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1.  Genetic architecture of ALS in Sardinia 
Neurobiology of aging  2014;35(12):2882.e7-2882.e12.
Conserved populations, such as Sardinians, displaying elevated rates of familial or sporadic 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 ITALSGEN 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 mutation of TARDBP and eight 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 co-occurrence 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 non-genetic factors.
doi:10.1016/j.neurobiolaging.2014.07.012
PMCID: PMC4252367  PMID: 25123918
Amyotrophic Lateral Sclerosis; Sardinia; phenotype; genetics; penetrance; prognosis
2.  ALS/FTD phenotype in two Sardinian families carrying both C9ORF72 and TARDBP mutations 
Background
In the isolated population of Sardinia, a Mediterranean island, ~25% of ALS cases carry either a p.A382T mutation of the TARDBP gene or a GGGGCC hexanucleotide repeat expansion in the first intron of the C9ORF72 gene.
Objective
To describe the co-presence of two genetic mutations in two Sardinian ALS patients.
Methods
We identified two index ALS cases carrying both the p.A382T missense mutation of TARDBP gene and the hexanucleotide repeat expansion of C9ORF72 gene.
Results
The index case of Family A had bulbar ALS and frontemporal dementia (FTD) at 43. His father, who carried the hexanucleotide repeat expansion of C9ORF72 gene, had spinal ALS and FTD at 64 and his mother, who carried the TARDBP gene p.A382T missense mutation, had spinal ALS and FTD at 69. The index case of Family B developed spinal ALS without FTD at 35 and had a rapid course to respiratory failure. His parents are healthy at 62 and 63. The two patients share the known founder risk haplotypes across both the C9ORF72 9p21 locus and the TARDBP 1p36.22 locus.
Conclusions
Our data show that in rare neurodegenerative causing genes can co-exist within the same individuals and are associated with a more severe disease course.
doi:10.1136/jnnp-2012-302219
PMCID: PMC4568835  PMID: 22550220
3.  Genome-Wide Analysis of the Heritability of Amyotrophic Lateral Sclerosis 
JAMA neurology  2014;71(9):1123-1134.
Importance
Considerable advances have been made in our understanding of the genetics underlying amyotrophic lateral sclerosis (ALS). Nevertheless, for the majority of patients who receive a diagnosis of ALS, the role played by genetics is unclear. Further elucidation of the genetic architecture of this disease will help clarify the role of genetic variation in ALS populations.
Objective
To estimate the relative importance of genetic factors in a complex disease such as ALS by accurately quantifying heritability using genome-wide data derived from genome-wide association studies.
Design, Setting, and Participants
We applied the genome-wide complex trait analysis algorithm to 3 genome-wide association study data sets that were generated from ALS case-control cohorts of European ancestry to estimate the heritability of ALS. Cumulatively, these data sets contained genotype data from 1223 cases and 1591 controls that had been previously generated and are publically available on the National Center for Biotechnology Information database of genotypes and phenotypes website (http://www.ncbi.nlm.nih.gov/gap). The cohorts genotyped as part of these genome-wide association study efforts include the InCHIANTI (aging in the Chianti area) Study, the Piemonte and Valle d’Aosta Register for Amyotrophic Lateral Sclerosis, the National Institute of Neurological Disorders and Stroke Repository, and an ALS specialty clinic in Helsinki, Finland.
Main Outcomes and Measures
A linear mixed model was used to account for all known single-nucleotide polymorphisms simultaneously and to quantify the phenotypic variance present in ostensibly outbred individuals. Variance measures were used to estimate heritability.
Results
With our meta-analysis, which is based on genome-wide genotyping data, we estimated the overall heritability of ALS to be approximately 21.0% (95% CI, 17.1–24.9) (SE = 2.0%), indicating that additional genetic variation influencing risk of ALS loci remains to be identified. Furthermore, we identified 17 regions of the genome that display significantly high heritability estimates. Eleven of these regions represent novel candidate regions for ALS risk.
