Comparative Analysis of C9orf72 and Sporadic Disease in a Large Multicenter ALS Population: The Effect of Male Sex on Survival of C9orf72 Positive Patients

We investigated whether the C9orf72 repeat expansion is associated with specific clinical features, comorbidities, and prognosis in patients with amyotrophic lateral sclerosis (ALS). A cohort of 1417 ALS patients, diagnosed between January 1, 2009 and December 31, 2013 by 13 Italian ALS Referral Centers, was screened for the C9orf72 repeat expansion, and the analyses were performed comparing patients carrying this expansion (ALS-C9Pos) to those negative for this and other explored ALS-related mutations (ALS without genetic mutations, ALSwoGM). Compared to the ALSwoGM group, ALS-C9Pos patients (n = 84) were younger at disease onset, at the first clinical observation and at diagnosis (p < 0.001). After correcting for these differences, we found that ALS-C9Pos patients had higher odds of bulbar onset, diagnosis of frontotemporal dementia (FTD) and family history of ALS, FTD, and Alzheimer's disease and had lower odds of spinal onset, non-invasive ventilation, hypertension and psychiatric diseases than ALSwoGM patients. Among these variables, those related to shorter survival time were: bulbar onset, presence of FTD, hypertension, psychiatric disease, and family history of ALS (p < 0.05). Cox proportional hazards regression multivariate analysis suggested that carrying the C9orf72 repeat expansion was an independent factor negatively impacting on survival time in men (HR 1.58, 95% CI 1.07–2.33, p = 0.021), but not in women (p > 0.05) as well as in the whole sample (p > 0.05). When compared to ALSwoGM, ALS-C9Pos showed an earlier disease onset, no significant diagnostic delay and a higher odds of bulbar onset, FTD and family history of ALS and dementia. Moreover, male sex drove the negative effect of expanded variant on survival, confirming the hypothesis that sex is likely to be a crucial factor in the biology of C9orf72-related disease.

[1]  A. Chiò,et al.  Cardiovascular diseases may play a negative role in the prognosis of amyotrophic lateral sclerosis , 2018, European journal of neurology.

[2]  P. Andersen,et al.  C9orf72 expansion is associated with accelerated decline of respiratory function and decreased survival in amyotrophic lateral sclerosis , 2018, Journal of Neurology, Neurosurgery, and Psychiatry.

[3]  E. Granieri,et al.  Riluzole and other prognostic factors in ALS: a population-based registry study in Italy , 2018, Journal of Neurology.

[4]  O. Hardiman,et al.  Clustering of Neuropsychiatric Disease in First-Degree and Second-Degree Relatives of Patients With Amyotrophic Lateral Sclerosis , 2017, JAMA neurology.

[5]  Giancarlo Logroscino,et al.  Erratum: Amyotrophic lateral sclerosis (Nature reviews. Disease primers (2017) 3 (17071)) , 2017 .

[6]  Fabrizio Esposito,et al.  Resting state fMRI correlates of Theory of Mind impairment in amyotrophic lateral sclerosis , 2017, Cortex.

[7]  A. Chiò,et al.  Comorbidity of dementia with amyotrophic lateral sclerosis (ALS): insights from a large multicenter Italian cohort , 2017, Journal of Neurology.

[8]  Adriano Chiò,et al.  Secular Trends of Amyotrophic Lateral Sclerosis: The Piemonte and Valle d’Aosta Register , 2017, JAMA neurology.

[9]  E. Tan,et al.  Intermediate C9orf72 alleles in neurological disorders: does size really matter? , 2017, Journal of Medical Genetics.

[10]  J. Rowe,et al.  Genetic screening in sporadic ALS and FTD , 2017, Journal of Neurology, Neurosurgery, and Psychiatry.

[11]  A. Chiò,et al.  Influence of arterial hypertension, type 2 diabetes and cardiovascular risk factors on ALS outcome: a population-based study , 2017, Amyotrophic lateral sclerosis & frontotemporal degeneration.

[12]  A. Chiò,et al.  Age-related penetrance of the C9orf72 repeat expansion , 2017, Scientific Reports.

[13]  P. Magnusson,et al.  Polygenic link between blood lipids and amyotrophic lateral sclerosis , 2017, Neurobiology of Aging.

