Impact of treatment with dimethyl fumarate on sleep quality in patients with relapsing-remitting multiple sclerosis: A multicentre Italian wearable tracker study

BackgroundSleep disorders are common in patients with multiple sclerosis and have a bidirectional interplay with fatigue and depression. ObjectiveTo evaluate the effect of treatment with oral dimethyl fumarate on the quality of sleep in relapsing-remitting multiple sclerosis. MethodsThis was a multicentre observational study with 223 relapsing-remitting multiple sclerosis subjects starting treatment with dimethyl fumarate (n=177) or beta interferon (n=46). All patients underwent subjective (Pittsburgh Sleep Quality Index) and objective (wearable tracker) measurements of quality of sleep. Fatigue, depression, and quality of life were also investigated and physical activity was monitored. ResultsPatients treated with dimethyl fumarate had significant improvement in the quality of sleep as measured with the Pittsburgh Sleep Quality Index (p<0.001). At all-time points, no significant changes in Pittsburgh Sleep Quality Index score were observed in the interferon group. Total and deep sleep measured by wearable tracker decreased at week 12 with both treatments, then remained stable for the total study duration. Depression significantly improved in patients treated with dimethyl fumarate. No significant changes were observed in mobility, fatigue and quality of life. ConclusionIn patients with relapsing-remitting multiple sclerosis, the treatment with dimethyl fumarate was associated with improvements in patient-reported quality of sleep. Further randomised clinical trials are needed to confirm the benefits of long-term treatment with dimethyl fumarate

Variants within the immunoregulatory CBLB gene are associated with multiple sclerosis

A genome wide association scan of ~6.6 million genotyped or imputed variants in 882 Sardinian Multiple Sclerosis (MS) cases and 872 controls suggested association of CBLB gene variants with disease, which was confirmed in 1,775 cases and 2,005 controls (overall P =1.60 × 10-10). CBLB encodes a negative regulator of adaptive immune responses and mice lacking the orthologue are prone to experimental autoimmune encephalomyelitis, the animal model of MS

Amyotrophic lateral sclerosis in Sardinia, insular Italy, 1995–2009

Recent genetic studies suggest a Sardinian type of amyotrophic lateral sclerosis (ALS). Thus, ALS incidence, prevalence and survival were investigated in a large population of Sardinians aimed to disclose populationspecific patterns and their temporal changes. This is a population-based incidence and prevalence study in northern and central Sardinia, insular Italy (over 700,000 population). Incidence rates were computed for the time interval 1995–2009 and by quinquennia. Prevalence was computed for prevalence days 31 December 2004 and 2009. Onset-based survival for 1995–2009 is also reported. All ALS patients (El Escorial Criteria) in the study area were retrospectively included. The ALS crude incidence from 2005–2009 was 2.5 (95 % CIs: 0.1, 4.9), 3.4 in men and 1.6 in women. Onset occurred most often between the age of 65–74 years in men and 55–64 years in women. The ALS incidence tended to increase over the period 1995–2009. The mean age at onset was 61.7 years with no difference based on gender, varying significantly from 59.9 years in 1995–1999 to 63.9 years in 2005–2009. On December 31, 2009, the ALS crude prevalence was 10.8 per 100,000 (95 % CIs: 8.6, 13.1), 13.8 in men and 8.0 in women, whereas it was 6.3 per 100,000 (95 % CIs: 4.1, 8.6) on December 31, 2004 (M:F ratio of 0.95). Mean survival from onset was 37.0 months, with no difference based on gender, and a tendency to decrease during the period 1995–2009, in relation to type and age of onset. The population-based incidence and prevalence data of ALS in Sardinians indicate an increase of the disease occurrence over the past 40 years, providing support for a populationspecific variant of ALS in Sardinia

ATXN2 is a modifier of phenotype in ALS patients of Sardinian ancestry

Intermediate-length CAG expansions (encoding 27-33 glutamines, polyQ) of the Ataxin2 (ATXN2) gene represent a risk factor for amyotrophic lateral sclerosis (ALS). Recently, it has been proposed that ≥31 CAG expansions may influence ALS phenotype. We assessed whether ATXN2 intermediate-length polyQ expansions influence ALS phenotype in a series of 375 patients of Sardinian ancestry. Controls were 247 neurologically healthy subjects, resident in the study area, age- and gender-matched to cases. The frequency of ≥31 polyQ ATNX2 repeats was significantly more common in ALS cases (4 patients vs. no control, p = 0.0001). All patients with ≥31 polyQ repeats had a spinal onset versus 73.3% of patients with <31 polyQ repeats. Patients with an increased number of polyQ repeats have a shorter survival than those with <31 repeats (1.2 vs. 4.2 years, p = 0.035). In this large series of ALS patients of Sardinian ancestry, we have found that ≥31 polyQ repeats of the ATXN2 gene influenced patients' phenotype, being associated to a spinal onset and a significantly shorter survival

Genetic architecture of ALS in Sardinia

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

Variants within the immunoregulatory <i>CBLB</i> gene are associated with multiple sclerosis

A genome-wide association scan of ~6.6 million genotyped or imputed variants in 882 Sardinian individuals with multiple sclerosis (cases) and 872 controls suggested association of CBLB gene variants with disease, which was confirmed in 1,775 cases and 2,005 controls (rs9657904, overall P = 1.60 × 10−10, OR = 1.40). CBLB encodes a negative regulator of adaptive immune responses, and mice lacking the ortholog are prone to experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis

Variants within the immunoregulatory CBLB gene are associated with multiple sclerosis

A genome wide association scan of ~6.6 million genotyped or imputed variants in 882 Sardinian Multiple Sclerosis (MS) cases and 872 controls suggested association of CBLB gene variants with disease, which was confirmed in 1,775 cases and 2,005 controls (overall P =1.60 × 10(-10)). CBLB encodes a negative regulator of adaptive immune responses and mice lacking the orthologue are prone to experimental autoimmune encephalomyelitis, the animal model of MS

ATXN2 is a modifier of phenotype in ALS patients of Sardinian ancestry

Abstract Intermediate-length CAG expansions (encoding 27-33 glutamines, polyQ) of the Ataxin2 (ATXN2) gene represent a risk factor for amyotrophic lateral sclerosis (ALS). Recently, it has been proposed that ≥31 CAG expansions may influence ALS phenotype. We assessed whether ATXN2 intermediate-length polyQ expansions influence ALS phenotype in a series of 375 patients of Sardinian ancestry. Controls were 247 neurologically healthy subjects, resident in the study area, age- and gender-matched to cases. The frequency of ≥31 polyQ ATNX2 repeats was significantly more common in ALS cases (4 patients vs. no control, p = 0.0001). All patients with ≥31 polyQ repeats had a spinal onset versus 73.3% of patients with &lt;31 polyQ repeats. Patients with an increased number of polyQ repeats have a shorter survival than those with &lt;31 repeats (1.2 vs. 4.2 years, p = 0.035). In this large series of ALS patients of Sardinian ancestry, we have found that ≥31 polyQ repeats of the ATXN2 gene influenced patients' phenotype, being associated to a spinal onset and a significantly shorter survival