Conclusions and Relevance
We found the heritability of ALS to be significantly higher than previously reported. We also identified multiple, novel genomic regions that we hypothesize may contain causative risk variants that influence susceptibility to ALS.
doi:10.1001/jamaneurol.2014.1184
PMCID: PMC4566960  PMID: 25023141
4.  State of play in amyotrophic lateral sclerosis genetics 
Nature neuroscience  2013;17(1):17-23.
doi:10.1038/nn.3584
PMCID: PMC4544832  PMID: 24369373
5.  Erythropoietin in amyotrophic lateral sclerosis: a multicentre, randomised, double blind, placebo controlled, phase III study 
Objective
To assess the efficacy of recombinant human erythropoietin (rhEPO) in amyotrophic lateral sclerosis (ALS).
Methods
Patients with probable laboratory-supported, probable or definite ALS were enrolled by 25 Italian centres and randomly assigned (1:1) to receive intravenous rhEPO 40 000 IU or placebo fortnightly as add-on treatment to riluzole 100 mg daily for 12 months. The primary composite outcome was survival, tracheotomy or >23 h non-invasive ventilation (NIV). Secondary outcomes were ALSFRS-R, slow vital capacity (sVC) and quality of life (ALSAQ-40) decline. Tolerability was evaluated analysing adverse events (AEs) causing withdrawal. The randomisation sequence was computer-generated by blocks, stratified by centre, disease severity (ALSFRS-R cut-off score of 33) and onset (spinal or bulbar). The main outcome analysis was performed in all randomised patients and by intention-to-treat for the entire population and patients stratified by severity and onset. The study is registered, EudraCT 2009-016066-91.
Results
We randomly assigned 208 patients, of whom 5 (1 rhEPO and 4 placebo) withdrew consent and 3 (placebo) became ineligible (retinal thrombosis, respiratory insufficiency, SOD1 mutation) before receiving treatment; 103 receiving rhEPO and 97 placebo were eligible for analysis. At 12 months, the annualised rate of death (rhEPO 0.11, 95% CI 0.06 to 0.20; placebo: 0.08, CI 0.04 to 0.17), tracheotomy or >23 h NIV (rhEPO 0.16, CI 0.10 to 0.27; placebo 0.18, CI 0.11 to 0.30) did not differ between groups, also after stratification by onset and ALSFRS-R at baseline. Withdrawal due to AE was 16.5% in rhEPO and 8.3% in placebo. No differences were found for secondary outcomes.
Conclusions
RhEPO 40 000 IU fortnightly did not change the course of ALS.
doi:10.1136/jnnp-2014-308996
PMCID: PMC4515982  PMID: 25595151
ALS; MOTOR NEURON DISEASE
6.  C9orf72 and UNC13A are shared risk loci for ALS and FTD: a genome-wide meta-analysis 
Annals of neurology  2014;76(1):120-133.
Objective
Substantial clinical, pathological and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD.
Methods
We used published GWAS data of 4,377 ALS patients and 13,017 controls and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes.
Results
Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) at C9orf72 on chromosome 9p21.2 (lowest p=2.6×10−12) and one SNP in UNC13A on chromosome 19p13.11 (p=1.0×10−11) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin, (p=3.91×10−7) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p=0.026; combined analysis p=1.01×10−7).
Interpretation
We identified common genetic variants at C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP.
doi:10.1002/ana.24198
PMCID: PMC4137231  PMID: 24931836
7.  ALS mutant FUS proteins are recruited into stress granules in induced pluripotent stem cell-derived motoneurons 
Disease Models & Mechanisms  2015;8(7):755-766.
ABSTRACT
Patient-derived induced pluripotent stem cells (iPSCs) provide an opportunity to study human diseases mainly in those cases for which no suitable model systems are available. Here, we have taken advantage of in vitro iPSCs derived from patients affected by amyotrophic lateral sclerosis (ALS) and carrying mutations in the RNA-binding protein FUS to study the cellular behavior of the mutant proteins in the appropriate genetic background. Moreover, the ability to differentiate iPSCs into spinal cord neural cells provides an in vitro model mimicking the physiological conditions. iPSCs were derived from FUSR514S and FUSR521C patient fibroblasts, whereas in the case of the severe FUSP525L mutation, in which fibroblasts were not available, a heterozygous and a homozygous iPSC line were raised by TALEN-directed mutagenesis. We show that aberrant localization and recruitment of FUS into stress granules (SGs) is a prerogative of the FUS mutant proteins and occurs only upon induction of stress in both undifferentiated iPSCs and spinal cord neural cells. Moreover, we show that the incorporation into SGs is proportional to the amount of cytoplasmic FUS, strongly correlating with the cytoplasmic delocalization phenotype of the different mutants. Therefore, the available iPSCs represent a very powerful system for understanding the correlation between FUS mutations, the molecular mechanisms of SG formation and ALS ethiopathogenesis.
