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We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer’s dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.

Motor neurone disease (MND), or amyotrophic lateral sclerosis (ALS), is a progressive, fatal neurodegenerative disease affecting upper and lower motor neurones. It eventually causes widespread weakness and wasting, spasticity, dysarthria, dysphonia, dysphagia and respiratory failure. The diagnosis is clinical, and it is important for management to establish this early. It presents with upper and lower motor neurone signs affecting the bulbar, cervicothoracic and lumbosacral regions (ALS), only lower motor neurone signs affecting one or more limbs (progressive muscular atrophy), purely bulbar region symptoms and signs (bulbar onset), or only upper motor neurone signs in the (usually lower) limbs (primary lateral sclerosis). Imaging, electrophysiological and other tests help the differential diagnosis of mimics, including potentially treatable conditions. The underlying cause remains uncertain. Only 5–10% of patients have a demonstrable genetic cause. There is no cure, and the greatest advances have been in improving multidisciplinary supportive management. This includes gastrostomy and nutritional support, respiratory monitoring and management, including provision of non-invasive ventilation, and communication aids. Drugs for symptomatic relief of excessive salivation and spasticity can help. Riluzole and edaravone (restricted acceptance) are used although their disease-modifying effects are said to be mild and are controversial. Genetic therapies are currently being trialled for C9orf72-and SOD1-related MND/ALS.

Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Failure to clear oral secretions can be debilitating for patients with amyotrophic lateral sclerosis (ALS), but the treatment of this symptom is poorly defined and there is no consensus on best practice. The objective of this study was to identify the treatments that are commonly prescribed, and to describe how experienced clinicians manage a patient with treatment resistant symptoms. Twenty-three clinicians were approached, of which 19 from 16 centres across the UK provided case report forms for a total of 119 ALS patients identified as having problematic oral secretions. The use of five anticholinergics, salivary gland botulinum toxin injections, conservative management approaches and carbocisteine were reported. Of the 72 patients who were evaluated following the initiation of a first anticholinergic, 61% had symptomatic improvement. Only 19% of patients achieved symptomatic improvement with the use of an alternative anticholinergic when an initial anticholinergic achieved no symptomatic improvement. Problems with thick and thin secretions often coexisted, with 37% of patients receiving treatment for both types of problem. In conclusion, a variety of treatment options are employed by expert clinicians for problematic oral secretions in ALS patients. The variation in management highlights the need for further prospective research in this area.

Facioscapulohumeral dystrophy (FSHD) is a rare inherited neuromuscular disease estimated to affect 1/15,000 people. Through basic research, remarkable progress has been made towards the development of targeted therapies. Patient identification, through registries or other means is essential for trial-readiness. The UK FSHD Patient Registry is a patient initiated registry that collects standardised and internationally agreed dataset of self-reported clinical details combined with professionally verified genetic information. It includes four additional questionnaires to capture patient reported outcomes related to pain, quality of life and scapular fixation. Between 2013 and 2015, 518 patients registered 243 males, 241 females with a mean age of 47.8 years. Most of the patients have FSHD type 1 (91.7 %), and weakness of the facial (59.2 %) was the most prevalent symptom at onset, followed by shoulder-girdle muscles (53.3 %) and distal (22.45 %) or proximal lower limb weakness (14.8 %). 85.57 % patients were ambulant or ambulant with assistance at the time of registration, 7.9 % report respiratory insufficiency. The registry has demonstrated utility with the recruitment of patients for a natural history study of infantile onset FSHD, and the longitudinal analysis of patient-related outcomes will provide much-needed baseline information to power future trials. The internationally agreed core dataset enables national registries to participate in a “Global FSHD registry”. We suggest that the registry’s ability to interoperate with other large datasets will be instrumental for sharing and exploiting data globally. Electronic supplementary material The online version of this article (doi:10.1007/s00415-016-8132-1) contains supplementary material, which is available to authorized users.

© 2018 Elsevier Inc., To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

C9orf72 hexanucleotide repeat expansions are the most common cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. The clinical presentation is often indistinguishable from classic FTD or ALS, although neuropsychiatric symptoms are more prevalent and, for ALS, behavioural and cognitive symptoms occur more frequently. Pathogenic repeat length is in the hundreds or thousands, but the minimum length that increases risk of disease, and how or whether the repeat size affects phenotype, are unclear. Like in many patients with FTD and ALS, neuronal inclusions that contain TARDBP are seen, but are not universal, and the characteristic pathological finding is of dipeptide repeat (DPR) proteins, formed by unconventional repeat-associated non-ATG translation. Possible mechanisms of neurodegeneration include loss of C9orf72 protein and function, RNA toxicity, and toxicity from the DPR proteins, but which of these is the major pathogenic mechanism is not yet certain.

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6; P=1 × 10−4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10−7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies., Relatives of patients with amyotrophic lateral sclerosis have an unexpectedly high incidence of schizophrenia. Here, the authors show a genetic link between the two conditions, suggesting shared neurobiological mechanisms.

Myotonic dystrophy type 1 (DM1) is the most frequent muscular dystrophy worldwide with complex, multi-systemic, and progressively worsening symptoms. There is currently no treatment for this inherited disorder and research can be challenging due to the rarity and variability of the disease. The UK Myotonic Dystrophy Patient Registry is a patient self-enrolling online database collecting clinical and genetic information. For this cross-sectional “snapshot” analysis, 556 patients with a confirmed diagnosis of DM1 registered between May 2012 and July 2016 were included. An almost even distribution was seen between genders and a broad range of ages was present from 8 months to 78 years, with the largest proportion between 30 and 59 years. The two most frequent symptoms were fatigue and myotonia, reported by 79 and 78% of patients, respectively. The severity of myotonia correlated with the severity of fatigue as well as mobility impairment, and dysphagia occurred mostly in patients also reporting myotonia. Men reported significantly more frequent severe myotonia, whereas severe fatigue was more frequently reported by women. Cardiac abnormalities were diagnosed in 48% of patients and more than one-third of them needed a cardiac implant. Fifteen percent of patients used a non-invasive ventilation and cataracts were removed in 26% of patients, 65% of which before the age of 50 years. The registry’s primary aim was to facilitate and accelerate clinical research. However, these data also allow us to formulate questions for hypothesis-driven research that may lead to improvements in care and treatment. Electronic supplementary material The online version of this article (doi:10.1007/s00415-017-8483-2) contains supplementary material, which is available to authorized users.

