Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Conventional vs controlled-release CBZ : A multicentre, double-blind, cross-over study

Efficacy of tolerability of a new controlled-release (CR) formulation of carbamazepine (CBZ) (Tegretol CR), were assessed in a formal multicentre, double-blind, cross-over trial, carried out in 48 epileptic patients (21 men, 27 women; mean age 34 years). Before entering the study, patietns (pts) had been taking conventional CBZ monotherapy, but without a complete seizure control (n = 22 pts), or with intermittent side-effects (n = 4 pts), or with seizures and intermittent side-effects (n = 22 pts). Eligible pts were given conventional CBZ and CR CBZ, in randomized sequence, at individualized daily doses, subdivided in the lowest number of administration. Each period of the cross-over consisted of a first phase of titration (lasting up to 2 months) and of a second phase of maintenance (lasting 1 month) used for evaluation. A 12-hour plasma CBZ and CBZ-epoxide profile concentrations, as well as efficacy and tolerability, were evaluated at the end of each period. The mean daily CBZ dose has been increased by 15% during administration of the CR formulation. Fluctuation indices of total CBZ and 10,11-epoxide plasma levels at steady-state were significantly (p < 0.02) lower during CR CBZ treatment, leading to a significant (p < 0.001) decrease of intermittent side-effects (6 pts on CR CBZ vs 36 on conventional CBZ). In addition, a complete seizure control was obtained in 4 pts when treated with CR CBZ; 38 pts on CR CBZ (vs 15 pts on conventional CBZ) were treated with a b.i.d. regimen

ATXN2 polyQ intermediate repeats are a modifier of ALS survival.

To analyze the frequency and clinical characteristics of patients with amyotrophic lateral sclerosis (ALS) with intermediate-length (CAG) expansion (encoding 27-33 glutamines, polyQ) in the ATXN2 gene, in a population-based cohort of Italian patients with ALS (discovery cohort), and to replicate the findings in an independent cohort of consecutive patients from an ALS tertiary center (validation cohort).PolyQ repeats were assessed in 672 patients with incident ALS in Piemonte and Valle d'Aosta regions, Italy, in the 2007-2012 period (discovery cohort); controls were 509 neurologically healthy age- and sex-matched subjects resident in the study area. The validation cohort included 661 patients with ALS consecutively seen between 2001 and 2013 in the ALS Clinic Center of the Catholic University in Rome, Italy.In the discovery cohort, the frequency of 6531 polyQ ATNX2 repeats was significantly more common in ALS cases (19 patients vs 1 control, p = 0.0001; odds ratio 14.8, 95\% confidence interval 1.9-110.8). Patients with an increased number of polyQ repeats had a shorter survival than those with <31 repeats (median survival, polyQ 6531, 1.8 years, interquartile range [IQR] 1.3-2.2; polyQ <31, 2.7 years, IQR 1.6-5.1; p = 0.001). An increased number of polyQ repeats remained independently significant at multivariable analysis. In the validation cohort, patients with 6531 polyQ repeats had a shorter survival than those with <31 repeats (median survival, polyQ 6531, 2.0 years, IQR 1.5-3.4; polyQ <31, 3.2 years, IQR 2.0-6.4; p = 0.007).ATXN2 polyQ intermediate-length repeat is a modifier of ALS survival. Disease-modifying therapies targeted to ATXN2 represent a promising therapeutic approach for ALS

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

The epidemiology and treatment of ALS: focus on the heterogeneity of the disease and critical appraisal of therapeutic trials.

Effective treatments for amyotrophic lateral sclerosis (ALS) have remained elusive. Only riluzole, a drug thought to affect glutamate metabolism, improves survival albeit to modest extent. Explanations for the negative results of therapeutic trials include a likely heterogeneity, both in disease susceptibility and pathogenic mechanisms, and faulty methodology of clinical trials. Further understanding of these factors will lead to improvements in patient stratification, and in the design of future clinical tria