Summary: Mutated FUS protein is aberrantly delocalized and recruited into stress granules in iPSC-derived motoneurons, which provide a new model system for amyotrophic lateral sclerosis.
doi:10.1242/dmm.020099
PMCID: PMC4486861  PMID: 26035390
ALS; FUS; TALE nucleases; iPSCs
8.  A de novo nonsense mutation of the FUS gene in an apparently familial ALS case 
Neurobiology of aging  2013;35(6):1513.e7-1513.e11.
Mutations in C9ORF72, SOD1, TARDBP and FUS genes account for approximately two third of familial cases and 5% of sporadic amyotrophic lateral sclerosis (ALS) cases. We present the first case of an ALS patient carrying a de novo nonsense mutation in exon 14 of the FUS gene (c.1483c>t; p.R495X) in a young patient with an apparently familial ALS. This mutation cause a phenotype characterized by a young age at onset, a rapid course (<24 months) and a bulbar onset with early respiratory involvement with a predominant lower motor neuron disease. De novo mutations could account for a sizable number of apparently sporadic ALS patients carrying mutations of ALS-related genes.
doi:10.1016/j.neurobiolaging.2013.12.028
PMCID: PMC3961545  PMID: 24439481
9.  A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis 
Fogh, Isabella | Ratti, Antonia | Gellera, Cinzia | Lin, Kuang | Tiloca, Cinzia | Moskvina, Valentina | Corrado, Lucia | Sorarù, Gianni | Cereda, Cristina | Corti, Stefania | Gentilini, Davide | Calini, Daniela | Castellotti, Barbara | Mazzini, Letizia | Querin, Giorgia | Gagliardi, Stella | Del Bo, Roberto | Conforti, Francesca L. | Siciliano, Gabriele | Inghilleri, Maurizio | Saccà, Francesco | Bongioanni, Paolo | Penco, Silvana | Corbo, Massimo | Sorbi, Sandro | Filosto, Massimiliano | Ferlini, Alessandra | Di Blasio, Anna M. | Signorini, Stefano | Shatunov, Aleksey | Jones, Ashley | Shaw, Pamela J. | Morrison, Karen E. | Farmer, Anne E. | Van Damme, Philip | Robberecht, Wim | Chiò, Adriano | Traynor, Bryan J. | Sendtner, Michael | Melki, Judith | Meininger, Vincent | Hardiman, Orla | Andersen, Peter M. | Leigh, Nigel P. | Glass, Jonathan D. | Overste, Daniel | Diekstra, Frank P. | Veldink, Jan H. | van Es, Michael A. | Shaw, Christopher E. | Weale, Michael E. | Lewis, Cathryn M. | Williams, Julie | Brown, Robert H. | Landers, John E. | Ticozzi, Nicola | Ceroni, Mauro | Pegoraro, Elena | Comi, Giacomo P. | D'Alfonso, Sandra | van den Berg, Leonard H. | Taroni, Franco | Al-Chalabi, Ammar | Powell, John | Silani, Vincenzo | Brescia Morra, Vincenzo | Filla, Alessandro | Massimo, Filosto | Marsili, Angela | Viviana, Pensato | Puorro, Giorgia | La Bella, Vincenzo | Logroscino, Giancarlo | Monsurrò, Maria Rosaria | Quattrone, Aldo | Simone, Isabella Laura | Ahmeti, Kreshnik B. | Ajroud-Driss, Senda | Armstrong, Jennifer | Birve, Anne | Blauw, Hylke M. | Bruijn, Lucie | Chen, Wenjie | Comeau, Mary C. | Cronin, Simon | Soraya, Gkazi Athina | Grab, Josh D. | Groen, Ewout J. | Haines, Jonathan L. | Heller, Scott | Huang, Jie | Hung, Wu-Yen | Jaworski, James M. | Khan, Humaira | Langefeld, Carl D. | Marion, Miranda C. | McLaughlin, Russell L. | Miller, Jack W. | Mora, Gabriele | Pericak-Vance, Margaret A. | Rampersaud, Evadnie | Siddique, Nailah | Siddique, Teepu | Smith, Bradley N. | Sufit, Robert | Topp, Simon | Vance, Caroline | van Vught, Paul | Yang, Yi | Zheng, J.G.
