Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

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

Motor neuron disease: Focusing the mind on ALS: updated practice parameters

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease and often known as Lou Gehrig disease in the US, is a devastating disease characterized by the progressive degeneration of motor neurons, which leads to an inability to control voluntary movement. The American Academy of Neurology (AAN) published the first comprehensive evidence-based guidelines on the management of ALS in 199

Motor neuron disease: Focusing the mind on ALS: updated practice parameters

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease and often known as Lou Gehrig disease in the US, is a devastating disease characterized by the progressive degeneration of motor neurons, which leads to an inability to control voluntary movement. The American Academy of Neurology (AAN) published the first comprehensive evidence-based guidelines on the management of ALS in 199

Predictors of survival in progressive supranuclear palsy and multiple system atrophy: a systematic review and meta-analysis

Objective To undertake a systematic review and meta-analysis of studies that investigated prognostic factors and survival in patients with progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). Methods Publications of at least 10 patients with a likely or confirmed diagnosis of PSP or MSA were eligible for inclusion. Methodological quality was rated using a modified version of the Quality in Prognostic Studies tool. For frequently examined prognostic factors, HRs derived by univariate and multivariate analysis were pooled in separate subgroups; other results were synthesised narratively and HRs could not be reported here. Results Thirty-seven studies presenting findings on 6193 patients (1911 PSP, 4282 MSA) fulfilled the inclusion criteria. We identified the following variables as unfavourable predictors of survival. In PSP, PSP-Richardson’s phenotype (univariate HR 2.53; 95% CI 1.69 to 3.78), early dysphagia and early cognitive symptoms. In MSA, severe dysautonomia and early development of combined autonomic and motor features but not MSA phenotype (multivariate HR 1.22; 95% CI 0.83 to 1.80). In PSP and MSA, survival was predicted by early falls (multivariate HR 2.32; 95% CI 1.94 to 2.77), the Neuroprotection and Natural History in Parkinson Plus Syndromes Parkinson Plus Score and the Clinical Global Impression Disease Severity Score but not sex (multivariate HR 0.93; 95% CI 0.67 to 1.28). There was conflicting evidence regarding the prognostic effect of age at onset and stridor. Conclusion Several clinical variables were strongly associated with shorter survival in PSP and MSA. Results on most prognostic factors were consistent across methodologically diverse studies; however, the lack of commonality of prognostic factors investigated is a significant limitation

Emerging magnetic resonance imaging techniques and analysis methods in amyotrophic lateral sclerosis

Objective markers of disease sensitive to the clinical activity, symptomatic progression, and underlying substrates of neurodegeneration are highly coveted in amyotrophic lateral sclerosis in order to more eloquently stratify the highly heterogeneous phenotype and facilitate the discovery of effective disease modifying treatments for patients. Magnetic resonance imaging (MRI) is a promising, non-invasive biomarker candidate whose acquisition techniques and analysis methods are undergoing constant evolution in the pursuit of parameters which more closely represent biologically-applicable tissue changes. Neurite Orientation Dispersion and Density Imaging (NODDI; a form of diffusion imaging), and quantitative Magnetization Transfer Imaging (qMTi) are two such emerging modalities which have each broadened the understanding of other neurological disorders and have the potential to provide new insights into structural alterations initiated by the disease process in ALS. Furthermore, novel neuroimaging data analysis approaches such as Event-Based Modeling (EBM) may be able to circumvent the requirement for longitudinal scanning as a means to comprehend the dynamic stages of neurodegeneration . Combining these and other innovative imaging protocols with more sophisticated techniques to analyse ever-increasing datasets holds the exciting prospect of transforming understanding of the biological processes and temporal evolution of the ALS syndrome, and can only benefit from multicentre collaboration across the entire ALS research community

Predictors of survival in progressive supranuclear palsy and multiple system atrophy: a systematic review and meta-analysis.