Summary Valosin-containing protein (VCP) is a highly expressed member of the type II AAA+ ATPase family. VCP mutations are the cause of inclusion body myopathy, Paget’s disease of the bone, and frontotemporal dementia (IBMPFD) and they account for 1%–2% of familial amyotrophic lateral sclerosis (ALS). Using fibroblasts from patients carrying three independent pathogenic mutations in the VCP gene, we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption. This mitochondrial uncoupling results in a significant reduction of cellular ATP production. Decreased ATP levels in VCP-deficient cells lower their energy capacity, making them more vulnerable to high energy-demanding processes such as ischemia. Our findings propose a mechanism by which pathogenic VCP mutations lead to cell death., Highlights ► VCP deficiency is associated with mitochondrial depolarization ► VCP deficiency leads to increased mitochondrial respiration and uncoupling ► ATP levels are decreased in VCP-deficient cells due to lower ATP production, In this study, Bartolome et al. show that three independent pathogenic VCP mutations induce mitochondrial uncoupling, resulting in low cellular ATP production, rendering the cells more susceptible to cell death under stress-induced ischemic conditions.

The genetic landscape of amyotrophic lateral sclerosis (ALS) is poorly understood. By examining known ALS-associated genes in a large cohort, Morgan, Shatunov et al. report an increase in mutations within the untranslated prime regions of the genes and a greater than expected number of patients with multiple potentially pathogenic variants., Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2. We found 11 patients (1%) carried more than one pathogenic variant (P = 0.001) consistent with an oligogenic basis of amyotrophic lateral sclerosis. These findings show that the genetic architecture of amyotrophic lateral sclerosis is complex and that variation in the regulatory regions of associated genes may be important in disease pathogenesis.

Motor neurone disease is a rapidly progressive and fatal neurodegenerative condition which causes progressive weakness, with normal sensation. It can occur at any age but is more frequent with increasing age. Key clinical presentations include bulbar (slurred or difficult speech, problems swallowing, tongue fasciculation), limb (typically in one limb with weakness and muscle wasting), respiratory (breathlessness, chest muscle fasciculation) and cognitive features (behavioural change, emotional lability, features of frontotemporal dementia). Although survival is typically three to five years from symptom onset, there is significant individual variation. Rarely, survival may be 20 years or longer. Favourable features include a limb rather than a bulbar presentation, preserved weight and respiratory function, younger age of onset and longer time from fist symptom to diagnosis. The patient should be linked to a multidisciplinary team able to provide support from the start with a designated individual as the point of contact, with regular, coordinated assessments, as the patient's needs change and their condition progresses. Gastrostomy is an important supportive intervention which maximizes nutrition, and minimizes aspiration and chest infection. Adequate nutrition and hydration is key to maximizing health and survival. It is possible for a patient to control a computer and speech by eye. movement alone. An important consideration is voice banking where the patient may store their voice before there is difficulty with speech so that it can be used at a later stage if they need a communication aid. Impaired cough and retention of respiratory secretions is frequent in the later stages, and may be managed with physiotherapy. The patient should be referred for expert respiratory assessment if needed.

BACKGROUND: Friedreich ataxia is a rare inherited autosomal recessive neurological disorder, characterised initially by unsteadiness in standing and walking, slowly progressing to wheelchair dependency usually in the late teens or early twenties. It is associated with slurred speech, scoliosis, and pes cavus. Heart abnormalities cause premature death in 60% of people with the disorder. There is no easily defined clinical or biochemical marker and no known treatment. This is the second update of a review first published in 2009 and previously updated in 2012. OBJECTIVES: To assess the effects of pharmacological treatments for Friedreich ataxia. SEARCH METHODS: On 29 February 2016 we searched The Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, EMBASE and CINAHL Plus. On 7 March 2016 we searched ORPHANET and TRIP. We also checked clinical trials registers for ongoing studies. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) or quasi‐RCTs of pharmacological treatments (including vitamins) in people with genetically‐confirmed Friedreich ataxia. The primary outcome was change in a validated Friedreich ataxia neurological score after 12 months. Secondary outcomes were changes in cardiac status as measured by magnetic resonance imaging or echocardiography, quality of life, mild and serious adverse events, and survival. We excluded trials of duration shorter than 12 months. DATA COLLECTION AND ANALYSIS: Three review authors selected trials and two review authors extracted data. We obtained missing data from the two RCTs that met our inclusion criteria. We collected adverse event data from included studies. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified more than 12 studies that used antioxidants in the treatment of Friedreich ataxia, but only two small RCTs, with a combined total of 72 participants, both fulfilled the selection criteria for this review and published results. One of these trials compared idebenone with placebo, the other compared high‐dose versus low‐dose coenzyme Q10 and vitamin E (the trialists considered the low‐dose medication to be the placebo). We identified two other completed RCTs, which remain unpublished; the interventions in these trials were pioglitazone (40 participants) and idebenone (232 participants). Other RCTs were of insufficient duration for inclusion. In the included studies, the primary outcome specified for the review, change in a validated Friedreich ataxia rating score, was measured using the International Co‐operative Ataxia Rating Scale (ICARS). The results did not reveal any significant difference between the antioxidant‐treated and the placebo groups (mean difference 0.79 points, 95% confidence interval ‐1.97 to 3.55 points; low‐quality evidence). The published included studies did not assess the first secondary outcome, change in cardiac status as measured by magnetic resonance imaging. Both studies reported changes in cardiac measurements assessed by echocardiogram. The ejection fraction was not measured in the larger of the included studies (44 participants). In the smaller study (28 participants), it was normal at baseline and did not change with treatment. End‐diastolic interventricular septal thickness showed a small decrease in the smaller of the two included studies. In the larger included study, there was no decrease, showing significant heterogeneity in the study results; our overall assessment of the quality of evidence for this outcome was very low. Left ventricular mass (LVM) was only available for the smaller RCT, which showed a significant decrease. The relevance of this change is unclear and the quality of evidence low. There were no deaths related to the treatment with antioxidants. We considered the published included studies at low risk of bias in six of seven domains assessed. One unpublished included RCT, a year‐long study using idebenone (232 participants), published an interim report in May 2010 stating that the study reached neither its primary endpoint, which was change in the ICARS score, nor a key cardiological secondary endpoint, but data were not available for verification and analysis. AUTHORS' CONCLUSIONS: Low‐quality evidence from two small, published, randomised controlled trials neither support nor refute an effect from antioxidants (idebenone, or a combination of coenzyme Q10 and vitamin E) on the neurological status of people with Friedreich ataxia, measured with a validated neurological rating scale. A large unpublished study of idebenone that reportedly failed to meet neurological or key cardiological endpoints, and a trial of pioglitazone remain unpublished, but on publication will very likely influence quality assessments and conclusions. A single study of idebenone provided low‐quality evidence for a decrease in LVM, which is of uncertain clinical significance but of potential importance that needs to be clarified. According to low‐quality evidence, serious and non‐serious adverse events were rare in both antioxidant and placebo groups. No non‐antioxidant agents have been investigated in RCTs of 12 months' duration.