Human Molecular Genetics  2013;23(8):2220-2231.
Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (∼90%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P = 1.11 × 10−8; OR 0.82) that was validated when combined with genotype data from a replication cohort (P = 8.62 × 10−9; OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P = 7.69 × 10−9; OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as ∼12% using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.
doi:10.1093/hmg/ddt587
PMCID: PMC3959809  PMID: 24256812
10.  No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis 
Human Molecular Genetics  2013;23(7):1916-1922.
Genome-wide association studies have been successful in identifying common variants that influence the susceptibility to complex diseases. From these studies, it has emerged that there is substantial overlap in susceptibility loci between diseases. In line with those findings, we hypothesized that shared genetic pathways may exist between multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). While both diseases may have inflammatory and neurodegenerative features, epidemiological studies have indicated an increased co-occurrence within individuals and families. To this purpose, we combined genome-wide data from 4088 MS patients, 3762 ALS patients and 12 030 healthy control individuals in whom 5 440 446 single-nucleotide polymorphisms (SNPs) were successfully genotyped or imputed. We tested these SNPs for the excess association shared between MS and ALS and also explored whether polygenic models of SNPs below genome-wide significance could explain some of the observed trait variance between diseases. Genome-wide association meta-analysis of SNPs as well as polygenic analyses fails to provide evidence in favor of an overlap in genetic susceptibility between MS and ALS. Hence, our findings do not support a shared genetic background of common risk variants in MS and ALS.
doi:10.1093/hmg/ddt574
PMCID: PMC3943520  PMID: 24234648
11.  Homozygosity analysis in amyotrophic lateral sclerosis 
European Journal of Human Genetics  2013;21(12):1429-1435.
Amyotrophic lateral sclerosis (ALS) may appear to be familial or sporadic, with recognised dominant and recessive inheritance in a proportion of cases. Sporadic ALS may be caused by rare homozygous recessive mutations. We studied patients and controls from the UK and a multinational pooled analysis of GWAS data on homozygosity in ALS to determine any potential recessive variant leading to the disease. Six-hundred and twenty ALS and 5169 controls were studied in the UK cohort. A total of 7646 homozygosity segments with length >2 Mb were identified, and 3568 rare segments remained after filtering ‘common' segments. The mean total of the autosomal genome with homozygosity segments was longer in ALS than in controls (unfiltered segments, P=0.05). Two-thousand and seventeen ALS and 6918 controls were studied in the pooled analysis. There were more regions of homozygosity segments per case (P=1 × 10−5), a greater proportion of cases harboured homozygosity (P=2 × 10−5), a longer average length of segment (P=1 × 10−5), a longer total genome coverage (P=1 × 10−5), and a higher rate of these segments overlapped with RefSeq gene regions (P=1 × 10−5), in ALS patients than controls. Positive associations were found in three regions. The most significant was in the chromosome 21 SOD1 region, and also chromosome 1 2.9–4.8 Mb, and chromosome 5 in the 65 Mb region. There are more than twenty potential genes in these regions. These findings point to further possible rare recessive genetic causes of ALS, which are not identified as common variants in GWAS.
doi:10.1038/ejhg.2013.59
PMCID: PMC3829775  PMID: 23612577
amyotrophic lateral sclerosis; homozygosity; recessive
12.  Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis 
Nature neuroscience  2014;17(5):664-666.
MATR3 is an RNA/DNA binding protein that interacts with TDP-43, a major disease protein linked to amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia. Using exome sequencing, we identified mutations in MATR3 in ALS kindreds. We also observed MATR3 pathology in the spinal cords of ALS cases with and without MATR3 mutations. Our data provide additional evidence supporting the role of aberrant RNA processing in motor neuron degeneration.
doi:10.1038/nn.3688
PMCID: PMC4000579  PMID: 24686783
14.  Homozygosity analysis in amyotrophic lateral sclerosis 
European journal of human genetics : EJHG  2013;21(12):10.1038/ejhg.2013.59.
