Could PLS represent a UMN-predominant ALS syndrome?

Primary lateral sclerosis (PLS) is a motor neuron condition marked by pure upper motor neuron (UMN) degeneration. PLS represents around 3% of all motor neuron diseases. Classically the prognosis of PLS is less severe than those of amyotrophic lateral sclerosis (ALS). This explains the necessity to distinguish both conditions as early as possible. The key hallmark between the two diseases is the involvement of the lower motor neuron (LMN) system which is classically considered spared in PLS contrary to ALS. Although it seemed clinically easy to distinguish PLS from ALS with the aid of clinical and complementary examinations, there is a large body of evidence highlighting that the LMN system might be impaired in PLS. This led us to suggest that PLS might be considered as an almost pure UMN ALS phenotype.

C9ORF72 hexanucleotide repeat expansion: From ALS and FTD to a broader pathogenic role?

The major gene underlying monogenic forms of amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) is C9ORF72. The causative mutation in C9ORF72 is an abnormal hexanucleotide (G4C2) repeat expansion (HRE) located in the first intron of the gene. The aim of this review is to propose a comprehensive update on recent developments on clinical, biological and therapeutics aspects related to C9ORF72 in order to highlight the current understanding of genotype-phenotype correlations, and also on biological machinery leading to neuronal death. We will particularly focus on the broad phenotypic presentation of C9ORF72-related diseases, that goes well beyond the classical phenotypes observed in ALS and FTD patients. Last, we will comment the possible therapeutical hopes for patients carrying a C9ORF72 HRE.

French National Protocol for genetic of amyotrophic lateral sclerosis.

Relationships between genes and amyotrophic lateral sclerosis (ALS) have been widely accepted since the first studies highlighting pathogenic mutations in the SOD1 gene 30years ago. Over the last three decades, scientific literature has clearly highlighted the central role played by genetic factors in the disease, in both clinics and pathophysiology, as well as in therapeutics. This implies that health professionals who care for patients with ALS are increasingly faced with patients and relatives eager to have answers to questions related to the role of genetic factors in the occurrence of the disease and the risk for their relatives to develop ALS. In order to address these public health issues, the French ALS network FILSLAN proposed to the Haute Autorité de santé (HAS) the drafting of a French National Protocol (PNDS) on ALS genetics. This PNDS was developed according to the "method for developing a national diagnosis and care protocol for rare diseases" published by the HAS in 2012 (methodological guide for PNDS available on the HAS website: http://www.has-sante.fr/). This document aims to provide the most recent data on the role of genes in ALS and to detail the implications for diagnosis and care.

Treatment of hereditary amyotrophic lateral sclerosis.

Currently, only four molecules can be prescribed for amyotrophic lateral sclerosis (ALS), of which only one is approved worldwide for this indication, riluzole. Although progress in the therapeutic field remains unsatisfactory, we have to notice that genetics have undergone impressive improvements over the last three decades and, by extension, our knowledge of ALS cases linked to a pathogenic mutation that accounts for 10% of all cases (either sporadic or familiar) and is currently called hereditary ALS (hALS). In many neurological diseases treatment targeting pathogenic genes have significatively improved the natural profile of the disease: this is perfectly illustrated for familial amyloid neuropathy and spinal muscular atrophy. Because of these findings and the urgent need to find a cure for ALS, many trials have focused on familial ALS targeting the four most important genes linked to the disease: C9orf72, SOD1, TARDBP and FUS. We propose in this review an update on the perspectives of treatment that may be available in mid-term in hALS and will discuss in the last part the potential consequences for asymptomatic relatives of patients with a hALS and for ALS patients.

Primary Lateral Sclerosis: Clinical, radiological and molecular features.

