Document Detail


Development and validation of pedigree classification criteria for frontotemporal lobar degeneration.
MedLine Citation:
PMID:  24081456     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
IMPORTANCE: A significant portion of frontotemporal lobar degeneration (FTLD) is due to inherited gene mutations, and we are unaware of a large sequential series that includes a recently discovered inherited cause of FTLD. There is also great need to develop clinical tools and approaches that will assist clinicians in the identification and counseling of patients with FTLD and their families regarding the likelihood of an identifiable genetic cause.
OBJECTIVES: To ascertain the frequency of inherited FTLD and develop validated pedigree classification criteria for FTLD that provide a standardized means to evaluate pedigree information and insight into the likelihood of mutation-positive genetic test results for C9orf72, MAPT, and GRN.
DESIGN: Information about pedigrees and DNA was collected from 306 serially assessed patients with a clinical diagnosis of FTLD. This information included gene test results for C9orf72, MAPT, and GRN. Pedigree classification criteria were developed based on a literature review of FTLD genetics and pedigree tools and then refined by reviewing mutation-positive and -negative pedigrees to determine differentiating characteristics.
SETTING: Academic medical center.
PARTICIPANTS: Patients with FTLD.
MAIN OUTCOMES AND MEASURES: Familial risk.
RESULTS: The rate of C9orf72, MAPT, or GRN mutation-positive FTLD in this series was 15.4%. Categories designating the risk level for hereditary cause were termed high, medium, low, apparent sporadic, and unknown significance. Thirty-nine pedigrees (12.7%) met criteria for high, 31 (10.1%) for medium, 46 (15.0%) for low, 91 (29.7%) for apparent sporadic, and 99 (32.4%) for unknown significance. The mutation-detection rates were as follows: high, 64.1%; medium, 29%; low, 10.9%; apparent sporadic, 1.1%; and unknown significance, 7.1%. Mutation-detection rates differed significantly between the high and other categories.
CONCLUSIONS AND RELEVANCE: Mutation rates are high in FTLD spectrum disorders, and the proposed criteria provide a validated standard for the classification of FTLD pedigrees. The combination of pedigree criteria and mutation-detection rates has important implications for genetic counseling and testing in clinical settings.
Authors:
Elisabeth M Wood; Dana Falcone; Eunran Suh; David J Irwin; Alice S Chen-Plotkin; Edward B Lee; Sharon X Xie; Vivianna M Van Deerlin; Murray Grossman
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  JAMA neurology     Volume:  70     ISSN:  2168-6157     ISO Abbreviation:  JAMA Neurol     Publication Date:  2013 Nov 
Date Detail:
Created Date:  2013-11-12     Completed Date:  2013-12-30     Revised Date:  2014-04-24    
Medline Journal Info:
Nlm Unique ID:  101589536     Medline TA:  JAMA Neurol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1411-7     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Aged, 80 and over
Amyotrophic Lateral Sclerosis / genetics*
Cohort Studies
Female
Frontotemporal Lobar Degeneration / classification*,  diagnosis,  genetics*
Genetic Testing
Humans
Intercellular Signaling Peptides and Proteins / genetics
Male
Middle Aged
Mutation / genetics*
Pedigree*
Proteins / genetics
Reproducibility of Results
tau Proteins / genetics
Grant Support
ID/Acronym/Agency:
AG017586/AG/NIA NIH HHS; AG032953/AG/NIA NIH HHS; AG033101/AG/NIA NIH HHS; AG10124/AG/NIA NIH HHS; K08 AG033101/AG/NIA NIH HHS; K08 AG039510/AG/NIA NIH HHS; NS044266/NS/NINDS NIH HHS; P01 AG017586/AG/NIA NIH HHS; P01 AG032953/AG/NIA NIH HHS; P30 AG010124/AG/NIA NIH HHS; R01 NS044266/NS/NINDS NIH HHS; R01 NS082265/NS/NINDS NIH HHS; T32 AG000255/AG/NIA NIH HHS; T32-AG00025/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/C9orf72 protein, human; 0/GRN protein, human; 0/Intercellular Signaling Peptides and Proteins; 0/MAPT protein, human; 0/Proteins; 0/tau Proteins
Comments/Corrections

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