Amyotrophic lateral sclerosis (ALS) may appear to be familial or sporadic, with recognized dominant and recessive inheritance in a proportion of cases. Sporadic ALS may be caused by rare homozygous recessive mutations. We studied patients and controls from the UK and a multinational pooled analysis of GWAS data on homozygosity in ALS to determine any potential recessive variant leading to the disease. 620 ALS and 5169 controls were studied in the UK cohort. A total of 7646 homozygosity segments with length >2Mb were identified, and 3568 rare segments remained after filtering “common” segments. The mean total of the autosomal genome with homozygosity segments was longer in ALS than in controls (unfiltered segments, p=0.05). 2017 ALS and 6918 controls were studied in the pooled analysis. There were more regions of homozygosity segments per case (p=1×10−5), a greater proportion of cases harboured homozygosity (p=2×10−5), a longer average length of segment (p=1×10−5), a longer total genome coverage (p=1×10−5), and a higher rate of these segments overlapped with RefSeq gene regions (p=1×10−5), in ALS patients than controls. Positive associations were found in three regions. The most significant was in the chromosome 21 SOD1 region, and also chromosome 1 2.9Mb to 4.8Mb, and chromosome 5 in the 65Mb region. There are more than twenty potential genes in these regions. These findings point to further possible rare recessive genetic causes of ALS which are not identified as common variants in GWAS.
doi:10.1038/ejhg.2013.59
PMCID: PMC3829775  PMID: 23612577
amyotrophic lateral sclerosis; homozygosity; genetics; recessive
15.  The p.A382T TARDBP gene mutation in Sardinian patients affected by Parkinson’s disease and other degenerative parkinsonisms 
Neurogenetics  2013;14(2):161-166.
Background
Based on our previous finding of the p.A382T founder mutation in ALS patients with concomitant parkinsonism in the Sardinian population, we hypothesized that the same variant may underlie PD and/or other forms of degenerative parkinsonism on this Mediterranean island.
Design
We screened a cohort of 611 patients with PD (544 cases) and other forms of degenerative parkinsonism (67 cases), and 604 unrelated controls for the c.1144G>A (p.A382T) missense mutation of the TARDBP gene.
Results
The p.A382T mutation was identified in 9 patients with parkinsonism. Of these, 5 (0.9% of PD patients) presented a typical PD (2 with familiar forms), while 4 patients (6.0% of all other forms of parkinsonism) presented a peculiar clinical presentation quite different from classical atypical parkinsonism with an overlap of extrapyramidal-pyramidal-cognitive clinical signs. The mutation was found in 8 Sardinian controls (1.3%) consistent with a founder mutation in the island population.
Conclusions
Our findings suggest that the clinical presentation of the p.A382T TARDBP gene mutation may include forms of parkinsonism in which the extrapyramidal signs are the crucial core of the disease at onset. These forms can present PSP or CBD-like clinical signs, with bulbar and/or extrabulbar pyramidal signs and cognitive impairment. No evidence of association has been found between TARDBP gene mutation and typical PD.
doi:10.1007/s10048-013-0360-2
PMCID: PMC3661017  PMID: 23546887
TARDBP gene mutation; degenerative parkinsonism; TDP-43 Proteinopathies; Sardinia
16.  UNC13A influences survival in Italian ALS patients: a population-based study 
Neurobiology of aging  2012;34(1):357.e1-357.e5.
