Elsevier

Neurobiology of Aging

Volume 35, Issue 12, December 2014, Pages 2882.e7-2882.e12
Neurobiology of Aging

Genetic report abstract
Genetic architecture of ALS in Sardinia

https://doi.org/10.1016/j.neurobiolaging.2014.07.012Get rights and content

Abstract

Conserved populations, such as Sardinians, displaying elevated rates of familial or sporadic amyotrophic lateral sclerosis (ALS) provide unique information on the genetics of the disease. Our aim was to describe the genetic profile of a consecutive series of ALS patients of Sardinian ancestry. All ALS patients of Sardinian ancestry, identified between 2008 and 2013 through the Italian ALS Genetic Consortium, were eligible to be included in the study. Patients and controls underwent the analysis of TARDBP, C9ORF72, SOD1, and FUS genes. Genetic mutations were identified in 155 out of 375 Sardinian ALS cases (41.3%), more commonly the p.A382T and p.G295S mutations of TARDBP and the GGGGCC hexanucleotide repeat expansion of C9ORF72. One patient had both p.G295S and p.A382T mutations of TARDBP and 8 carried both the heterozygous p.A382T mutation of TARDBP and a repeat expansion of C9ORF72. Patients carrying the p.A382T and the p.G295S mutations of TARDBP and the C9ORF72 repeat expansion shared distinct haplotypes across these loci. Patients with cooccurrence of C9ORF72 and TARDBP p.A382T missense mutation had a significantly lower age at onset and shorter survival. More than 40% of all cases on the island of Sardinia carry a mutation of an ALS-related gene, representing the highest percentage of ALS cases genetically explained outside of Scandinavia. Clinical phenotypes associated with different genetic mutations show some distinctive characteristics, but the heterogeneity between and among families carrying the same mutations implies that ALS manifestation is influenced by other genetic and nongenetic factors.

Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of the adult life, characterized by a progressive deterioration of motor function, causing death because of respiratory failure within 2–4 years after onset. In Caucasian population, 90% of patients appear sporadically (sporadic ALS), whereas ∼10% of patients have a family history positive for ALS or frontotemporal dementia (FTD) (familial ALS, FALS). The commonest genes implied in ALS so far are C9ORF72, SOD1, TARDBP, and FUS (Renton et al., 2014), with marked differences between ethnic groups and geographical regions. Examples of this diversity include the virtual absence of SOD1 mutations in Ireland and the Netherlands (Kenna et al., 2013, van Blitterswijk et al., 2012), the extremely high frequency of C9ORF72 repeat expansions in Scandinavia (Majounie et al., 2012, Smith et al., 2013), and the high frequency of OPTN mutations combined with the relative scarcity of C9ORF72 repeat expansions observed in Japan (Konno et al., 2013, Maruyama et al., 2010).

Sardinia, the second largest Mediterranean island, represents a genetic isolate, characterized by a high frequency of autoimmune disorders (such as multiple sclerosis and diabetes mellitus type 1) and monogenic diseases (such a Wilson disease). As might be expected, this population displays decreased genetic and allelic heterogeneity. We and others have reported that ALS patients of Sardinian ancestry have a higher frequency than expected of the TARDBP p.A382T missense mutation and of the rate of familial ALS (Chiò et al., 2011, Orrù et al., 2012). Despite this, the incidence of ALS in Sardinians retrospectively investigated seems to be within the range of European studies (Pugliatti et al., 2013).

In this report, we describe the genetic profile of a larger series of ALS patients of Sardinian ancestry and extend our analysis to include other ALS genes (C9ORF72, SOD1, TARDBP, and FUS).

Section snippets

Patients

All ALS patients of Sardinian ancestry (i.e., defined as subjects with both parents of Sardinian origin) were eligible to be included in the study. Patients were identified between 2008 and 2013 through the Italian ALS Genetic Consortium, which includes 16 ALS centers in Italy (Chiò et al., 2012a). Clinical information, including cognitive status, were collected on all patients. ALS patients met the El Escorial–revised criteria for definite, probable, probable laboratory-supported, or possible

Results

We identified a cohort of 375 ALS cases with Sardinian ancestry, 236 men and 139 women with a mean (standard deviation) age at symptom onset of 61.1 (12.1) years. Ninety-nine patients (26.4%) had bulbar-onset disease, whereas the remaining 276 (73.6%) cases reported spinal onset of symptoms. A positive family history for ALS, FTD, or both was reported in 100 cases (26.7%).

Discussion

In our study of a large cohort of Sardinian ALS patients, a causative genetic mutation was identified in >40% of cases. The most common mutations were the p.A382T missense mutation in TARDBP, the pathogenic repeat expansion of C9ORF72, and the p.G295S missense mutation of TARDBP. Moreover, several patients carried a double mutation, more commonly the combination of C9ORF72 and TARDBP p.A382T missense mutation, and a smaller number were homozygous for TARDBP missense mutations. Overall, detected

Disclosure statement

AC serves on a scientific advisory board for Biogen Idec, Cytokinetics, and Italfarmaco. GB, MP, FM, MGM, MRM, GF, AC, LDP, PO, TBC, DL, AT, UM, AC, CM, AC, MBa, MBr, HAP, AER, MAN, BJT, and GR report no conflicts of interest. The sponsor organizations had no role in data collection and analysis and did not participate to writing and approving the article. The information reported in the article has never been reported elsewhere.

Acknowledgements

We thank the patients and research subjects who contributed samples for this study. This work was in part supported by the Italian Ministry of Health (Ministero della Salute, Ricerca Sanitaria Finalizzata, 2010, grant RF-2010–2309849), the European Community's Health Seventh Framework Programme (FP7/2007-2013 under grant agreement no. 259867), and the Joint Programme—Neurodegenerative Disease Research (Sophia Project, supported by the Italian Ministry of Health, and Strength Project, supported

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    See Supplementary Appendix for the other members of ITALSGEN and SARDINIALS.

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