Objective: To assess the frequency and the phenotype of a large series of Italian sALS and fALS with C9ORF72 repeat expansions. Background Recently we found that large expansions of hexanucleotide repeats (GGGGCC) in the first intron of the C9ORF72 gene, located in the chromosome 9p21, are related to familial and sporadic ALS cases(Renton et al, 2011). Design/Methods: We assessed 126 index fALS (106 Italians, 20 of Sardinians) and 601 sALS (485 Italians, 116 Sardinians), negative for other ALS-related genes mutations. Patients were collected through the ITALSGEN consortium. Repeat primer PCR to screen the presence of the hexanucleotide expansion in the first intron of C9ORF72 have been performed. Controls were 353 neurologically healthy subjects of Italian ancestry and 96 of Sardinian ancestry. Results: In controls, the number of repeats was under 25 (range 0-23). Among Italians 16 sALS (3.3%) and 42 (39.6%) had an increase of C9ORF72 gene repeats. Among Sardinian 9 sALS (7.8%) and 11 fALS (55.5%) had an increase of C9ORF72 gene repeats. In Italians, a north to south decreasing gradient of C9ORF72 hexanucleotide repeat expansions was found. Compared to patients without repeats, subjects with repeat expansion had a higher frequency of frontotemporal dementia (FTD)(p=0.0001). A tendency toward an anticipation of age at onset was found, with a greater anticipation if the transmitting parent was the mother. The penetrance was 63% (95% CI, 56-69%) at 70 years, and 81% at 80 years (75-87%). The penetrance was significantly higher in men (70% at 70 years) than in women (54% at 70 years)(p=0.03). Conclusions: Th expansions of the C9ORF72 gene are the most common genetic mutation in Italian sALS and fALS and are particularly frequent in subjects of Sardinian ancestry. The complexity of the phenotype of pedigrees related to this mutation, which include cases with ALS, ALS-FTD and FTD, challenge the current notion of familial ALS. Disclosure: Dr. Chio has nothing to disclose. Dr. Borghero has nothing to disclose. Dr. Sabatelli has nothing to disclose. Dr. Corbo has nothing to disclose. Dr. Mora has nothing to disclose. Dr. Giannini has nothing to disclose. Dr. Conforti has nothing to disclose. Dr. Penco has nothing to disclose. Dr. Calvo has nothing to disclose. Dr. Pugliatti has nothing to disclose. Dr. Sotgiu has nothing to disclose. Dr. Logroscino has received personal compensation for activities with Novartis, Glaxo and Boerhinger. Dr. Traynor has received personal compensation in an editorial capacity for the journal Neurology. Dr. Renton has nothing to disclose. Dr. Majounie has nothing to disclose. Dr. Lauria has nothing to disclose. Dr. Caponnetto has nothing to disclose. Dr. Mandrioli has nothing to disclose. Dr. Salvi has received research support from Fondazione Hilarescere. Dr. Volanti has nothing to disclose. Dr. La Bella has nothing to disclose. Dr. Monsurro has nothing to disclose. Dr. Zollino has nothing to disclose. Dr. Ossola has nothing to disclose. Dr. Brunetti has nothing to disclose. Dr. Restagno has nothing to disclose.
Objective: Mutations in the progranulin (PGRN) gene were recently described as the cause of ubiquitin positive frontotemporal dementia (FTD). Clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and FTD prompted us to screen PGRN in patients with ALS and ALS–FTD. Methods: The PGRN gene was sequenced in 272 cases of sporadic ALS, 40 cases of familial ALS and in 49 patients with ALS–FTD. Results: Missense changes were identified in an ALS–FTD patient (p.S120Y) and in a single case of limb onset sporadic ALS (p.T182M), although the pathogenicity of these variants remains unclear. Conclusion:PGRN mutations are not a common cause of ALS phenotypes.
The presence of fetal DNA in maternal plasma can be exploited to develop new procedures for non-invasive prenatal diagnosis. Tests to detect 7 frequent beta-globin gene mutations in people of Mediterranean origin were applied to the analysis of maternal plasma in couples where parents carried different mutations. A mutant enrichment amplification protocol was optimized by using peptide nucleic acids (PNAs) to clamp maternal wild-type alleles. By this approach, 41 prenatal diagnoses were performed by microelectronic microchip analysis, with total concordance of results obtained on fetal DNA extracted from chorionic villi. Among these, 27/28 were also confirmed by direct sequencing and 4 by pyrosequencing.
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