Dataset Information

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 (ALS) and frontotemporal dementia (FTD) are associated with a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72. We have assessed 1757 Italian sporadic ALS cases, 133 from Sardinia, 101 from Sicily, and 1523 from mainland Italy. Sixty (3.7%) of 1624 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 (1238 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 1 year less than cases who did not carry this mutation. In conclusion, we found that C9ORF72 hexanucleotide repeat expansions represents a sizeable proportion of apparent sporadic ALS in the Italian and Sardinian population, representing by far the most common mutation in Italy and the second most common in Sardinia.

SUBMITTER: Sabatelli M

PROVIDER: S-EPMC3372681 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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C9ORF72 hexanucleotide repeat expansions in the Italian sporadic ALS population.

Sabatelli Mario M Conforti Francesca Luisa FL Zollino Marcella M Mora Gabriele G Monsurrò Maria Rosaria MR Volanti Paolo P Marinou Kalliopi K Salvi Fabrizio F Corbo Massimo M Giannini Fabio F Battistini Stefania S Penco Silvana S Lunetta Christian C Quattrone Aldo A Gambardella Antonio A Logroscino Giancarlo G Simone Isabella I Bartolomei Ilaria I Pisano Fabrizio F Tedeschi Gioacchino G Conte Amelia A Spataro Rossella R La Bella Vincenzo V Caponnetto Claudia C Mancardi Gianluigi G Mandich Paola P Sola Patrizia P Mandrioli Jessica J Renton Alan E AE Majounie Elisa E Abramzon Yevgeniya Y Marrosu Francesco F Marrosu Maria Giovanna MG Murru Maria Rita MR Sotgiu Maria Alessandra MA Pugliatti Maura M Rodolico Carmelo C Moglia Cristina C Calvo Andrea A Ossola Irene I Brunetti Maura M Traynor Bryan J BJ Borghero Giuseppe G Restagno Gabriella G Chiò Adriano A

Neurobiology of aging 20120313 8

It has been recently reported that a large proportion of patients with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72. We have assessed 1757 Italian sporadic ALS cases, 133 from Sardinia, 101 from Sicily, and 1523 from mainland Italy. Sixty (3.7%) of 1624 mainland Italians and Sicilians and 9 (6.8%) of the 133 Sardinian sporadic ALS cases carried the pathogenic repeat exp ...[more]

PMID: 22418734

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Project description:Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of a disease spectrum associated with TDP-43 pathology. Strong evidence supporting this is the existence of kindreds with family members affected by FTD, ALS or mixed features of FTD and ALS, referred to as FTD-MND. Some of these families have linkage to chromosome 9, with hexanucleotide expansion mutation in a noncoding region of C9ORF72. Discovery of the mutation defines c9FTD/ALS. Prior to discovery of mutations in C9ORF72, it was assumed that TDP-43 pathology in c9FTD/ALS was uniform. In this study, we examined the neuropathology and clinical features of 20 cases of c9FTD/ALS from a brain bank for neurodegenerative disorders. Included are six patients clinically diagnosed with ALS, eight FTD, one FTD-MND and four Alzheimer-type dementia. Clinical information was unavailable for one patient. Pathologically, the cases all had TDP-43 pathology, but there were three major pathologic groups: ALS, FTLD-MND and FTLD-TDP. The ALS cases were morphologically similar to typical sporadic ALS with almost no extramotor TDP-43 pathology; all had oligodendroglial cytoplasmic inclusions. The FTLD-MND showed predominantly Mackenzie Type 3 TDP-43 pathology, and all had ALS-like pathology in motor neurons, but more extensive extramotor pathology, with oligodendroglial cytoplasmic inclusions and infrequent hippocampal sclerosis. The FTLD-TDP cases had several features similar to FTLD-TDP due to mutations in the gene for progranulin, including Mackenzie Type 1 TDP-43 pathology with neuronal intranuclear inclusions and hippocampal sclerosis. FTLD-TDP patients were older and some were thought to have Alzheimer-type dementia. In addition to the FTD and ALS clinical presentations, the present study shows that c9FTD/ALS can have other presentations, possibly related to age of onset and the presence of hippocampal sclerosis. Moreover, there is pathologic heterogeneity not only between ALS and FTLD, but also within the FTLD group. Further studies are needed to address the molecular mechanism of clinical and pathological heterogeneity of c9FTD/ALS due to mutations in C9ORF72.

Dataset Information

C9ORF72 hexanucleotide repeat expansions in the Italian sporadic ALS population.

Publications

C9ORF72 hexanucleotide repeat expansions in the Italian sporadic ALS population.

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