Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of the motor pathways, invariably leading to death within a few years of onset. Most cases of ALS are sporadic, but familial forms ...of the disease (FALS) constitute 10% of the cases. Since the first identification of a causative gene in the 1990s and with recent advances in genetics, more than twenty genes have now been linked to FALS. This increased number of genes led to a tremendous amount of research, clearly contributed to a better understanding of the pathophysiology of this disorder, and paved the way for the development of new therapeutics and new hope for this fatal disease.
•Familial amyotrophic lateral sclerosis (FALS) represents <10% of the total ALS patients.•FALS are mainly due to the mutations of four genes: C9ORF72, SOD1, FUS and TDP-43.•The increased number of genes has clearly contributed to a better understanding of the pathophysiology of ALS.•This increased number of genes also risk to led to difficulties to their classification.•Gene therapy is probably a therapeutic way to explore in ALS.
To explore the link between bioenergetics and motor neuron degeneration, we used a computational model in which detailed morphology and ion conductance are paired with intracellular ATP production ...and consumption. We found that reduced ATP availability increases the metabolic cost of a single action potential and disrupts K+/Na+ homeostasis, resulting in a chronic depolarization. The magnitude of the ATP shortage at which this ionic instability occurs depends on the morphology and intrinsic conductance characteristic of the neuron. If ATP shortage is confined to the distal part of the axon, the ensuing local ionic instability eventually spreads to the whole neuron and involves fasciculation-like spiking events. A shortage of ATP also causes a rise in intracellular calcium. Our modeling work supports the notion that mitochondrial dysfunction can account for salient features of the paralytic disorder amyotrophic lateral sclerosis, including motor neuron hyperexcitability, fasciculation, and differential vulnerability of motor neuron subpopulations.
•Comprehensive computational model of motor neuron•Model representation of vulnerable and resistant motor neurons to ALS•Shortage in ATP causes deadly alterations in both Na+/K+ and Ca++ homeostasis•Localized ATP deficit triggers ion dyshomeostasis and fasciculation-like spikes
Results from a computational model by Le Masson et al. suggest that ATP deficits can cause potentially deadly ion disregulation, particularly in ALS-vulnerable motor neurons. Modest bioenergetics defects in the model account for a number of salient features of this paralytic disorder.
Following infection of the central nervous system (CNS), the immune system is faced with the challenge of eliminating the pathogen without causing significant damage to neurons, which have limited ...capacities of renewal. In particular, it was thought that neurons were protected from direct attack by cytotoxic T lymphocytes (CTL) because they do not express major histocompatibility class I (MHC I) molecules, at least at steady state. To date, most of our current knowledge on the specifics of neuron-CTL interaction is based on studies artificially inducing MHC I expression on neurons, loading them with exogenous peptide and applying CTL clones or lines often differentiated in culture. Thus, much remains to be uncovered regarding the modalities of the interaction between infected neurons and antiviral CD8 T cells in the course of a natural disease. Here, we used the model of neuroinflammation caused by neurotropic Borna disease virus (BDV), in which virus-specific CTL have been demonstrated as the main immune effectors triggering disease. We tested the pathogenic properties of brain-isolated CD8 T cells against pure neuronal cultures infected with BDV. We observed that BDV infection of cortical neurons triggered a significant up regulation of MHC I molecules, rendering them susceptible to recognition by antiviral CTL, freshly isolated from the brains of acutely infected rats. Using real-time imaging, we analyzed the spatio-temporal relationships between neurons and CTL. Brain-isolated CTL exhibited a reduced mobility and established stable contacts with BDV-infected neurons, in an antigen- and MHC-dependent manner. This interaction induced rapid morphological changes of the neurons, without immediate killing or impairment of electrical activity. Early signs of neuronal apoptosis were detected only hours after this initial contact. Thus, our results show that infected neurons can be recognized efficiently by brain-isolated antiviral CD8 T cells and uncover the unusual modalities of CTL-induced neuronal damage.
The ataxic neuropathies Mathis, Stéphane; Duval, Fanny; Soulages, Antoine ...
Journal of neurology,
10/2021, Volume:
268, Issue:
10
Journal Article
Peer reviewed
Ataxia is a frequent symptom in neurological cases with many causes. Sensory ataxia (due to involvement of the proprioceptive pathways) is observed in conditions affecting the central nervous system ...(spinal cord disorder) and the peripheral nervous system (peripheral neuropathy). The latter correspond to what we refer to as ‘ataxic neuropathies’. Ataxic neuropathies represent a wide and heterogeneous spectrum of disorders that may affect dorsal root nerves, dorsal root ganglia, nerve trunks, distal nerve endings or all of them together. The identification of a predominant sensory ataxia in a case of peripheral neuropathy should raise the possibility of some specific etiologies. We propose here to present the main causes of ataxic neuropathies, which are identified with diagnostic workflows that are dictated by the topography of the likely sites of lesions in the proprioceptive pathway together with the timing of their occurrence (acute, subacute, or chronic).