OBJECTIVE To undertake a systematic review and meta-analysis of studies that investigated prognostic factors and survival in patients with progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). METHODS Publications of at least 10 patients with a likely or confirmed diagnosis of PSP or MSA were eligible for inclusion. Methodological quality was rated using a modified version of the Quality in Prognostic Studies tool. For frequently examined prognostic factors, HRs derived by univariate and multivariate analysis were pooled in separate subgroups; other results were synthesised narratively and HRs could not be reported here. RESULTS Thirty-seven studies presenting findings on 6193 patients (1911 PSP, 4282 MSA) fulfilled the inclusion criteria. We identified the following variables as unfavourable predictors of survival. In PSP, PSP-Richardson's phenotype (univariate HR 2.53; 95% CI 1.69 to 3.78), early dysphagia and early cognitive symptoms. In MSA, severe dysautonomia and early development of combined autonomic and motor features but not MSA phenotype (multivariate HR 1.22; 95% CI 0.83 to 1.80).In PSP and MSA, survival was predicted by early falls (multivariate HR 2.32; 95% CI 1.94 to 2.77), the Neuroprotection and Natural History in Parkinson Plus Syndromes Parkinson Plus Score and the Clinical Global Impression Disease Severity Score but not sex (multivariate HR 0.93; 95% CI 0.67 to 1.28). There was conflicting evidence regarding the prognostic effect of age at onset and stridor. CONCLUSION Several clinical variables were strongly associated with shorter survival in PSP and MSA. Results on most prognostic factors were consistent across methodologically diverse studies; however, the lack of commonality of prognostic factors investigated is a significant limitation

An overview of microRNAs as biomarkers of ALS

Amyotrophic lateral sclerosis (ALS; MND, motor neuron disease) is a debilitating neurodegenerative disease affecting 4.5 per 100,000 people per year around the world. There is currently no cure for this disease, and its causes are relatively unknown. Diagnosis is based on a battery of clinical tests up to a year after symptom onset, with no robust markers of diagnosis or disease progression currently identified. A major thrust of current research is to identify potential non-invasive markers (“biomarkers”) in body fluids such as blood and/or cerebrospinal fluid (CSF) to use for diagnostic or prognostic purposes. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), are found at detectable and stable levels in blood and other bodily fluids. Specific ncRNAs can vary in levels between ALS patients and non-ALS controls without the disease. In this review, we will provide an overview of early findings, demonstrate the potential of this new class as biomarkers, and discuss future challenges and opportunities taking this forward to help patients with ALS

Corrigendum: an overview of MicroRNAs as biomarkers of ALS

A Corrigendum on An Overview of MicroRNAs as Biomarkers of ALS by Joilin, G., Leigh, P. N., Newbury, S. F., and Hafezparast, M. (2019). Front. Neurol. 10:186. doi: 10.3389/fneur.2019.00186 In the original article, there was a mistake in Table 1 as published. Some of the miRNAs listed in the table were incorrectly placed in the wrong column and/or row. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated

Late-onset Tay-Sachs disease

We discuss the assessment and differential diagnoses of a young adult Hungarian man with a 1-year history of a progressive and symmetric amyotrophic lateral sclerosis-like syndrome, along with irregular action tremor and stimulus-sensitive myoclonus of the arms. MR scan of the brain showed isolated cerebellar atrophy and formal neuropsychometric testing identified significant subclinical deficits in attention, processing speed and memory. We suspected a form of GM2 gangliosidosis, and white cell enzyme analysis showed markedly reduced enzymatic activity of ß-hexosaminidase A. Genetic testing subsequently revealed two heterozygous pathogenic mutations in the HEXA gene (c.1499delT p.(Leu500fs) and c.805G>A p.(Gly269Ser)), confirming the very rare diagnosis of adult-onset Tay-Sachs disease

Analysis of terms used for the diagnosis and classification of amyotrophic lateral sclerosis and motor neuron disease

There is no test for amyotrophic lateral sclerosis (ALS) and so attempts have been made to produce standardized diagnostic criteria based on clinical and electrophysiological findings, e.g. El Escorial. However, the phenotypic classification of the subtypes of ALS is also based on clinical features leading to conflation of diagnosis and phenotype. We used a five-question online survey with ALS specialists to explore the range of descriptors and how they are used. Of 101 specialists approached, 72 completed the survey. The most frequently used labels were ‘ALS’, ‘PLS’ and ‘familial’. Labels other than the El Escorial categories were mainly used as clinical descriptors (83%). Approximately 50% of respondents recorded that the El Escorial criteria had no useful role in patient discussion or in the diagnostic process. Only 31% of respondents rated their current classification system above the median for being logical. A more rational system explicitly distinguishing diagnostic and phenotypic criteria is essentia