The common variant rs12608932, located within an intron of UNC13A gene on chromosome 19p13.3, has been suggested to influence susceptibility to ALS, as well as survival, in patients of north European descent. To examine this possibility further, we evaluated the association of rs12608932 with susceptibility and survival in a population-based cohort of 500 Italian ALS patients and 1,457 Italian control samples. Although rs12608932 was not associated to ALS susceptibility in our series (p=0.124), it was significantly associated with survival under the recessive model (median survival for AA/AC genotypes = 3.5 years [IQR 2.2–6.4]; CC = 2.5 years [IQR 1.6–4.2]; p=0.017). Furthermore, rs12608932 genotype remained an independent prognostic factor in Cox multivariable analysis adjusting for other factors known to influence survival (p=0.023). Overall, minor allele carrier status of rs12608932 was strongly associated with an ~1-year reduction of survival in ALS patients, making it a significant determinant of phenotype variation. The identification of UNC13A as a modifier of prognosis among sporadic ALS patients potentially provides a new therapeutic target aimed at slowing disease progression.
doi:10.1016/j.neurobiolaging.2012.07.016
PMCID: PMC3483408  PMID: 22921269
17.  Extramotor Damage Is Associated with Cognition in Primary Lateral Sclerosis Patients 
PLoS ONE  2013;8(12):e82017.
Objectives
This is a cross-sectional study aimed at investigating cognitive performances in patients with primary lateral sclerosis (PLS) and using diffusion tensor (DT) magnetic resonance imaging (MRI) to determine the topographical distribution of microstructural white matter (WM) damage in patients with or without cognitive deficits.
Methods
DT MRI scans were obtained from 21 PLS patients and 35 age- and sex-matched healthy controls. All PLS patients underwent a comprehensive neuropsychological battery. Tract-based-spatial-statistics (TBSS) was used to perform a whole-brain voxel-wise analysis of fractional anisotropy (FA), axial, radial (radD) and mean diffusivity (MD).
Results
Ten PLS patients had abnormal scores in at least one neuropsychological test (PLS with cognitive deficits, PLS-cd). Compared with healthy controls and cognitively unimpaired PLS patients (PLS-cu), PLS-cd cases showed decreased FA and increased MD and radD in the corticospinal tract (CST), corpus callosum, brainstem, anterior limb of internal capsule, superior and inferior longitudinal fasciculi, fornix, thalamic radiations, and parietal lobes, bilaterally. Compared with healthy controls, PLS-cd patients showed further decreased FA and increased radD in the cerebellar WM, bilaterally. Compared with controls, PLS-cu patients showed decreased FA in the mid-body of corpus callosum. In PLS, executive and language test scores correlated with WM damage.
Conclusions
This is the first study evaluating the relationship between cognitive performance and WM tract damage in PLS patients. PLS can be associated with a multi-domain cognitive impairment. WM damage to interhemispheric, limbic and major associative WM tracts seem to be the structural correlate of cognitive abnormalities in these patients.
doi:10.1371/journal.pone.0082017
PMCID: PMC3857796  PMID: 24349172
18.  Extensive genetics of ALS 
Neurology  2012;79(19):1983-1989.
Objective:
To assess the frequency and clinical characteristics of patients with mutations of major amyotrophic lateral sclerosis (ALS) genes in a prospectively ascertained, population-based epidemiologic series of cases.
Methods:
The study population includes all ALS cases diagnosed in Piemonte, Italy, from January 2007 to June 2011. Mutations of SOD1, TARDBP, ANG, FUS, OPTN, and C9ORF72 have been assessed.
Results:
Out of the 475 patients included in the study, 51 (10.7%) carried a mutation of an ALS-related gene (C9ORF72, 32; SOD1, 10; TARDBP, 7; FUS, 1; OPTN, 1; ANG, none). A positive family history for ALS or frontotemporal dementia (FTD) was found in 46 (9.7%) patients. Thirty-one (67.4%) of the 46 familial cases and 20 (4.7%) of the 429 sporadic cases had a genetic mutation. According to logistic regression modeling, besides a positive family history for ALS or FTD, the chance to carry a genetic mutation was related to the presence of comorbid FTD (odds ratio 3.5; p = 0.001), and age at onset ≤54 years (odds ratio 1.79; p = 0.012).
Conclusions:
We have found that ∼11% of patients with ALS carry a genetic mutation, with C9ORF72 being the commonest genetic alteration. Comorbid FTD or a young age at onset are strong indicators of a possible genetic origin of the disease.
doi:10.1212/WNL.0b013e3182735d36
PMCID: PMC3484987  PMID: 23100398
19.  Valosin-containing protein mutations in sporadic amyotrophic lateral sclerosis 
Neurobiology of Aging  2012;33(9):2231.e1-2231.e6.
