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

被引:19
作者
Gabryelewicz, Tomasz [2 ]
Masellis, Mario [3 ,4 ]
Berdynski, Mariusz [2 ]
Bilbao, Juan M. [5 ]
Rogaeva, Ekaterina [6 ]
George-Hyslop, Peter St. [3 ,6 ,7 ]
Barczak, Anna [2 ]
Czyzewski, Krzysztof [2 ]
Barcikowska, Maria [2 ]
Wszolek, Zbigniew [8 ]
Black, Sandra E. [1 ,3 ]
Zekanowski, Cezary [2 ]
机构
[1] Univ Toronto, Brill Chair Neurol, LC Campbell Cognit Neurol Res Unit, Sunnybrook Res Inst,Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada
[2] Polish Acad Sci, Dept Neurodegenerat Disorders, Mossakowski Med Res Ctr, Warsaw, Poland
[3] Univ Toronto, Div Neurol, Dept Med, Toronto, ON M4N 3M5, Canada
[4] Univ Toronto, Neurogenet Div, Ctr Addict & Mental Hlth, Toronto, ON M4N 3M5, Canada
[5] Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Pathol, Toronto, ON M4N 3M5, Canada
[6] Univ Toronto, Ctr Res Neurodegenerat Dis, Toronto, ON M4N 3M5, Canada
[7] Univ Cambridge, Cambridge Inst Med Res, Cambridge CB2 1TN, England
[8] Mayo Clin, Dept Neurol, Rochester, NY USA
关键词
Corticobasal syndrome; frontotemporal dementia; haploinsufficiency; parkinsonism; progranulin mutation; progressive non-fluent aphasia; FRONTOTEMPORAL LOBAR DEGENERATION; CORTICOBASAL SYNDROME; DEMENTIA; MUTATION; VARIABILITY; CRITERIA; DISEASE; MAPT; CHROMOSOME-17; PHENOTYPE;
D O I
10.3233/JAD-2010-101413
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:1123 / 1133
页数:11
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