Multifocal motor neuropathy with conduction block is an important differential diagnosis of motor neuron disease/amyotrophic lateral sclerosis. Typical presentation is weakness with relatively mild muscle wasting in the hand of a young male. Treatment with intravenous immunoglobulin is usually effective.

A large expansion of the hexanucleotide repeat in the C9ORF72 gene is the most frequent identified genetic cause of ALS. It also causes other neurodegenerative diseases, especially frontotemporal dementia, and there may be clinical overlap in an individual and within families. Inheritance is autosomal dominant, although due to variable penetrance affected individuals may appear sporadic.

Background: Peripheral nerve vasculitis is an important condition which can be diagnostically challenging and is one of the principal current indications for nerve and muscle biopsy. Previous studies have suggested that combined nerve and muscle biopsy (usually of the superficial peroneal nerve and peroneus brevis muscle) produces a higher diagnostic yield than nerve biopsy alone in the investigation of vasculitis. Objective: To determine whether in our two centres combined nerve (usually the sural) and muscle (usually vastus lateralis) improved diagnostic yield versus nerve biopsy alone. Methods: We interrogated our database of all nerve biopsies (usually of the sural nerve) performed at our institutions over 5 years and identified 53 cases of biopsy proven peripheral nerve vasculitis. Clinicopathological and neurophysiological data in these patients was reviewed. Results: The most common clinical presentation was with a painful asymmetric axonal polyneuropathy or mononeuritis multiplex (66% of cases). Nerve biopsy demonstrated definite vasculitis in 36 %, probable vasculitis in 62% and no vasculitis in 2% of cases. In 24 patients a muscle biopsy (usually vastus lateralis) was also performed and vasculitis was demonstrated in 46% of these (in 13% showing definite and 33% probable vasculitis). There was only one patient in whom vasculitis was demonstrated in muscle but not in peripheral nerve. Conclusion: In our hands, combined nerve (usually sural) and vastus lateralis muscle biopsy did not significantly increase the diagnostic yield versus nerve biopsy alone. We suggest that a sensible approach to the diagnosis of peripheral nerve vasculitis is to choose a nerve to biopsy which is clinically affected and amenable to biopsy. If the sural nerve is chosen our data suggests that it is not routinely worth doing a vastus lateralis biopsy at the same time, whereas if the superficial peroneal nerve is chosen, it seems appropriate to do a combined superficial peroneal nerve and peroneus brevis biopsy. It is still not known if both the sural and superficial peroneal nerves are involved clinically which one gives the higher yield if biopsied.

Our objective was to better understand UK-wide practice in managing sialorrhoea in motor neuron disease among specialist clinicians. We used a survey of neurologists in the UK with a special interest in motor neuron disease designed to establish clinicians' attitudes towards treatment options and resources for sialorrhoea management. Twenty-three clinicians replied, representing 21 centres. Sixteen centres were specialist MND Care Centres. Clinicians estimated seeing a total of 1391 newly diagnosed patients with MND in 2011. One hundred and ninety-three patients were described. Forty-two percent of patients reviewed in clinicians' last clinic had sialorrhoea and 46% of those with sialorrhoea had uncontrolled symptoms. Clinicians' preferred drugs were hyoscine patches, amitriptyline, carbocisteine and botulinum toxin. Botulinum toxin was used in 14 centres. Risk of dysphagia and staff skills were identified as the main barriers to botulinum toxin use. This survey suggests that there may be as many as 1700 patients with MND in the UK who have symptoms of sialorrhoea and that symptoms may be poorly controlled in nearly half. Treatment strategies varied, reflecting the lack of evidence based guidelines. The use of specialist treatments was influenced by local infrastructure. This study highlights the need for further work to develop evidence based guidance.

We aimed to assess whether rural residence is associated with amyotrophic lateral sclerosis in the south-east of England using a population based register. Previous studies in different populations have produced contradictory findings. Residence defined by London borough or non-metropolitan district at time of diagnosis was recorded for each incident case in the South-East England ALS Register between 1995 and 2005. Each of the 26 boroughs or districts of the catchment area of the register was classified according to population density. Age- and sex-adjusted incidence of ALS was calculated for each region and the relationship with population density tested by linear regression, thereby controlling for the underlying population structure. We found that population density in region of residence at diagnosis explained 25% of the variance in ALS rates (r = 0.5, p < 0.01). Thus, in this cohort in the south-east of England, people with ALS were more likely to be resident in areas of high population density at diagnosis.

Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved., To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) or motor neuron disease is a rapidly progressive neurodegenerative disorder. The primary involvement is of motor neurons in the brain, spinal cord and peripherally. There is secondary weakness of muscles and primary involvement of other brain regions, especially involving cognition. SOURCES OF DATA: Peer-reviewed journal articles and reviews. PubMed.gov AREAS OF AGREEMENT: The pathogenesis of ALS remains largely unknown. There are a wide range of potential mechanisms related to neurodegeneration. An increasing number of genetic factors are recognized. AREAS OF CONTROVERSY: There remains controversy, or lack of knowledge, in explaining how cellular events manifest as the complex human disease. There is controversy as to how well cellular and animal models of disease relate to the human disease. GROWING POINTS: Large-scale international collaborative genetic epidemiological studies are replacing local studies. Therapies related to pathogenesis remain elusive, with the greatest advances to date relating to provision of care (including multidisciplinary management) and supportive care (nutrition and respiratory support). AREAS TIMELY FOR DEVELOPING RESEARCH: The identification of C9orf72 hexanucleotide repeats as the most frequent genetic background to ALS, and the association with frontotemporal dementia, gives the potential of a genetic background against which to study other risk factors, triggers and pathogenic mechanisms, and to develop potential therapies.

We report two patients with facioscapulohumeral muscular dystrophy (FSHD) presenting with atypical clinical features. Both were found to have antibodies to acetylcholine receptor (AChR-abs) and improved with immunosuppression. AChR-abs have also been reported in patients with other genetic myopathies and it is unlikely that the association is coincidental. There is increasing evidence that muscle fibre degeneration can cause innate immune responses (autoinflammation) that may lead to the breaking of immune tolerance and the generation of autoantibodies to muscle proteins. We compare and contrast this process with the pathogenesis of archetypical myasthenia gravis.

Summary Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons that results in progressive weakness and death from respiratory failure, commonly within about 3 years. Previous studies have shown association of a locus on chromosome 9p with ALS and linkage with ALS–frontotemporal dementia. We aimed to test whether this genomic region is also associated with ALS in an independent set of UK samples, and to identify risk factors associated with ALS in a further genome-wide association study that combined data from the independent analysis with those from other countries. Methods We collected samples from patients with sporadic ALS from 20 UK hospitals and obtained UK control samples from the control groups of the Depression Case Control study, the Bipolar Affective Case Control Study, and the British 1958 birth cohort DNA collection. Genotyping of DNA in this independent analysis was done with Illumina HumanHap550 BeadChips. We then undertook a joint genome-wide analysis that combined data from the independent set with published data from the UK, USA, Netherlands, Ireland, Italy, France, Sweden, and Belgium. The threshold for significance was p=0·05 in the independent analysis, because we were interested in replicating a small number of previously reported associations, whereas the Bonferroni-corrected threshold for significance in the joint analysis was p=2·20×10 −7 Findings After quality control, samples were available from 599 patients and 4144 control individuals in the independent set. In this analysis, two single nucleotide polymorphisms in a locus on chromosome 9p21.2 were associated with ALS: rs3849942 (p=2·22×10 −6 ; odds ratio [OR] 1·39, 95% CI 1·21–1·59) and rs2814707 (p=3·32×10 −6 ; 1·38, 1·20–1·58). In the joint analysis, which included samples from 4312 patients with ALS and 8425 control individuals, rs3849942 (p=4·64×10 −10 ; OR 1·22, 95% CI 1·15–1·30) and rs2814707 (p=4·72×10 −10 ; 1·22, 1·15–1·30) were associated with ALS. Interpretation We have found strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent GWAS of ALS and linkage studies of ALS–frontotemporal dementia. Our findings together with these earlier findings suggest that genetic variation at this locus on chromosome 9 causes sporadic ALS and familial ALS–frontotemporal dementia. Resequencing studies and then functional analysis should be done to identify the defective gene. Funding ALS Therapy Alliance, the Angel Fund, the Medical Research Council, the Motor Neurone Disease Association of Great Britain and Northern Ireland, the Wellcome Trust, and the National Institute for Health Research Dementias and Neurodegenerative Diseases Research Network (DeNDRoN).

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motoneuron degeneration. Although viral delivery of IGF-I has shown therapeutic efficacy in the SOD1(G93A) mouse model of ALS, clinical trials of IGF-I in ALS patients have led to conflicting results. Here we examine the effects of an IGF-I splice variant, mechano-growth factor (MGF) which has previously been shown to have greater neuroprotective effects than IGF-I in a number of models of neurodegeneration. A mammalian expression plasmid containing either MGF or, for comparison, the IGF-I cDNA sequence was delivered to the hindlimb muscles of SOD1(G93A) mice at 70 days of age, at symptom onset. Treatment with either IGF-I or MGF resulted in a significant improvement in hindlimb muscle strength, and an increase in motor unit and motoneuron survival. Significantly more motoneurons survived in MGF treated mice.