We recently reported that mutations in the VCP gene are a cause of 1–2% of familial amyotrophic lateral sclerosis (ALS) cases, but their role in the pathogenesis of sporadic ALS is unclear. We undertook mutational screening of VCP in 701 sporadic ALS cases. Three pathogenic variants (p.Arg159Cys, p.Asn387Thr, and p.R662C) were found in three US cases, each of whom presented with progressive upper and lower motor neuron signs consistent with definite ALS by El Escorial diagnostic criteria. Our data indicate that VCP mutations may underlie apparently sporadic ALS, but account for less than 1% of this form of disease.
doi:10.1016/j.neurobiolaging.2012.04.005
PMCID: PMC3391327  PMID: 22572540
Amyotrophic lateral sclerosis; valosin-containing protein; mutations; sporadic disease
20.  C9ORF72 hexanucleotide repeat expansions in the Italian sporadic ALS population 
Neurobiology of Aging  2012;33(8):1848.e15-1848.e20.
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.
doi:10.1016/j.neurobiolaging.2012.02.011
PMCID: PMC3372681  PMID: 22418734
Amyotrophic lateral sclerosis; C9ORF72; frontotemporal dementia; survival
21.  Pathogenic VCP Mutations Induce Mitochondrial Uncoupling and Reduced ATP Levels 
Neuron  2013;78(1):57-64.
Summary
Valosin-containing protein (VCP) is a highly expressed member of the type II AAA+ ATPase family. VCP mutations are the cause of inclusion body myopathy, Paget’s disease of the bone, and frontotemporal dementia (IBMPFD) and they account for 1%–2% of familial amyotrophic lateral sclerosis (ALS). Using fibroblasts from patients carrying three independent pathogenic mutations in the VCP gene, we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption. This mitochondrial uncoupling results in a significant reduction of cellular ATP production. Decreased ATP levels in VCP-deficient cells lower their energy capacity, making them more vulnerable to high energy-demanding processes such as ischemia. Our findings propose a mechanism by which pathogenic VCP mutations lead to cell death.
Highlights
► VCP deficiency is associated with mitochondrial depolarization ► VCP deficiency leads to increased mitochondrial respiration and uncoupling ► ATP levels are decreased in VCP-deficient cells due to lower ATP production
In this study, Bartolome et al. show that three independent pathogenic VCP mutations induce mitochondrial uncoupling, resulting in low cellular ATP production, rendering the cells more susceptible to cell death under stress-induced ischemic conditions.
doi:10.1016/j.neuron.2013.02.028
PMCID: PMC3843114  PMID: 23498975
22.  SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis 
Neurology  2012;79(15):1556-1562.
Objective:
There is increasing evidence that common genetic risk factors underlie frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Recently, mutations in the sequestosome 1 (SQSTM1) gene, which encodes p62 protein, have been reported in patients with ALS. P62 is a multifunctional adapter protein mainly involved in selective autophagy, oxidative stress response, and cell signaling pathways. The purpose of our study was to evaluate the frequency of SQSTM1 mutations in a dataset of unrelated patients with FTLD or ALS, in comparison with healthy controls and patients with Paget disease of bone (PDB).
Methods:
Promoter region and all exons of SQSTM1 were sequenced in a large group of subjects, including patients with FTLD or ALS, healthy controls, and patients with PDB. The clinical characteristics of patients with FTLD or ALS with gene mutations were examined.
Results:
We identified 6 missense mutations in the coding region of SQSTM1 in patients with either FTLD or ALS, none of which were found in healthy controls or patients with PDB. In silico analysis suggested a pathogenetic role for these mutations. Furthermore, 7 novel noncoding SQSTM1 variants were found in patients with FTLD and patients with ALS, including 4 variations in the promoter region.
Conclusions:
SQSTM1 mutations are present in patients with FTLD and patients with ALS. Additional studies are warranted in order to better investigate the role of p62 in the pathogenesis of both FTLD and ALS.
doi:10.1212/WNL.0b013e31826e25df
PMCID: PMC3655323  PMID: 22972638
23.  Frequency of the C9ORF72 hexanucleotide repeat expansion in ALS and FTD in diverse populations: a cross-sectional study 
Lancet Neurology  2012;11(4):323-330.
