Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.

Objective: To identify the genetic variants associated with juvenile ALS.

Design, Setting, And Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation.

Investigating the Causal Effect of Brain Expression of , , , , Genes on Multiple Sclerosis: A Two-Sample Mendelian Randomization Approach.

Multiple Sclerosis (MS) exhibits considerable heterogeneity in phenotypic expression, course, prognosis and response to therapy. This suggests this disease involves multiple, as yet poorly understood, causal mechanisms. In this work we assessed the possible causal link between gene expression level of five selected genes related to the pro-inflammatory NF-κB signaling pathway (i.

Patients' Disalignment in Two Different Healthcare Settings.

Among the important bulk of research devoted to medical consultations, one recurrently discussed issue has been that of patients' alignment with practitioners' recommendations. If this question has not always been formulated in terms of alignment, all the studied cases deal with how patients comply, or not, with practitioners' first actions. They show that social actions such as suggestions, proposals, offers, etc.

Acid sensing ion channel 2: A new potential player in the pathophysiology of multiple sclerosis.

Acid-sensing ion channels (ASICs) are proton-gated channels involved in multiple biological functions such as: pain modulation, mechanosensation, neurotransmission, and neurodegeneration. Earlier, we described the genetic association, within the Nuoro population, between Multiple Sclerosis (MS) and rs28936, located in ASIC2 3'UTR. Here we investigated the potential involvement of ASIC2 in MS inflammatory process.

Percutaneous Endoscopic Transgastric Jejunostomy (PEG-J) Tube Placement for Levodopa-Carbidopa Intrajejunal Gel Therapy in the Interventional Radiology Suite: A Long-term Follow-up.

Background: Percutaneous endoscopic gastrojejunostomy (PEG) and radiologically inserted gastrojejunostomy (RIG) are both safe and effective techniques for gastrojejunal tube placement. The authors compared these 2 procedures in patients with advanced Parkinson's disease (PD) who required the continuous intrajejunal delivery of a levodopa/carbidopa gel suspension (LCIG).

Methods: Outcomes were retrospectively collated from 30 PEG and 12 RIG procedures performed at 2 centers in patients with advanced PD for the delivery of LCIG.

Investigating multiple sclerosis genetic susceptibility on the founder population of east-central Sardinia via association and linkage analysis of immune-related loci.

Background: A wealth of single-nucleotide polymorphisms (SNPs) responsible for multiple sclerosis (MS) susceptibility have been identified; however, they explain only a fraction of MS heritability.

Objectives: We contributed to discovery of new MS susceptibility SNPs by studying a founder population with high MS prevalence.

Methods: We analyzed ImmunoChip data from 15 multiplex families and 94 unrelated controls from the Nuoro Province, Sardinia, Italy.

Posterior Reversible Encephalopathy Syndrome with Bilateral Independent Epileptic Foci Precipitated By Guillain-Barrè Syndrome.

We report the case of a 56-year-old woman who developed status epilepticus (SE) related to independent occipital foci as clinical manifestation of posterior reversible encephalopathy syndrome (PRES) in the background of Guillain-Barrè syndrome (GBS). SE resulted from a series of focal seizures clinically characterized by left- and rightward deviations of the head and consequent oculoclonic movements. Electroencephalography recorded independent seizure activity in both occipital regions with alternate involvement of the two cerebral hemispheres.

TBK1 is associated with ALS and ALS-FTD in Sardinian patients.

Recently, mutations in the TANK-binding kinase 1 (TBK1) gene were identified as a cause for amyotrophic lateral sclerosis (ALS) with or without comorbid frontotemporal dementia. We have assessed the frequency and clinical characteristics of TBK1 mutations in a cohort of ALS patients of Sardinian ancestry. Whole-exome sequencing was performed on Hiseq2000 platform (Illumina).

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.

A novel LIPE nonsense mutation found using exome sequencing in siblings with late-onset familial partial lipodystrophy.

Background: Familial lipodystrophies are rare inherited disorders associated with redistribution of body fat and development of dyslipidemia, insulin resistance, and diabetes. We previously reported 2 siblings with unusual late-onset familial partial lipodystrophy in whom heretofore known causative genes had been excluded. We hypothesized they had a mutation in a novel lipodystrophy gene.

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.

Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls.

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 population-specific 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).

Clinical and molecular characterization of limb-girdle muscular dystrophy due to LAMA2 mutations.

Introduction: In this study we describe the clinical and molecular characteristics of limb-girdle muscular dystrophy (LGMD) due to LAMA2 mutations.

Methods: Five patients clinically diagnosed with LGMD and showing brain white matter hyperintensities on MRI were evaluated using laminin α2 genetic and protein testing.

