatment with memantine in a family member with early symptoms, based on the clinical phenotype and the lack of specific treatment, appears to stabilize the disease course and increase the glucose metabolism in cortical and subcortical areas, as determined by serial [F18]FDG-PET scanning before and after initiation of treatment. Neuropathological examination of a second affected and mutation-positive family member showed moderate atrophy of the temporal lobes including the hippocampi. Microscopy revealed abundant numbers of tau-positive neurofibrillary tangles in all cortical areas and in some brainstem nuclei corresponding to a diagnosis of frontotemporal lobe degeneration on the basis of a MAPT mutation. Conclusions: The clinical and genetic heterogeneity of autosomal dominant inherited dementia must be taken into account in the genetic counselling and genetic testing of families with autosomal dominantly inherited dementia in general. P3-281
A NOVEL PROGRANULIN MUTATION IN GENE CAUSING FRONTOTEMPORAL DEMENTIA IN A BRAZILIAN FAMILY
Rodrigo R. Schultz1,2, Stuart M. Pickering-Brown3, 1University of Santo Amaro, Sa˜o Paulo, Brazil; 2Federal University of Sa˜o Paulo, Sa˜o Paulo, Brazil; 3University of Manchester, Manchester, United Kingdom. Contact e-mail:
[email protected] Background: Frontotemporal lobar degeneration (FTLD) is blanket term encompassing the clinical syndromes of frontotemporal dementia, progressive non-fluent aphasia and semantic dementia. There are two main pathological subtypes associated with FTLD, tauopathy and TDP-43opathy. It has been demonstrated that mutations in the tau and progranulin genes, both on chromosome 17q21, can cause some familial forms of tauopathy and TDP-43opathy respectively. The objective is to identify the genetic cause of FTD in a Brazilian family. Methods: Clinical study. We described two patients (brothers) in a Brazilian family with hereditary frontotemporal dementia (FTD). According to the history taken from some members of their family there are a lot of relatives with dementia, motor disturbances reminiscent to amyotrophic lateral sclerosis (ALS) or both. Molecular study. Genomic DNA was extracted from peripheral blood leukocytes. We sequenced progranulin and tau in both samples. Results: Case reports. Patient 1. This 69-year-old man started 4 years ago with insidious onset and gradual progression of aspontaneity and economy speech but normal comprehension. Apathy resulted in a desire to remain housebound. Neurological examination at age 68 revealed an altered speech output and a slight resting tremor and rigidity at his right superior limb. A brain MRI and SPECT showed fronto-temporal disturbances. Patient 2. This 74-year-old man started 3 years ago with insidious onset of memory loss and disorientation. He quickly developed behavioral disorders as apathy, overeating, depression, anxiety, wandering, disinhibition and urine incontinence. Grasp, snout and sucking reflexes were presented. Performance on neuropsychological tests evidenced a dementia with fronto-temporal disturbances. After seven months of treatment parkinsonian signs became evident. He had an abnormal brain SPECT and MRI. Molecular study. Progranulin sequencing revealed a 4bp deletion of exon 10 causing the following change R418Efx70X in both patients. Conclusions: In this paper we identified a novel progranulin mutation causing familial FTLD. While neuropathological data is currently unavailable for this family we predict it is likely a type 3 TDP-43opathy. We believe this is the first reported progranulin mutation from Brazil further confirming the wide spread nature of this genetic cause of FTLD.