[14]  B. Dickerson,et al.  Psychiatric Presentations of C9orf72 Mutation: What Are the Diagnostic Implications for Clinicians? , 2017, The Journal of neuropsychiatry and clinical neurosciences.

[15]  Brian D. Freibaum,et al.  The Role of Dipeptide Repeats in C9ORF72-Related ALS-FTD , 2017, Front. Mol. Neurosci..

[16]  A. Al-Chalabi,et al.  Gene discovery in amyotrophic lateral sclerosis: implications for clinical management , 2017, Nature Reviews Neurology.

[17]  J. Hodges,et al.  The neural correlates and clinical characteristics of psychosis in the frontotemporal dementia continuum and the C9orf72 expansion , 2016, NeuroImage: Clinical.

[18]  A. Al-Chalabi,et al.  C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis , 2016, Journal of Neurology, Neurosurgery & Psychiatry.

[19]  William T. Hu,et al.  Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population , 2016, Neurology.

[20]  M. van Tol,et al.  The frontotemporal syndrome of ALS is associated with poor survival , 2016, Journal of Neurology.

[21]  G. Coppola,et al.  C9orf72 repeat expansions that cause frontotemporal dementia are detectable among patients with psychosis , 2016, Psychiatry Research.

[22]  G. Sobue,et al.  Factors affecting longitudinal functional decline and survival in amyotrophic lateral sclerosis patients , 2015, Amyotrophic lateral sclerosis & frontotemporal degeneration.

[23]  J. Kirby,et al.  The widening spectrum of C9ORF72-related disease; genotype/phenotype correlations and potential modifiers of clinical phenotype , 2014, Acta Neuropathologica.

[24]  O. Hardiman,et al.  Aggregation of neurologic and neuropsychiatric disease in amyotrophic lateral sclerosis kindreds: A population‐based case–control cohort study of familial and sporadic amyotrophic lateral sclerosis , 2013, Annals of neurology.

[25]  S. Petri,et al.  Prevalence and prognostic impact of comorbidities in amyotrophic lateral sclerosis , 2013, European journal of neurology.

[26]  Jonathan M. Bekisz,et al.  Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis , 2012, Journal of Neurology, Neurosurgery & Psychiatry.

[27]  P. Tsai,et al.  A hexanucleotide repeat expansion in C9ORF72 causes familial and sporadic ALS in Taiwan , 2012, Neurobiology of Aging.

[28]  F. Marrosu,et al.  C9ORF72 hexanucleotide repeat expansions in the Italian sporadic ALS population , 2012, Neurobiology of Aging.

[29]  Janel O. Johnson,et al.  Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study , 2012, The Lancet Neurology.

[30]  F. Marrosu,et al.  Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72. , 2012, Brain : a journal of neurology.

[31]  A. Al-Chalabi,et al.  Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study , 2012, The Lancet Neurology.

[32]  J. Hardy,et al.  Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72. , 2012, Brain : a journal of neurology.

[33]  A. Chiò,et al.  Brain hypermetabolism in amyotrophic lateral sclerosis: a FDG PET study in ALS of spinal and bulbar onset , 2012, European Journal of Nuclear Medicine and Molecular Imaging.

[34]  Philippe Amouyel,et al.  Modifying effect of arterial hypertension on amyotrophic lateral sclerosis , 2012, Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases.

[35]  David Heckerman,et al.  A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD , 2011, Neuron.

[36]  Bruce L. Miller,et al.  Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS , 2011, Neuron.

[37]  A. Chiò,et al.  Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study , 2011, Journal of Neurology, Neurosurgery & Psychiatry.

[38]  E. Beghi,et al.  Prognostic factors in ALS: A critical review , 2009, Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases.

[39]  M. Naumann,et al.  Disease progression in amyotrophic lateral sclerosis: Predictors of survival , 2002, Muscle & nerve.

[40]  M. Swash,et al.  El Escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral sclerosis , 2000, Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases.

[41]  A. Al-Chalabi,et al.  Amyotrophic lateral sclerosis , 2017, Nature Reviews Disease Primers.

[42]  A. Chiò,et al.  Factors predicting survival in ALS: a multicenter Italian study , 2016, Journal of Neurology.

[43]  A. Ludolph,et al.  Amyotrophic lateral sclerosis. , 2012, Current opinion in neurology.