Primary Lateral Sclerosis (PLS) is an uncommon motor neuron disorder. Despite the well-recognisable constellation of clinical manifestations, the initial diagnosis can be challenging and therapeutic options are currently limited. There have been no recent clinical trials of disease-modifying therapies dedicated to this patient cohort and awareness of recent research developments is limited. The recent consensus diagnostic criteria introduced the category 'probable' PLS which is likely to curtail the diagnostic journey of patients. Extra-motor clinical manifestations are increasingly recognised, challenging the view of PLS as a 'pure' upper motor neuron condition. The post mortem literature of PLS has been expanded by seminal TDP-43 reports and recent PLS studies increasingly avail of meticulous genetic profiling. Research in PLS has gained unprecedented momentum in recent years generating novel academic insights, which may have important clinical ramifications.

Phenotypic variability in amyotrophic lateral sclerosis.

Clinically, ALS phenotypes depend on the areas of the body that are affected, the different degrees of involvement of upper and lower motor neurons, the degrees of involvement of other systems, particularly cognition and behavior, and rates of progression. Phenotypic variability of ALS is characteristic and can be declined on the distribution of motor manifestations but also on the presence of extra-motor signs present in a variable manner in ALS patients. Neuropathologically, ALS is defined by the loss of UMN and LMN and the presence of two representative motor neuronal cytoplasmic inclusions, Bunina bodies and 43kDa Transactivation Response DNA Binding Protein (TDP-43) - positive cytoplasmic inclusions. The distribution of cytopathology and neuronal loss in patients is variable and this variability is directly related to phenotypic variability. Key regulators of phenotypic variability in ALS have not been determined. The functional decrement of TDP-43, and region-specific neuronal susceptibility to ALS, may be involved. Due to the selective vulnerability among different neuronal systems, lesions are multicentric, region-oriented, and progress at different rates. They may vary from patient to patient, which may be linked to the clinicopathological variability across patients.

Therapeutic news in ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by death of motor neurons in the cortex and the spinal cord. This loss of motor neurons causes progressive weakness and amyotrophy. To date, the median duration of survival in patients with ALS, from first symptoms to death, is estimated to be 36 months. Currently the treatment is limited to two options: riluzole which prolongs survival for a few months and edaravone which is available in only a few countries and also has a small impact on disease progression. There is an urgent need for more effective drugs in this disease to significantly improve progression. Over the last 30 years, all trials have failed to find a curative drug for ALS. This is due, partially, to the heterogeneity of the clinical features and the pathophysiology of motor neuron death. We present in this review the various treatment options currently being developed for ALS, with an emphasis on the range of therapeutic approaches being explored, from old drugs tested in a new indication to innovative drugs obtained via biotechnology or gene therapy.

Behavioral, Hormonal, Inflammatory, and Metabolic Effects Associated with FGF21-Pathway Activation in an ALS Mouse Model.

In amyotrophic lateral sclerosis (ALS), motor neuron degeneration occurs simultaneously with systemic metabolic dysfunction and neuro-inflammation. The fibroblast growth factor 21 (FGF21) plays an important role in the regulation of both phenomena and is a major hormone of energetic homeostasis. In this study, we aimed to determine the relevance of FGF21 pathway stimulation in a male mouse model of ALS (mutated SOD1-G93A mice) by using a pharmacological agonist of FGF21, R1Mab1. Mice (SOD1-WT and mutant SOD1-G93A) were treated with R1Mab1 or vehicle. Longitudinal data about clinical status (motor function, body weight) and biological parameters (including hormonal, immunological, and metabolomics profiles) were collected from the first symptoms to euthanasia at week 20. Multivariate models were performed to identify the main parameters associated with R1Mab1 treatment and to link them with clinical status, and metabolic pathways involving the discriminant metabolites were also determined. A beneficial clinical effect of R1Mab1 was revealed on slow rotarod (p = 0.032), despite a significant decrease in body weight of ALS mice (p < 0.001). We observed a decrease in serum TNF-α, MCP-1, and insulin levels (p = 0.0059, p = 0.003, and p = 0.01, respectively). At 16 weeks, metabolomics analyses revealed a clear discrimination (CV-ANOVA = 0.0086) according to the treatment and the most discriminant pathways, including sphingolipid metabolism, butanoate metabolism, pantothenate and CoA biosynthesis, and the metabolism of amino acids like tyrosine, arginine, proline, glycine, serine, alanine, aspartate, and glutamate. Mice treated with R1Mab1 had mildly higher performance on slow rotarod despite a decrease on body weight and could be linked with the anti-inflammatory effect of R1Mab1. These results indicate that FGF21 pathway is an interesting target in ALS, with a slight improvement in motor function combined with metabolic and anti-inflammatory effects.