Peripheral neuropathies have various causes, both infectious and non-infectious. When we think of “epidemics”, we often refer to an infectious or even post-infectious origin. Nevertheless, the ...history of mankind is marked by episodes of epidemics of peripheral neuropathies of non-infectious nature, either of nutritional or toxic origin: we present here the main causes of such epidemics.
The history of mankind is marked by numerous epidemics, some of which involved diseases of the peripheral nervous system, either infectious or otherwise. We describe here the three main infectious ...causes of epidemics that affect the peripheral nervous system: leprosy, poliomyelitis and diphtheria. We then discuss the main epidemics of immune-mediated origin.
Amyotrophic lateral sclerosis (ALS) is a fatal motor disease in adults. Its pathophysiology remains mysterious, but tremendous advances have been made with the discovery of the most frequent ...mutations of its more common familial form linked to the
gene. Although most cases are still considered sporadic, these genetic mutations have revealed the role of RNA production, processing and transport in ALS, and may be important players in all ALS forms. There are no disease-modifying treatments for adult human neurodegenerative diseases, including ALS. As in spinal muscular atrophy, RNA-targeted therapies have been proposed as potential strategies for treating this neurodegenerative disorder. Successes achieved in various animal models of ALS have proven that RNA therapies are both safe and effective. With careful consideration of the applicability of such therapies in humans, it is possible to anticipate ongoing in vivo research and clinical trial development of RNA therapies for treating ALS.
Background
Anti-MAG polyneuropathy (anti-MAG PN) is an immune-mediated peripheral sensorimotor neuropathy characterized by distal demyelination and ataxia. However, this disorder, unlike other ...immune-mediated neuropathies, is difficult to treat in most cases.
Method
We retrospectively collected all anti-MAG PN patients followed in two hospitals for a period of 12 years to determine prognostic factors, especially those that indicated a good response to the various therapeutic strategies used.
Results
Forty-seven patients were included in the study; of these, 61% had a classical ‘distal demyelinating pattern’, 34.2% had a ‘CIDP-like pattern’, and the others had an ‘axonal pattern’. The most commonly used treatments were intravenous immunoglobulin (IVIg) as the first-line treatment and rituximab as the second- or third-line treatment. No prognostic factor was identified for IVIg, but electrophysiological parameters at onset were better in patients with a good response to rituximab than in non-responder patients, even though mild or high disability was observed in nearly half the patients at last examination.
Conclusion
Even though disability seems to progress in most cases despite the treatments used, our results suggest that an early electrophysiological reduction in sensory nerves could be considered a ‘red flag’ for the prompt initiation of rituximab to try to delay long-term disability.
Noninvasive ventilation (NIV) improves survival and quality of life in amyotrophic lateral sclerosis (ALS) patients. NIV initiation is mostly conducted at hospital, but a recurrent lack of hospital ...beds led to the necessity of exploring an at-home initiation process. Here, we report data from our NIV initiation cohort of ALS patients. Could our at-home NIV initiation process with telemonitoring in ALS patients be an efficient solution for adherence and nocturnal hypoxaemia correction?
We performed a retrospective analysis of data collected from 265 ALS patients treated at the Bordeaux ALS Centre for whom NIV initiation was carried out between September 2017 and June 2021, with two modalities: at-home initiation or in-hospital initiation. The primary outcome was adherence to NIV at 30 days. The secondary outcome was at-home NIV initiation process efficiency of nocturnal hypoxaemia correction.
At 30 days, NIV adherence (mean >4 h·day
) was 66% of the total population, 70% of the at-home NIV initiation subgroup and 52% of the in-hospital NIV initiation subgroup. Nocturnal hypoxaemia correction was observed in 79% of adherent patients in the at-home NIV initiation subgroup. Mean delay of NIV prescription and at-home NIV initiation was 8.7 days (+/-6.5)
29.5 days in hospital.
Our study shows that our at-home NIV initiation process in ALS patients is a good option to provide rapid access to NIV with good adherence and efficiency. Further literature on the benefits of at-home NIV initiation is welcomed, especially to evaluate long-term efficiency and global cost analysis.
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