The occurrence of endoplasmic reticulum (ER) stress in the sporadic form of amyotrophic lateral sclerosis (ALS) is unknown, despite it has been recently documented in experimental models of the familial form. Here we show that spinal cord from patients with sporadic ALS showed signs of ER stress, such as increased levels of ER chaperones such as protein-disulfide isomerase, and increased phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha). Among the potential causes of such ER stress proteasomal impairment was confirmed in the same samples by demonstrating increased ubiquitin immunoreactivity and increased protein lipoxidative (125%), glycoxidative (55%) and direct oxidative damage (62%) over control values, as evidenced by mass-spectrometry and immunological methods. We found that protein oxidative damage was strongly associated to ALS-specific changes in fatty acid concentrations, specifically of n-3 series (as docosahexaenoic acid), and in the amount of mitochondrial components as respiratory complexes I and III, suggesting a mitochondrial dysfunction leading to increased free radical production. Oxidative stress was also evidenced in frontal cortex, suggesting that this region is affected early in ALS. As those events were partially reproduced by threohydroxyaspartate exposure in organotypic spinal cord cultures, we concluded that changes in fatty acid composition, mitochondrial function and proteasome activity, which may be driven by excitotoxicity, lead to oxidative stress and finally contribute to ER stress in sporadic ALS.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Of the environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) can cause amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). We assessed its frequency in 781 sporadic ALS (sALS) and 155 familial ALS (fALS) cases, and in 248 Spanish controls. We tested the presence of the reported founder haplotype among mutation carriers and in 171 Ceph Europeans from Utah (CEU), 170 Yoruba Africans, 81 Han Chinese, and 85 Japanese subjects. The C9orf72 expansion was present in 27.1% of fALS and 3.2% of sALS. Mutation carriers showed lower age at onset (P = 0.04), shorter survival (P = 0.02), greater co‐occurrence of FTD (P = 8.2 × 10−5), and more family history of ALS (P = 1.4 × 10−20), than noncarriers. No association between alleles within the normal range and the risk of ALS was found (P = 0.12). All 61 of the mutation carriers were tested and a patient carrying 28 hexanucleotide repeats presented with the founder haplotype. This haplotype was found in 5.6% Yoruba Africans, 8.9% CEU, 3.9% Japanese, and 1.6% Han Chinese chromosomes.

Electrodiagnostic studies play a key role in the evaluation of patients with Guillain-Barré syndrome (GBS). However, at early stages patients may not meet current neurophysiologic criteria. We report electrodiagnostic findings for 18 patients with suspected GBS within 4 days of clinical onset. Fifteen patients (83%) showed abnormality in the motor nerve conduction study. Prolonged distal motor latency (DML) was the most frequent demyelinating parameter (seen in 55% of patients). Abnormal late responses were noted in 14 patients (77%). Electrodiagnostic study of cranial nerves was abnormal in eight (44%), and motor nerve conduction velocity was abnormal in only six patients (23%). The study shows a predominant motor neuropathy pattern followed by a sural-sparing pattern; no patients showed a strictly normal electrodiagnostic study. Reduced distal compound muscle action potential and prolonged DML in the demyelinating range were associated with severity of GBS on admission. After the electrodiagnostic study, 5 patients (27%) already fulfilled electrodiagnostic criteria for acute inflammatory demyelinating polyneuropathy (AIDP), 1 (5%) for the axonal variant of GBS, and 13 (72%) were classified as equivocal. We conclude that exhaustive electrodiagnostic studies of patients with suspected GBS in very early stages are useful in the diagnosis and management of the condition.

Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy (HMSN) is a genetically heterogeneous group of conditions that affect the peripheral nervous system. The disease is characterized by degeneration or abnormal development of peripheral nerves and exhibits a range of patterns of genetic transmission. In the majority of cases, CMT first appears in infancy, and its manifestations include clumsiness of gait, predominantly distal muscular atrophy of the limbs, and deformity of the feet in the form of foot drop. It can be classified according to the pattern of transmission (autosomal dominant, autosomal recessive, or X linked), according to electrophysiological findings (demyelinating or axonal), or according to the causative mutant gene. The classification of CMT is complex and undergoes constant revision as new genes and mutations are discovered. In this paper, we review the most efficient diagnostic algorithms for the molecular diagnosis of CMT, which are based on clinical and electrophysiological data.

The objective of this study is to analyze the prevalence to cognitive function impairment (CI) in a pragmatic cohort of subjects with different types of neuropathic pain under standard conditions of care by means of a cross-sectional baseline analysis of a sample of patients with NeP enrolled in a pragmatic, prospective, multicenter study evaluating the effectiveness of gabapentin. A total of 1519 patients (58.8% women), aged > or =18 years (mean [SD]=56.0 [13.7]), with neuropathic or mixed neuropathic and nociceptive pain for a mean (SD) of 1.1 (2.8) years were enrolled in the study. Pain was assessed with the short form of the McGill Pain Questionnaire, and cognitive function was measured with the Mini-Mental State Examination (MMSE). A score < or =24 on the MMSE was considered as CI. Multivariate logistic regression models were used to estimate CI prevalence. CI prevalence was substantially higher in patients with NeP than that reported in the general Spanish population, and significantly higher than in patients with mixed neuropathic and nociceptive pain: 11.4% (8.5%-14.3%) vs. 6.4% (4.6%-8.7%), P=0.006 (adjusted odds ratio=1.88 [1.21-2.91]). Prevalence significantly increased with age, up to 32.2% (20.6%-45.6%) in those with NeP, and to 28.2% (15.0%-44.9%) in those with mixed syndromes, for the age group > or =75 years, P<0.001 within age groups. Symptoms of anxiety and obesity, and to a lesser extent, symptoms of depression, were also factors associated with a higher prevalence rate of CI. This analysis showed that, after adjusting for confounding factors, the prevalence of CI was substantially higher in patients with NeP than those with mixed pain and the reference general population. Age, anxiety, depression, and obesity were factors found to be significantly associated with CI.