SummaryBackgroundAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of upper and lower motor neurons, associated with frontotemporal dementia (FTD) in about 14% of incident cases. We assessed the frequency of the recently identified C9orf72 repeat expansion in familial and apparently sporadic cases of ALS and characterised the cognitive and clinical phenotype of patients with this expansion.MethodsA population-based register of patients with ALS has been in operation in Ireland since 1995, and an associated DNA bank has been in place since 1999. 435 representative DNA samples from the bank were screened using repeat-primed PCR for the presence of a GGGGCC repeat expansion in C9orf72. We assessed clinical, cognitive, behavioural, MRI, and survival data from 191 (44%) of these patients, who comprised a population-based incident group and had previously participated in a longitudinal study of cognitive and behavioural changes in ALS.FindingsSamples from the DNA bank included 49 cases of known familial ALS and 386 apparently sporadic cases. Of these samples, 20 (41%) cases of familial ALS and 19 (5%) cases of apparently sporadic ALS had the C9orf72 repeat expansion. Of the 191 patients for whom phenotype data were available, 21 (11%) had the repeat expansion. Age at disease onset was lower in patients with the repeat expansion (mean 56·3 [SD 8·3] years) than in those without (61·3 [10·6] years; p=0·043). A family history of ALS or FTD was present in 18 (86%) of those with the repeat expansion. Patients with the repeat expansion had significantly more co-morbid FTD than patients without the repeat (50% vs 12%), and a distinct pattern of non-motor cortex changes on high-resolution 3 T magnetic resonance structural neuroimaging. Age-matched univariate analysis showed shorter survival (20 months vs 26 months) in patients with the repeat expansion. Multivariable analysis showed an increased hazard rate of 1·9 (95% 1·1–3·7; p=0·035) in those patients with the repeat expansion compared with patients without the expansionInterpretationPatients with ALS and the C9orf72 repeat expansion seem to present a recognisable phenotype characterised by earlier disease onset, the presence of cognitive and behavioural impairment, specific neuroimaging changes, a family history of neurodegeneration with autosomal dominant inheritance, and reduced survival. Recognition of patients with ALS who carry an expanded repeat is likely to be important in the context of appropriate disease management, stratification in clinical trials, and in recognition of other related phenotypes in family members.FundingHealth Seventh Framework Programme, Health Research Board, Research Motor Neuron, Irish Motor Neuron Disease Association, The Motor Neurone Disease Association of Great Britain and Northern Ireland, ALS Association.

Background: In recent years, there has been a paradigm shift in the method of healthcare delivery to amyotrophic lateral sclerosis (ALS) patients with the emergence of multidisciplinary ALS clinics that cater exclusively for patients with this condition. The impact of multidisciplinary management has not been previously evaluated. Methods: Using data from the Irish ALS Register, we conducted a prospective, population based study of all ALS cases diagnosed in Ireland over a five year period to evaluate the effectiveness of a multidisciplinary clinic on ALS survival. Results: Eighty two (24%) patients attended the multidisciplinary ALS clinic, with the remaining 262 (76%) cases followed in a general neurology clinic. The ALS clinic cohort was an average of five years younger (60.1 v 65.6 years) and were more likely to receive riluzole than the general neurology cohort (99% v 61%). The median survival of the ALS clinic cohort was 7.5 months longer than for patients in the general neurology cohort (logrank = 15.4, p < 0.0001). Overall, one year mortality was decreased by 29.7%. Prognosis of bulbar onset patients was extended by 9.6 months if they attended the ALS clinic. Using multivariate analysis, attendance at the ALS clinic was an independent covariate of survival (HR = 1.47, p = 0.02). Conclusions: ALS patients who received their care at a multidisciplinary clinic had a better prognosis than patients attending a general neurology clinic. The data suggest that active and aggressive management enhances survival, particularly among ALS patients with bulbar dysfunction. The effect of clinic type must be considered in future clinical trials design.

Sequence variations with biologic effect in ALS have been identified in the gene for vascular endothelial growth factor (VEGF). The gene for a related protein, angiogenin, lies on chromosome 14q11.2. Analysis of the angiogenin (ANG) gene in the authors' population has demonstrated a significant allelic association with the rs11701 single nucleotide polymorphism (SNP) and identified a novel mutation in two individuals with sporadic ALS that potentially inhibits angiogenin function. These observations propose a candidate region for ALS on chromosome 14q11.2 and suggest that other genes with similar function to VEGF may be important in the pathogenesis of ALS.

465 Irish residents were diagnosed with ALS during the study periods. The annual incidence rate of ALS in Ireland remained stable over this time (2.0 cases per 100,000 person-years; 95% CI 1.9, 2.2). Median survival of Irish ALS patients was 16.4 months and did not change during the study period. Demographics and clinical features of the incident and prevalent Irish ALS cohorts were markedly different.

Riluzole is the only therapy proven in clinical trials to prolong amyotrophic lateral sclerosis (ALS) survival (approximately three months). Questions remain concerning riluzole's effectiveness in everyday practice, the appropriate duration of treatment, which certain subtypes of ALS specifically benefit from the medication, and whether early administration prolongs survival in ALS patients. We report the results of a population-based outcome study of riluzole in the Irish ALS population over a five-year period. Using data from the Irish ALS Register, we examined the survival of patients diagnosed with ALS between 1 January 1996 and 31 December 2000 who attended a general neurology clinic (n = 264 patients, MD = 16). An intention to treat analysis is employed. 149 (61 %) patients were prescribed riluzole and the remaining 99 (39 %) were not. Riluzole therapy reduced mortality rate by 23 % and 15 % at 6 and 12 months respectively and prolonged survival by approximately four months. This beneficial effect was lost in prolonged follow-up. Suspected or possible ALS patients receiving riluzole experienced similar improvement in survival as the overall cohort. Survival benefit was more marked among patients with bulbar-onset disease. Multivariate analysis did not show riluzole to be an independent predictor of survival. We conclude that riluzole therapy improves ALS survival in everyday clinical practice by a short period of time. This beneficial effect is transient and stopping the medication in advanced ALS should be reconsidered. Bulbar-onset patients appear to particularly benefit from riluzole for unclear reasons. Our initial observations support riluzole use in early ALS.