Advances in disease-modifying pharmacotherapies for the treatment of amyotrophic lateral sclerosis.

INTRODUCTION: To date, riluzole and edaravone are the only two drugs that have successfully passed clinical trials for the treatment of Amyotrophic Lateral Sclerosis (ALS). Unfortunately, both drugs exhibit very modest effects. Most other drugs have failed at phase III to show significant effects in phase III when tested in larger cohorts. This pattern necessitates improvements in the approach to ALS pharmacotherapy. AREAS COVERED: The authors discuss the two approved drugs, as well as several examples of drug candidates whose clinical trials did not demonstrate efficacy in phase III. Post-hoc analyses reveal that future clinical trials should include disease-staging procedures, longer-term trials to correctly assess survival, genetic studies of participants to aid in stratification, and more similarity between the protocols on preclinical models and clinical trials. Finally, they discuss the trials in process that demonstrate some of these suggestions and improvements. EXPERT OPINION: The approval of riluzole and edaravone was essentially a desperate attempt to provide urgent pharmacotherapy to the ALS community. To evolve toward more efficient therapies, we must conduct clinical trials with optimal stratification based on rapid/slow progressors and cognitive decline. Pharmaco-metabolomics should allow for the identification of biomarkers that are adapted for a given drug.

Pre-symptomatic diagnosis in ALS.

Pathophysiology of amyotrophic lateral sclerosis (ALS) remains partially understood even though it is accepted worldwide that motor neuron death results from a pluri-factorial process with a variable role of genetic factors. Although not distinguishable from a clinical point of view, familial forms of ALS (fALS, 10% of cases) and sporadic forms (sALS, 90% of cases) can be described. Since the identification of superoxide dismutase 1 gene (SOD1) mutations, more than 30 genes have been linked to fALS. Among these genes, five (C9ORF72, SOD1, TARDBP, FUS, TBK1) seem predominant with mutation frequencies of 40%, 20%, 5%, <5%, <5% in fALS and 6%, 3%, and <1% for the last three in sALS, respectively. The situation that classically leads to request genetic screening is the presence of a familial history of motor neuron disorders (MND) or fronto-temporal lobar dementia (FTLD). However, this dichotomy between fALS and sALS based on familial history can lead to mistakes since illegitimacy, ignorance of MND, FTD or psychiatric disorders within the family due to a familial censorship or lack of familial relationship, or a recessive autosomal inheritance could wrongly lead to failing to recognize a familial form. The significant development of genetic research and easier access to genetic tests in fALS increase the number of situations for which gene mutations are identified. The consequence is an increase in genetic requests from relatives of ALS patients who are eager to know their own genetic status and their own individual risk to develop ALS. Pre-symptomatic testing is thus becoming a daily issue in ALS Centers. This led us to propose a framework for such pre-symptomatic genetic testing for people at risk for developing ALS.

Antibody- and macrophage-mediated segmental demyelination in chronic inflammatory demyelinating polyneuropathy: clinical, electrophysiological, immunological and pathological correlates.