Results: The patients had slowly progressive, mild muscular dystrophy with various degrees of CNS involvement.

A patient carrying a homozygous p.A382T TARDBP missense mutation shows a syndrome including ALS, extrapyramidal symptoms, and FTD.

We have recently published data showing that a founder mutation of the TARDBP gene (p.A382T) accounts for approximately one third of amyotrophic lateral sclerosis (ALS) cases on the Mediterranean island of Sardinia (Chiò et al., 2011).

Broadening the phenotype of TARDBP mutations: the TARDBP Ala382Thr mutation and Parkinson's disease in Sardinia.

Mutations in the TARDBP gene are a cause of autosomal dominant amyotrophic lateral sclerosis (ALS) and of frontotemporal lobar degeneration (FTLD), but they have not been found so far in patients with Parkinson's disease (PD). A founder TARDBP mutation (p.Ala382Thr) was recently identified as the cause of ~30% of ALS cases in Sardinia, a Mediterranean genetic isolate.

Large proportion of amyotrophic lateral sclerosis cases in Sardinia due to a single founder mutation of the TARDBP gene.

Objective: To perform an extensive screening for mutations of amyotrophic lateral sclerosis (ALS)-related genes in a consecutive cohort of Sardinian patients, a genetic isolate phylogenically distinct from other European populations.

Design: Population-based, prospective cohort study.

Patients: A total of 135 Sardinian patients with ALS and 156 healthy control subjects of Sardinian origin who were age- and sex-matched to patients.

Amyotrophic lateral sclerosis-frontotemporal lobar dementia in 3 families with p.Ala382Thr TARDBP mutations.

Background: TAR DNA-binding protein 43, encoded by the TARDBP gene, has been identified as the major pathological protein of frontotemporal lobar dementia (FTLD) with or without amyotrophic lateral sclerosis (ALS) and sporadic ALS. Subsequently, mutations in the TARDBP gene have been detected in 2% to 3% of patients with ALS (both familial and sporadic ALS). However, to our knowledge, there is only 1 description of 2 patients with FTLD and TARDBP gene mutations who later developed motor neuron disease.

Association between protective and deleterious HLA alleles with multiple sclerosis in Central East Sardinia.

The human leukocyte antigen (HLA) complex on chromosome 6p21 has been unambiguously associated with multiple sclerosis (MS). The complex features of the HLA region, especially its high genic content, extreme polymorphism, and extensive linkage disequilibrium, has prevented to resolve the nature of HLA association in MS. We performed a family based association study on the isolated population of the Nuoro province (Sardinia) to clarify the role of HLA genes in MS.

Partial status epilepticus related to independent occipital foci in posterior reversible encephalopathy syndrome (PRES).

Posterior reversible encephalopathy syndrome (PRES) is an acute disorder characterised by a variable association of neurologic symptoms with potentially reversible oedematous abnormalities mainly in the parieto-occipital regions of the brain. Despite the significant incidence of seizures, the EEG characteristics of epileptic disorders related to PRES have rarely been investigated. We report the case of an 85-year-old man who presented with generalised tonic-clonic seizures and prolonged disturbances of consciousness as clinical manifestations of PRES due to moderate exacerbation of chronic hypertension.

Association between the ACCN1 gene and multiple sclerosis in Central East Sardinia.

Multiple genome screens have been performed to identify regions in linkage or association with Multiple Sclerosis (MS, OMIM 126200), but little overlap has been found among them. This may be, in part, due to a low statistical power to detect small genetic effects and to genetic heterogeneity within and among the studied populations. Motivated by these considerations, we studied a very special population, namely that of Nuoro, Sardinia, Italy.

Risk for relatives of patients with multiple sclerosis in central Sardinia, Italy.

Multiple sclerosis (MS) is a chronic, inflammatory, disabling disease of the central nervous system, known for its complex interplay between genetic and environmental factors. We used life table techniques to calculate age-adjusted recurrence risks for different categories of relatives of MS patients from Central Sardinia (Italy), a genetically homogeneous, stable population with a high degree of consanguinity. We included 313 probands and a total of 12,717 relatives in the analysis.

Multiple sclerosis recurrence risk for siblings in an isolated population of Central Sardinia, Italy.

Studies of twins, adoptees, half siblings, and familial recurrence risk have shown that genetic and non-genetic factors are involved in multiple sclerosis (MS) etiology. Age at onset, gender, and parental MS status seem to influence sibling risk. We studied the recurrence risk in siblings of MS patients in an isolated population of Sardinia, Italy, which is genetically homogeneous, inbred, and very stable, with a high MS frequency.