C9ORF72 hexanucleotide repeat expansions in the Italian sporadic ALS population

Abstract

It has been recently reported that a large proportion of patients with familial amyotrophic lateral sclerosis (familial ALS) and frontotemporal dementia (FTD) are associated with a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72. We have assessed 1,757 Italian sporadic ALS cases, 133 from Sardinia, 101 from Sicily, and 1,523 from mainland Italy. Sixty (3.7%) of 1,624 mainland Italians and Sicilians and 9 (6.8%) of the 133 Sardinian sporadic ALS cases carried the pathogenic repeat expansion. None of the 619 regionally-matched control samples (1,238 chromosomes) carried the expansion. Twenty-five cases (36.2%) had behavioral FTD in addition to ALS. FTD or unspecified dementia was also detected in 19 pedigrees (27.5%) in first-degree relatives of ALS patients. Cases carrying the C9ORF72 hexanucleotide expansion survived one year less than cases who did not carry this mutation. In conclusion, we found that C9ORF72 hexanucloetide repeat expansions represents a sizeable proportion of apparent sporadic ALS in the Italian and Sardinian population, representing by far the commonest mutation in Italy and the second more common in Sardinia.

Neural substrate of cognitive theory of mind impairment in amyotrophic lateral sclerosis

“…One limitation of the present study is that we did not screen our patients for the C9ORF72 mutation, which is a major cause of familial FTD, ALS-FTD and both familial and apparently sporadic ALS (Sabatelli et al, 2012). Further studies are therefore needed to look for possible correlations between the presence of this mutation and ToM impairments in patients with ALS.…”

Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population

“…[4][5][6][7][8] Other studies, however, describe C9Pos patients with ALS as exhibiting clinical features similar to those with sporadic disease, only with a more rapidly progressive disease course. 9,10 Table e-1 at Neurology.org summarizes previous reports comparing C9Pos to C9Neg cohorts. Additionally, the pathologic expansion has been identified in 5%-10% of patients with ALS designated as sporadic, though these analyses have excluded family histories of nonmotor manifestations that are seen in people with the C9 expansion, specifically frontotemporal dementia (FTD).…”

“…Additionally, the pathologic expansion has been identified in 5%-10% of patients with ALS designated as sporadic, though these analyses have excluded family histories of nonmotor manifestations that are seen in people with the C9 expansion, specifically frontotemporal dementia (FTD). 1,9,11 There are practical advantages in defining the clinical similarities and differences between C9Pos and C9Neg patients, including whether mechanistic findings from C9 models can be generalized to C9Neg ALS, and whether ALS clinical trials should focus specifically on the C9Pos population. The Emory ALS Center maintains a large collection of DNA samples from patients with ALS along with their demographic and clinical characteristics.…”

Cross-Sectional Survey of Relevant Literatures as to the Current Proposed Disease Mechanisms and Treatments of Amyotrophic Lateral Sclerosis (ALS)

“…68 In an international cross-sectional study evaluating 4448 ALS patients, 37% of individuals with FALS are in possession of this mutation, having as many as 700-1600 copies of the repeat sequence compared to controls who only have 23 copies. 69 Comparable studies have been conducted in French (46% FALS, 8% SALS), 70 Italian (46% FALS), 71 Greek (50% FALS, 8.2% SALS), 72 Turkish (18.3% FALS, 3.1% SALS), 73 Slavic (5.9% SALS), 74 and Russian (15% FALS, 2.5% SALS) 75 populations testing positive for the GGGGCC repeat. Studies on Chinese SALS populations have yielded results indicating this sequence is not correlated to their patient populations, potentially describing a predilection for the C9orf72 hexanucleotide repeat for Caucasians.…”