Free radical accumulation and oxidative stress have been proposed as contributing to the progression of amyotrophic lateral sclerosis (motor neuron disease). A range of antioxidant medications is available, and has been studied. We aimed to examine the effects of antioxidant medication in the treatment of people with amyotrophic lateral sclerosis, and searched the Cochrane Neuromuscular Disease Group Trials register (August 2005), MEDLINE (January 1966 to August 2005), EMBASE (January 1980 to August 2005) and other sources. Selection criteria were all randomized or quasi-randomized controlled trials of antioxidant treatment for amyotrophic lateral sclerosis. The authors independently applied the selection criteria, assessed study quality and two authors performed independent data extraction. The search identified 23 studies for consideration but only nine studies met the inclusion criteria. Only two studies used our predetermined primary outcome measure as the primary outcome measure (survival at 12 months treatment). However, sufficient data were available from four studies to allow analysis of this outcome measure, and a meta-analysis was performed. In the individual studies no significant effect was observed for vitamin E 500 mg twice daily; vitamin E 1 g five times daily; acetylcysteine 50 mg/kg daily subcutaneous infusion; or a combination of L-methionine 2 g, vitamin E 400 International Units, and selenium 0.03 mg three times daily (Alsemet). No significant effect on the primary outcome measure was observed in a meta analysis of all antioxidants combined. No significant differences were demonstrated in any of the secondary outcome measures. In the opinion of the reviewers, there is insufficient evidence of efficacy of individual antioxidants, or antioxidants in general, in the treatment of people with amyotrophic lateral sclerosis. One study reported a mild positive effect, but this was not supported by the analysis we used. Generally, the studies were poorly designed, and underpowered, with low numbers of participants and of short duration. Further well-designed trials of medications such as vitamin C and E are unlikely to be performed. If future trials of antioxidant medications are performed, careful attention should be given to sample size, outcome measures, and duration of the trial. The high tolerance and safety, and relatively low cost of vitamins C and E, and other considerations related to the lack of other effective treatments for amyotrophic lateral sclerosis, explain the continuing use of these vitamins by physicians and people with amyotrophic lateral sclerosis. While there is no substantial clinical trial evidence to support their clinical use, there is no clear contraindication.

Background/Aims: We aimed to estimate the incidence and prevalence of amyotrophic lateral sclerosis (ALS) in the South East of England. The reported incidence of ALS varies between 0.44 and 3.2 per 100,000 person years. This can partly be explained by differences in design and diagnostic criteria used. There is little population data concerning England, particularly the South East. Methods: A population study of South-East England (total population: 2,890,482) was carried out and multiple sources including our tertiary centre and district general hospitals were used for complete case ascertainment. Results: Between 1 January 2002 and 30 June 2006 we identified 138 people (76 males; 62 females) with a new diagnosis of ALS, giving a crude incidence of 1.06 per 100,000 person years. The projected age- and gender-adjusted annual incidence rate for England and Wales was 1.10 (95% CI 0.80–1.40). 142 people were alive on 30 June 2006, giving a point prevalence of 4.91 per 100,000 population. Conclusion: Our incidence and prevalence rates are similar to those reported in comparable studies from other countries. This argues against the role of a specific exogenous factor in the aetiology of ALS in South-East England.

Sir, Recently, Bannwarth and colleagues reported that mutations in CHCHD10 were causative of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), with compelling segregation data and functional investigations well supporting these findings (Bannwarth et al. , 2014). In a number of follow-up studies, CHCHD10 was screened in ALS, FTD and other neurodegenerative disorder cohorts—including autosomal dominant mitochondrial myopathy and late-onset spinal motor neuronopathy—and novel putative disease-causing variants were identified (Chaussenot et al. , 2014; Johnson et al. , 2014; Muller et al. , 2014; Ajroud-Driss et al. , 2015; Chio et al. , 2015; Kurzwelly et al. , 2015; Penttila et al. , 2015; Ronchi et al. , 2015; Zhang et al. , 2015). In particular, one variant, the Pro34Ser in exon 2, was reported by three studies to be present in >1% of ALS and FTD cases in Caucasian populations (Chaussenot et al. , 2014; Chio et al. , 2015; Ronchi et al. , 2015). In the context of ALS, this is a remarkable finding and would make the CHCHD10 Pro34Ser variant …

OBJECTIVE: To test blood and CSF neurofilament light chain (NfL) levels in relation to disease progression and survival in amyotrophic lateral sclerosis (ALS). METHODS: Using an electrochemiluminescence immunoassay, NfL levels were measured in samples from 2 cohorts of patients with sporadic ALS and healthy controls, recruited in London (ALS/control, plasma: n = 103/42) and Oxford (ALS/control, serum: n = 64/36; paired CSF: n = 38/20). NfL levels in patients were measured at regular intervals for up to 3 years. Change in ALS Functional Rating Scale-Revised score was used to assess disease progression. Survival was evaluated using Cox regression and Kaplan-Meier analysis. RESULTS: CSF, serum, and plasma NfL discriminated patients with ALS from healthy controls with high sensitivity (97%, 89%, 90%, respectively) and specificity (95%, 75%, 71%, respectively). CSF NfL was highly correlated with serum levels (r = 0.78, p < 0.0001). Blood NfL levels were approximately 4 times as high in patients with ALS compared with controls in both cohorts, and maintained a relatively constant expression during follow-up. Blood NfL levels at recruitment were strong, independent predictors of survival. The highest tertile of blood NfL at baseline had a mortality hazard ratio of 3.91 (95% confidence interval 1.98-7.94, p < 0.001). CONCLUSION: Blood-derived NfL level is an easily accessible biomarker with prognostic value in ALS. The individually relatively stable levels longitudinally offer potential for NfL as a pharmacodynamic biomarker in future therapeutic trials. CLASSIFICATION OF EVIDENCE: This report provides Class III evidence that the NfL electrochemiluminescence immunoassay accurately distinguishes patients with sporadic ALS from healthy controls.

