Intra-Familial Clinical Heterogeneity due to FTLD-U with TDP-43 Proteinopathy Caused by a Novel Deletion in Progranulin Gene (PGRN)

Article type: Research Article

Authors: Gabryelewicz, Tomasz^{a; 1} | Masellis, Mario^{b; c; d; 1} | Berdynski, Mariusz^{a; 1} | Bilbao, Juan M.^e | Rogaeva, Ekaterina^f | St. George-Hyslop, Peter^{c; f; g} | Barczak, Anna^a | Czyzewski, Krzysztof^a | Barcikowska, Maria^a | Wszolek, Zbigniew^h | Black, Sandra E.^{b; c; 2; *} | Zekanowski, Cezary^{a; 2}

Affiliations: [a] Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland | [b] LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada | [c] Department of Medicine, Division of Neurology, University of Toronto, Toronto, Canada | [d] Neurogenetics Division, Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada | [e] Department of Pathology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada | [f] Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Canada | [g] Cambridge Institute for Medical Research, University of Cambridge, UK | [h] Department of Neurology, Mayo Clinic, Rochester, NY, USA

Correspondence: [*] Correspondence to: Dr. Sandra E. Black, Brill Chair in Neurology, Sunnybrook Health Sciences Centre, Room A4 21, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5. Tel.: +1 416 480 4551; Fax: +1 416 480 4552; E-mail: [email protected].

Note: [1] These authors have contributed equally to the work described in the article.

Note: [2] These authors have contributed equally as senior authors.

Abstract: Frontotemporal dementia (FTD) is one of the commonest forms of early-onset dementia, accounting for up to 20% of all dementia patients. Recently, it has been shown that mutations in progranulin gene (PGRN) cause many familial cases of FTD. Members of a family affected by FTD spectrum disorders were ascertained in Poland and Canada. Clinical, radiological, molecular, genetic, and pathological studies were performed. A sequencing analysis of PGRN exons 1–13 was performed in the proband. Genotyping of the identified PGRN mutation and pathological analysis was carried out in the proband's brother. The onset of symptoms of FTD in the proband included bradykinesia, apathy, and somnolence followed by changes in personality, cognitive deficits, and psychotic features. The proband's clinical diagnosis was FTD and parkinsonism (FTDP). DNA sequence analysis of PGRN revealed a novel, heterozygous mutation in exon 11 (g.2988_2989delCA, P439_R440fsX6). The mutation introduced a premature stop codon at position 444. The proband's brother with the same mutation had a different course first presenting as progressive non-fluent aphasia, and later evolving symptoms of behavioral variant of FTD. He also developed parkinsonism late in the disease course evolving into corticobasal syndrome. Pathological analysis in the brother revealed Frontotemporal Lobar Degeneration-Ubiquitin (FTLD-U)/TDP-43 positive pathology. The novel PGRN mutation is a disease-causing mutation and is associated with substantial intra-familial clinical heterogeneity. Although presenting features were different, rapid and substantial deterioration in the disease course was observed in both family members.

Keywords: Corticobasal syndrome, frontotemporal dementia, haploinsufficiency, parkinsonism, progranulin mutation, progressive non-fluent aphasia

DOI: 10.3233/JAD-2010-101413

Journal: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1123-1133, 2010