C9ORF72 hexanucleotide expansions of 20-22 repeats are associated with frontotemporal deterioration

被引:77
作者
Gomez-Tortosa, Estrella [1 ]
Gallego, Jesus [2 ]
Guerrero-Lopez, Rosa [3 ,4 ]
Marcos, Alberto [5 ]
Gil-Neciga, Eulogio [6 ]
Jose Sainz, Maria [1 ]
Diaz, Asuncion [7 ]
Franco-Macias, Emilio [6 ]
Jose Trujillo-Tiebas, Maria [2 ]
Ayuso, Carmen [2 ]
Perez-Perez, Julian [8 ]
机构
[1] Fdn Jimenez Diaz, Dept Neurol, E-28040 Madrid, Spain
[2] Fdn Jimenez Diaz, Dept Genet, E-28040 Madrid, Spain
[3] IIS FJD, Madrid, Spain
[4] CIBERER, Madrid, Spain
[5] Hosp Clin San Carlos, Dept Neurol, Madrid, Spain
[6] Hosp Virgen del Rocio, Dept Neurol, Seville, Spain
[7] Ctr Invest Biol, E-28006 Madrid, Spain
[8] Secugen SL, Madrid, Spain
关键词
AMYOTROPHIC-LATERAL-SCLEROSIS; DIAGNOSTIC-CRITERIA; BEHAVIORAL VARIANT; DEMENTIA; FEATURES; FTD; ALS;
D O I
10.1212/WNL.0b013e31827f08ea
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Objective: Expansions of more than 30 hexanucleotide repetitions in the C9ORF72 gene are a common cause of frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). However, the range of 20-30 repetitions is rarely found and still has unclear significance. A screening of our cohort of cases with FTD (n = 109) revealed 4 mutation carriers (>30 repetitions) but also 5 probands with 20-22 confirmed repetitions. This study explored the possible pathogenic correlation of the 20-22 repeats expansion (short expansion). Methods: Comparison of clinical phenotypes between cases with long vs short expansions; search for segregation in the families of probands with short expansion; analysis of the presence of the common founder haplotype, described for expansions >30 repeats, in the cases having the short expansion; and analysis of the distribution of hexanucleotide repeat alleles in a control population. Results: No different patterns were found in the clinical phenotype or aggressiveness of the disease when comparing cases with long or short expansions. Cases in both groups had psychiatric symptoms during 1-3 decades before evolving insidiously to cognitive deterioration. The study of the families with short expansion showed clear segregation of the 20-22 repeats allele with the disease. Moreover, this 20-22 repeats allele was associated in all cases with the pathogenic founder haplotype. None of 216 controls had alleles with more than 14 repetitions. Conclusions: Description of these families suggests that short C9ORF72 hexanucleotide expansions are also related to frontotemporal cognitive deterioration. Neurology (R) 2013;80:366-370
引用
收藏
页码:366 / 370
页数:5
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