Facioscapulohumeral muscular dystrophy (FSHD) is an incurable disease, characterized by skeletal muscle weakness and wasting. Genetically, FSHD is characterized by contraction or hypomethylation of repeat D4Z4 units on chromosome 4, which causes aberrant expression of the transcription factor DUX4 from the last repeat. Many genes have been implicated in FSHD pathophysiology, but an integrated molecular model is currently lacking. We developed a novel differential network methodology, Interactome Sparsification and Rewiring ( InSpiRe ), which detects network rewiring between phenotypes by integrating gene expression data with known protein interactions. Using InSpiRe , we performed a meta-analysis of multiple microarray datasets from FSHD muscle biopsies, then removed secondary rewiring using non-FSHD datasets, to construct a unified network of rewired interactions. Our analysis identified β-catenin as the main coordinator of FSHD-associated protein interaction signalling, with pathways including canonical Wnt, HIF1-α and TNF-α clearly perturbed. To detect transcriptional changes directly elicited by DUX4 , gene expression profiling was performed using microarrays on murine myoblasts. This revealed that DUX4 significantly modified expression of the genes in our FSHD network. Furthermore, we experimentally confirmed that Wnt/β-catenin signalling is affected by DUX4 in murine myoblasts. Thus, we provide the first unified molecular map of FSHD signalling, capable of uncovering pathomechanisms and guiding therapeutic development.

There is evidence that in sporadic amyotrophic lateral sclerosis (ALS) immunological mechanisms may be involved in the pathophysiology of the disease. We tested whether purified IgG from ALS patients induce cell death in rat mixed primary spinal cord cultures and compared this with the effect of IgG purified from patients with Guillain-Barré syndrome (GBS) or from healthy donors. Treatment with ALS-IgG increases caspase-3 apoptosis when compared with control IgG or with GBS-IgG, but does not induce death by necrosis. Because ALS is characterized by the selective loss of motor neurones, we next assessed the differential effect of ALS-IgG on motor neurones or astrocytes. We showed, semiquantitatively, that motor neurones are more susceptible to apoptosis when cultures were treated with ALS-IgG compared with control-IgG. In conclusion, we have demonstrated in primary spinal cord cultures that IgG from patients with ALS induces apoptosis selectively in motor neurones, and that the caspase-3 pathway is involved. This suggests that immunological mechanisms may contribute to the selective loss of motor neurones in ALS.

It is generally believed that the maximum shortening velocity ( Vo) of a skeletal muscle fiber type does not vary unless a change in myosin heavy chain (MHC) isoform composition occurs. However, recent findings have shown that Voof a given fiber type can change after training, suggesting the hypothesis that the function of myosin can vary without a change in isoform. The present study addressed the latter hypothesis by studying the function of isolated myosin isoforms by the use of the in vitro motility assay (IVMA) technique. Four young (age 23–29 yr, YO) and four elderly men (age 68–82 yr, EL) underwent a 12-wk progressive resistance training program of the knee extensor muscles and to one pre- and one posttraining biopsy of the vastus lateralis muscle. The significant increase in one-repetition maximum posttraining in both YO and EL indicated that training was effective. After training, MHC isoform composition showed a shift from MHC2Xtoward MHC2Ain YO and no shift in EL. The velocity of sliding ( Vf) of actin filaments on pure myosin isoforms extracted from single fibers was studied in IVMA. One hundred sixty IVMA samples were prepared from 480 single fibers, and at least 50 filaments were analyzed in each experiment. Whereas no training-induced change was observed in Vfof myosin isoform 1 either in YO or in EL, a significant increase in Vfof myosin isoform 2A after training was observed in both YO (18%) and EL (19%). The results indicate that resistance training can change the velocity of the myosin molecule.

We investigated 185 families with ALS for evidence of anticipation and mitochondrial inheritance. Although initial analysis demonstrated significant anticipation of age at death between generations in patients with familial ALS, further analysis demonstrated features of regression to the mean, suggesting that the perceived differences are the result of bias. In addition, there was no evidence of an effect of preferential maternal inheritance, which would have supported transmission of mitochondrial DNA mutations.

Chronic inflammatory demyelinating polyneuropathy (CIPD) is characterised by progressive weakness, hyporeflexia and electrophysiological evidence of demyelination with maximal neurological deficit reached after at least 8 weeks progression. CIPD rarely affects children. We present a neonate with clinical features compatible with congenital CIPD. A term male infant of non-consanguineous parents was referred to us at birth with weakness and contractures affecting his legs, suggesting a prenatal onset of immobility. He also had evidence of bulbar dysfunction with poor suck, recurrent aspiration and requiring nasogastric feeding. He had no antigravity movements in the legs, bilateral wrist drop, distal joint contractures and absent deep tendon reflexes. Electromyography showed neurogenic changes, with nerve conduction velocities markedly reduced, increased distal motor latency and dispersed compound muscle action potentials. Cerebrospinal fluid protein was raised. Sural nerve biopsy demonstrated decreased numbers of myelinated fibres and inflammatory cell infiltrates. Muscle biopsy showed denervation. He only received supportive treatment and by 6 months he had fully recovered, and all electrophysiological parameters had normalised.

Classically, the course of Charcot-Marie-Tooth (CMT) disease is gradually progressive. We describe eight atypical patients who developed acute or subacute deterioration. Seven of these had genetically proven CMT disease type 1A (CMT1A) due to chromosome 17p11.2-12 duplication, and one had X-linked disease (CMTX) due to a mutation in the GJB1 gene. In this group there was sufficient clinical, electrophysiological and neuropathological information to indicate a diagnosis of a superimposed inflammatory polyneuropathy. The age range of the patients was 18-69 years, with a mean of 39 years. A family history of a similar neuropathic condition was present in only four patients. All eight had an acute or subacute deterioration following a long asymptomatic or stable period. Seven had neuropathic pain or prominent positive sensory symptoms. Nerve biopsy demonstrated excess lymphocytic infiltration in all eight patients. Five patients were treated with steroids and/or intravenous immunoglobulin, with variable positive response; three patients received no immunomodulatory treatment. Inflammatory neuropathy has previously been recognized in patients with hereditary neuropathy, with uncharacterized genetic defects and with CMT1B. We present detailed assessments of patients with CMT1A and CMTX, including nerve biopsy, and conclude that coexistent inflammatory neuropathy is not genotype-specific in hereditary motor and sensory neuropathy. Although this was not a formal epidemiological study, estimates of the prevalence of CMT disease and chronic inflammatory demyelinating polyneuropathy indicate that the association is more frequent than would be expected by chance. This has implications for understanding the pathogenesis of inflammatory neuropathies and raises important considerations in the management of patients with hereditary neuropathies. If a patient with CMT disease experiences an acute or subacute deterioration in clinical condition, treatment of a coexistent inflammatory neuropathy with steroids or immunoglobulin should be considered.

