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C9ORF72 hexanucleotide expansions of 20-22 repeats are associated with frontotemporal deterioration
Estrella Gómez-Tortosa1, Jesús Gallego, Rosa Guerrero-López
1Department of Neurology, Fundación Jiménez Díaz, Madrid, Spain. egomezt@fjd.es
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.
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