BACKGROUND AND PURPOSE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous autoimmune disorder critically lacking diagnostic biomarkers. Autoantibodies to nodal and paranodal components have recently been described in a small subset of patients. Here, the diagnostic value of immune reactivity toward the myelin compartment was investigated. METHODS: Ninety-four French CIDP patients were retrospectively studied. The reactivity toward the peripheral nerve was investigated. Sural nerve biopsies were examined by electron microscopy and immunofluorescence. RESULTS: Twenty-one patients (22%) and three patients (3%) presented with a strong immunoglobulin G or immunoglobulin M reactivity respectively against the myelin compartment. The clinical, electrophysiological and morphological features were examined in nine of these patients for whom sural nerve biopsies were available. Seven patients were electrodiagnosed with definite CIDP, one with possible CIDP and one was unclassifiable but sural nerve biopsy argued for CIDP diagnosis. Electron microscopy of sural nerve biopsies demonstrated the presence of macrophage-mediated demyelination restricted to the internode in all nine patients. Immunolabelling for voltage-gated sodium channels, myelin and axonal markers confirmed the presence of segmental demyelination and of remyelination. The nodal and paranodal regions, however, were unaffected in these patients. Nerve conduction studies corroborated the multifocal and segmental profile, and seven patients showed increased duration of proximal (1.5-5.1 times) and/or distal (1.2-3.4 times) compound muscle action potential in at least two nerves. CONCLUSION: Antibody- and macrophage-mediated demyelination appears responsible for conduction alterations in CIDP patients and nerve immunostaining assays may serve as a supportive diagnostic biomarker.

Typical bulbar ALS can be linked to GARS mutation.

Background: Amyotrophic lateral sclerosis is the most frequent motor neuron disorders (MND) in adults. The role of genetic factors is worldwide accepted, and currently, more than 30 genes have been linked to this disease. Genetics was also the matter of numerous studies in distal hereditary motor neuropathies (dHMN). GARS is classically linked to a predominant dHMN and, until now, no mutation has been described in GARS in other MND. Case Report: We report the case of a 70-year-old woman who developed a classical bulbar ALS phenotype. Owing to his familial history of ALS, a genetic screening was performed excluding the main genes linked to ALS and revealing a heterozygous missense mutation in GARS gene with a high probability of pathogenicity. Conclusion: This first description of mutation in GARS in ALS, extends once more the genetic overlap between ALS and other MND.

Staging amyotrophic lateral sclerosis: A new focus on progression.

Amyotrophic lateral sclerosis (ALS) is a heterogenous motoneuronal neurodegenerative condition with a panel of phenotypes exhibiting different clinical patterns. Two compounds are currently available for the treatment of ALS but the majority of trials have failed to show a positive effect on prognosis. One of the explanations which could be put forward involves the way efficacy is evaluated: clinicians agree that the ALSFRS-revised scale used in all trials does not fit with highlighting a positive effect. So, the development and validation of new tools allowing a reliable assessment of ALS has become a key issue in clinical research. Over the last three years, two functional scales (the King's College and MiToS staging systems) have been proposed. These scales rely on two different approaches to ALS: an anatomical and prognostic concept, and loss of autonomy. Both scales propose five stages. We will discuss below the contribution of these two scales to clinical evaluation and the questions which remain to be resolved in the future.

Age-dependent neurodegeneration and organelle transport deficiencies in mutant TDP43 patient-derived neurons are independent of TDP43 aggregation.

TAR DNA-binding protein 43 (TDP43) plays a significant role in familiar and sporadic amyotrophic lateral sclerosis (ALS). The diverse postulated mechanisms by which TDP43 mutations cause the disease are not fully understood. Human wildtype and TDP43 S393L and G294V mutant spinal motor neuron cultures were differentiated from patient-derived iPSCs. Mutant hTDP43 and wildtype motor neuron cultures did not differ in neuron differentiation capacity during early maturation stage. During aging we detected a dramatic neurodegeneration including neuron loss and pathological neurofilament abnormalities only in TDP43 mutant cultures. Additionally mitochondria and lysosomes of aging spinal motor neurons revealed robust TDP43 mutation dependent abnormal phenotypes in size, shape, speed and motility which all appeared without TDP43 mislocalization or aggregation formation. Furthermore, D-sorbitol - known to induce stress granules and cytoplasmic mislocalization of TDP43 - rescued axonal trafficking phenotypes without signs of TDP43 mislocalization or aggregation formation. Our data indicate TDP43 mutation-dependent but cytosolic aggregation-independent mechanisms of motor neuron degeneration in TDP43 ALS.