There are two known autosomal dominant genes for the hereditary ulcero-mutilating neuropathies: SPTLC1 (hereditary sensory neuropathy type 1) and RAB7 (Charcot-Marie-Tooth disease type 2B). We report a family with autosomal dominant ulcero-mutilating neuropathy, developing in the teens and characterized by ulcers, amputations, sensory involvement in the feet but no motor features. Sequencing the RAB7 gene showed a novel heterozygous A to C mutation, changing asparagine to threonine at codon 161. The mutation is situated adjacent to a previously identified valine to methionine mutation at codon 162, implying a hotspot for mutations in the highly conserved C terminus of RAB7.

The authors describe a patient with hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP) who has two compound heterozygote mutations of the PANK2 gene. IVS4–1 G>T segregates with the lipid and erythrocyte changes in the mother and sister. No other family members have the lipid, erythrocyte, or clinical abnormalities. The father and two brothers are heterozygous for Met327Thr. One other mutation has been found in this PANK2 region associated with the HARP phenotype, suggesting a local genotype effect.

Chronic inflammatory demyelinating polyneuropathy (CIDP) may cause significant disability, but severe respiratory complications are uncommon. We describe the case of a 49-year-old man with clinical features of CIDP for 5 years who died of respiratory failure. Post-mortem findings of denervation in diaphragm muscle and axonal loss in phrenic nerve are presented. Severe ventilatory failure may occur in CIDP when neuropathy affects the respiratory muscles. Attention to early clinical features of respiratory insufficiency may facilitate the prevention of more severe features of respiratory failure.

Motor neurone disease is a progressive neurodegenerative disorder leading to severe disability and death. It is clinically characterised by mixed upper and lower motor neurone involvement affecting bulbar, limb, and respiratory musculature. Recent guidelines have established diagnostic criteria and defined management of the condition. In a proportion of familial amyotrophic lateral sclerosis there is a mutation in the gene encoding the enzyme copper/zinc superoxide dismutase 1; this has allowed mutation screening and generated considerable laboratory based research. The diagnosis must be given with care and consideration and close follow up is essential. Management involves a multidisciplinary team based in the hospital and the community. Riluzole is the only drug shown to have a disease modifying effect and has been approved by the National Institute for Clinical Excellence. The essence of care is good symptomatic management, including nutritional support with percutaneous endoscopic gastrostomy and ventilatory care with non-invasive ventilation. Palliative care should be introduced before the terminal stages after careful discussion with the patient and carers. Knowledge of this condition has grown dramatically recently with a parallel improvement in treatment and ability to deal with the most troublesome problems.

Krabbe's disease (globoid cell leucodystrophy) is a disorder involving the white matter of the peripheral and central nervous systems. Mutations in the gene for the lysosomal enzyme galactocerebrosidase (GALC) result in low enzymatic activity and decreased ability to degrade galactolipids found in myelin. The disease is classically of infantile onset, but adult onset cases have been reported. Magnetic resonance imaging (MRI) of the brain shows characteristic abnormalities. A unique family with Krabbe's disease is described, with proven GALC deficiency but normal MRI. A neurological phenotype is present in heterozygotes and the family shows the extent of homozygotic phenotypic diversity that can be seen in this disorder.

We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474 ALS cases and 567 controls, and a Dutch dataset of 1328 ALS cases and 691 controls were analyzed. In addition, to increase power, we systematically searched PubMed for case-control studies published after 1 August 2010 that investigated the association between ATXN2 intermediate repeats and ALS. We conducted a meta-analysis of the new and existing studies for the relative risks of ATXN2 intermediate repeat alleles of between 24 and 34 CAG trinucleotide repeats and ALS. There was an overall increased risk of ALS for those carrying intermediate sized trinucleotide repeat alleles (odds ratio 3.06 [95% confidence interval 2.37-3.94]; p = 6 × 10(-18)), with an exponential relationship between repeat length and ALS risk for alleles of 29-32 repeats (R(2) = 0.91, p = 0.0002). No relationship was seen for repeat length and age of onset or survival. In contrast to trinucleotide repeat diseases, intermediate ATXN2 trinucleotide repeat expansion in ALS does not predict age of onset but does predict disease risk. publisher: Elsevier articletitle: ATXN2 trinucleotide repeat length correlates with risk of ALS journaltitle: Neurobiology of Aging articlelink: http://dx.doi.org/10.1016/j.neurobiolaging.2016.11.010 content_type: article copyright: © 2016 The Author(s). Published by Elsevier Inc. ispartof: Neurobiology of Aging vol:51 pages:178- ispartof: location:United States status: published