Background
A hexanucleotide repeat expansion in the C9ORF72 gene has recently been shown to cause a large proportion of amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD).
Methods
We screened 4,448 patients diagnosed with ALS and 1,425 patients diagnosed with FTD drawn from diverse populations for the hexanucleotide expansion using a repeat-primed PCR assay. ALS and FTD were diagnosed according to the El Escorial and Lund-Manchester criteria respectively. Familial status was based on self-reported family history of similar neurodegenerative diseases at the time of sample collection. Haplotype data of 262 patients carrying the expansion were compared with the known Finnish founder risk haplotype across the chromosomal locus. Age-related penetrance was calculated by the Kaplan-Meier method using data from 603 individuals carrying the expansion.
Findings
The mutation was observed among 7·0% (n = 236 of 3,377) of Caucasians, 4·1% (n = 2 of 49) of African-Americans, and 8·3% (n = 6 of 72) of Hispanic individuals diagnosed with sporadic ALS, whereas the rate was 6·0% (n = 59 of 981) among Caucasians diagnosed with sporadic FTD. Among Asians, 5·0% (n = 1 of 20) of familial ALS and 66·6% (n = 2 of 3) of familial FTD cases carried the repeat expansion. In contrast, mutations were not observed among patients of Native American (n = 3 sporadic ALS), Indian (n = 31 sporadic ALS, n = 31 sporadic FTD), and Pacific Islander (n = 90 sporadic ALS) ethnicity. All patients with the repeat expansion carried, either partially or fully, the founder haplotype suggesting that the expansion occurred on a single occasion in the past (~1,500 years ago). The pathogenic expansion was non-penetrant below 35 years of age, increasing to 50·0% penetrance by 58 years of age, and was almost fully penetrant by 80 years of age.
Interpretation
We confirm that a common single Mendelian genetic lesion is implicated in a large proportion of sporadic and familial ALS and FTD. Testing for this pathogenic expansion will be important in the management and genetic counseling of patients with these fatal neurodegenerative diseases.
Funding
See Acknowledgements.
doi:10.1016/S1474-4422(12)70043-1
PMCID: PMC3322422  PMID: 22406228
24.  Risk of Guillain-Barré syndrome after 2010–2011 influenza vaccination 
European Journal of Epidemiology  2013;28(5):433-444.
Influenza vaccination has been implicated in Guillain Barré Syndrome (GBS) although the evidence for this link is controversial. A case–control study was conducted between October 2010 and May 2011 in seven Italian Regions to explore the relation between influenza vaccination and GBS. The study included 176 GBS incident cases aged ≥18 years from 86 neurological centers. Controls were selected among patients admitted for acute conditions to the Emergency Department of the same hospital as cases. Each control was matched to a case by sex, age, Region and admission date. Two different analyses were conducted: a matched case–control analysis and a self-controlled case series analysis (SCCS). Case–control analysis included 140 cases matched to 308 controls. The adjusted matched odds ratio (OR) for GBS occurrence within 6 weeks after influenza vaccination was 3.8 (95 % CI: 1.3, 10.5). A much stronger association with gastrointestinal infections (OR = 23.8; 95 % CI 7.3, 77.6) and influenza-like illness or upper respiratory tract infections (OR = 11.5; 95 % CI 5.6, 23.5) was highlighted. The SCCS analysis included all 176 GBS cases. Influenza vaccination was associated with GBS, with a relative risk of 2.1 (95 % CI 1.1, 3.9). According to these results the attributable risk in adults ranges from two to five GBS cases per 1,000,000 vaccinations.
doi:10.1007/s10654-013-9797-8
PMCID: PMC3672511  PMID: 23543123
Influenza vaccination; Guillain-Barrè Syndrome; Case–control study; Self controlled case series
25.  Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72 
Brain  2012;135(3):784-793.
A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for ∼40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis–frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis–frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6–7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7–2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for ∼60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis.
doi:10.1093/brain/awr366
PMCID: PMC3286333  PMID: 22366794
amyotrophic lateral sclerosis; familial ALS, C9ORF72 gene; phenotype–genotype correlation

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