Summary Background Amyotrophic lateral sclerosis shares characteristics with some cancers, such as onset being more common in later life, progression usually being rapid, the disease affecting a particular cell type, and showing complex inheritance. We used a model originally applied to cancer epidemiology to investigate the hypothesis that amyotrophic lateral sclerosis is a multistep process. Methods We generated incidence data by age and sex from amyotrophic lateral sclerosis population registers in Ireland (registration dates 1995–2012), the Netherlands (2006–12), Italy (1995–2004), Scotland (1989–98), and England (2002–09), and calculated age and sex-adjusted incidences for each register. We regressed the log of age-specific incidence against the log of age with least squares regression. We did the analyses within each register, and also did a combined analysis, adjusting for register. Findings We identified 6274 cases of amyotrophic lateral sclerosis from a catchment population of about 34 million people. We noted a linear relationship between log incidence and log age in all five registers: England r 2 =0·95, Ireland r 2 =0·99, Italy r 2 =0·95, the Netherlands r 2 =0·99, and Scotland r 2 =0·97; overall r 2 =0·99. All five registers gave similar estimates of the linear slope ranging from 4·5 to 5·1, with overlapping confidence intervals. The combination of all five registers gave an overall slope of 4·8 (95% CI 4·5–5·0), with similar estimates for men (4·6, 4·3–4·9) and women (5·0, 4·5–5·5). Interpretation A linear relationship between the log incidence and log age of onset of amyotrophic lateral sclerosis is consistent with a multistage model of disease. The slope estimate suggests that amyotrophic lateral sclerosis is a six-step process. Identification of these steps could lead to preventive and therapeutic avenues. Funding UK Medical Research Council; UK Economic and Social Research Council; Ireland Health Research Board; The Netherlands Organisation for Health Research and Development (ZonMw); the Ministry of Health and Ministry of Education, University, and Research in Italy; the Motor Neurone Disease Association of England, Wales, and Northern Ireland; and the European Commission (Seventh Framework Programme).

Objective To investigate the role of longitudinal plasma neurofilament heavy chain protein (NfH) levels as an indicator of clinical progression and survival in amyotrophic lateral sclerosis (ALS). Methods A cross-sectional study involving 136 clinically heterogeneous patients with ALS and 104 healthy and neurological controls was extended to include a prospective analysis of 74 of these ALS cases, with samplings at approximately 3-month intervals in a follow-up period of up to 3 years. We analysed the correlation between longitudinal NfH-phosphoform levels and disease progression. Temporal patterns of NfH changes were evaluated using multilevel linear regression. Results Baseline plasma NfH levels were higher than controls only in patients with ALS with short disease duration to baseline sampling. Compared with controls, fast-progressing patients with ALS, particularly those with a short diagnostic latency and disease duration, had higher plasma NfH levels at an early stage and lower levels closer to end-stage disease. Lower NfH levels between visits were associated with rapid functional deterioration. We also detected antibodies against NfH, NfH aggregates and NfH cleavage products. Conclusions Disease progression in ALS involves defined trajectories of plasma NfH levels, reflecting speed of neurological decline and survival. Intervisit plasma NfH changes are also indicative of disease progression. This study confirms that longitudinal measurements of NfH plasma levels are more informative than cross-sectional studies, where the time of sampling may represent a bias in the interpretation of the results. Autoantibodies against NfH aggregates and NfH cleavage products may explain the variable expression of plasma NfH with disease progression. Trail registration number NIHRID6160.

UNLABELLED\ud \ud The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS); it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK) and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3∶1) to receive single dose intravenous ozanezumab (0.01, 0.1, 1, 5, or 15 mg/kg) or placebo. In Part 2, 36 subjects were randomized (3∶1) to receive two repeat doses of intravenous ozanezumab (0.5, 2.5, or 15 mg/kg) or placebo, approximately 4 weeks apart. The primary endpoints were safety and tolerability (adverse events [AEs], vital signs, electrocardiogram (ECG), and clinical laboratory tests). Secondary endpoints included PK, immunogenicity, functional endpoints (clinical and electrophysiological), and biomarker parameters. Overall, ozanezumab treatment (0.01-15 mg/kg) was well tolerated. The overall incidence of AEs in the repeat dose 2.5 mg/kg and 15 mg/kg ozanezumab groups was higher than in the repeat dose placebo group and repeat dose 0.5 mg/kg ozanezumab group. The majority were considered not related to study drug by the investigators. Six serious AEs were reported in three subjects receiving ozanezumab; none were considered related to study drug. No study drug-related patterns were identified for ECG, laboratory, or vital signs parameters. One subject (repeat dose 15 mg/kg ozanezumab) showed a weak, positive anti-ozanezumab-antibody result. PK results were generally consistent with monoclonal antibody treatments. No apparent treatment effects were observed for functional endpoints or muscle biomarkers. Immunohistochemical staining showed dose-dependent co-localization of ozanezumab with Nogo-A in skeletal muscle. In conclusion, single and repeat dose ozanezumab treatment was well tolerated and demonstrated co-localization at the site of action. These findings support future studies with ozanezumab in ALS.\ud \ud TRIAL REGISTRATION\ud \ud ClinicalTrials.gov NCT00875446 GSK-ClinicalStudyRegister.com GSK ID 111330.

Genetic mutations have been identified in the major motor neuron diseases, including ALS, spinal muscular atrophy, bulbospinal muscular atrophy (Kennedy's disease), the hereditary spastic paraplegias, and rarer conditions such as GM2 gangliosidosis (hexosaminidase A deficiency). These include mutations in the SOD1 gene, deletions of the telomeric copy of the SMN gene, expansions of the trinucleotide repeat region in the first exon of the androgen receptor gene, other rare mutations, and diseases where linkage has been established but the gene not identified. Identification of one of these genetic abnormalities will allow specific diagnosis in patients. Because cure is not yet available, presymptomatic testing is seldom indicated; in such cases, careful counseling is appropriate.

Background Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders that share significant clinical, pathological and genetic overlap and are considered to represent different ends of a common disease spectrum. Mutations in Profilin1 have recently been described as a rare cause of familial ALS. The PFN1 E117G missense variant has been described in familial and sporadic cases, and also found in controls, casting doubt on its pathogenicity. Interpretation of such variants represents a significant clinical-genetics challenge. Objective and results Here, we combine a screen of a new cohort of 383 ALS patients with multiple-sequence datasets to refine estimates of the ALS and FTD risk associated with PFN1 E117G. Together, our cohorts add up to 5118 ALS and FTD cases and 13 089 controls. We estimate a frequency of E117G of 0.11% in controls and 0.25% in cases. Estimated odds after population stratification is 2.44 (95% CI 1.048 to ∞ ,M antelHaenszel test p=0.036). Conclusions Our results show an association between E117G and ALS, with a moderate effect size.