Current Concepts on Genetic Aspects of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS), neurodegenerative motor neuron disorder is characterized as multisystem disease with important contribution of genetic factors. The etiopahogenesis of ALS is not fully elucidate, but the dominant theory at present relates to RNA processing, as well as protein aggregation and miss-folding, oxidative stress, glutamate excitotoxicity, inflammation and epigenetic dysregulation. Additionally, as mitochondria plays a leading role in cellular homeostasis maintenance, a rising amount of evidence indicates mitochondrial dysfunction as a substantial contributor to disease onset and progression. The aim of this review is to summarize most relevant findings that link genetic factors in ALS pathogenesis with different mechanisms with mitochondrial involvement (respiratory chain, OXPHOS control, calcium buffering, axonal transport, inflammation, mitophagy, etc.). We highlight the importance of a widening perspective for better understanding overlapping pathophysiological pathways in ALS and neurodegeneration in general. Finally, current and potentially novel therapies, especially gene specific therapies, targeting mitochondrial dysfunction are discussed briefly.

Wide range of reduced penetrance alleles in spinal and bulbar muscular atrophy: a model-based approach

BackgroundSpinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s disease, is an X-linked motor neuron disorder caused by an expanded CAG repeat in the gene coding for the androgen receptor (AR). The range and significance of reduced penetrance alleles in SBMA has not been fully determined to date. We presently sought to determine the range of reduced penetrance alleles in SBMA.MethodsThrough systematic literature review and meta-analysis, we collected and analysed data from 2576 patients with SBMA and compared the distributions of the CAG repeat number (CAG)n in the AR gene between patients and 112 248 control alleles of the general population.ResultsOur analysis revealed an unexpectedly high frequency of expanded SBMA-associated alleles, with (CAG)n ≥35 present in 107/100,000 and (CAG)n ≥38 present in 27/100,000 of the general population. Consequently, we suggest an updated model describing the distribution of expanded alleles in the general population. We argue against the established cut-off principle for the penetrance of SBMA and suggest that penetrance gradually increases from 35 to approximately 46 (CAG)n, above which it reaches a plateau approaching maximum value.ConclusionAsymptomatic men of the general population with no/unknown SBMA family history are free of risk when carrying (CAG)n ≤34, are at intermediate but increasing risk for developing SBMA when carrying (CAG)n ≈35–46 and have close to 100% risk of developing the disease when carrying (CAG)n ≥47. The above observations should be helpful and clinically useful when providing genetic counselling to individuals and families bearing SBMA-associated alleles.

Neuroprotective methodologies in treatment of Multiple Sclerosis: Current status of Clinical and Pre-clinical findings

: Multiple sclerosis an idiopathic and autoimmune associated motor neuron disorder that attacks myelinated neurons in specific brain regions of young people, especially females; characterized by oligodendrocytes destruction causes demyelination, neuroinflammation, mitochondrial abnormalities, oxidative stress and neurotransmitter deficits associated with motor and cognitive dysfunctions, vertigo and muscle weakness. The limited intervention of pharmacologically active compounds like interferon-β, mitoxantrone, fingolimod and monoclonal antibodies used clinically are majorly associated with adverse drug reactions. Pre-clinically, gliotoxin ethidium bromide mimics the behavioral and neurochemical alterations in multiple sclerosis like experimental animals associated with the down regulation of adenyl cyclase/cAMP/CREB further responsible for varieties of neuropathogenic factors. Despite the considerable investigation of neuroprotection in curing multiple sclerosis, some complications still constrained. As of now approachable drugs give only symptomatic alleviation but don’t end the development of illness. In this way, the advancement of unused helpful techniques remains neglected restorative requires. The limitations of current steady treatment may be because of their activity at one of many neurotransmitters included or their failure to up direct signaling flag bearers detailed to have a vital part in neuronal sensitivity, biosynthesis of neurotransmitters and its discharge, development and separation of neuron, synaptic versatility and cognitive working. Therefore, the current review strictly focused on the exploration of various clinical and pre-clinical features available for multiple sclerosis to understand the pathogenic mechanisms and to introduced pharmacological interventions associated with the upregulation of intracellular adenyl cyclase/cAMP/CREB activation to ameliorate multiple sclerosis like features.

Plasma pNfH differentiate SBMA from ALS

Background and aim:Spinal bulbar muscular atrophy (SBMA) is a progressive adult-onset X-linked neuromuscular disease. Although traditionally considered a motor neuron disorder, recent advances have highlighted a primary myopathic component. We evaluated levels of phosphorylated neurofilament heavy chain (pNfH), a known biomarker for neurodegeneration, in SBMA.Materials and methods:We collected plasma and serum from 46 SBMA, 50 ALS and 50 healthy control cases, alongside with plasma from a mouse model of SBMA (AR100) and littermate controls. We measured pNfH plasma levels using Single molecule array (Simoa), we assessed functional scales and we gathered demographic data. We analysed data using Mann-Whitney U test, Kruskal-Wallis test and Cox regression analysis.Results:Plasma pNfH levels were significantly increased in ALS, but, intriguingly, there was no change in SBMA. These results were also confirmed in SBMA mice. The ROC curve highlighted that pNfH levels can effectively distinguish between ALS and SBMA (AUC 0.95).Conclusions:Unexpectedly, levels of pNfH are normal in SBMA, whilst they are increased in ALS, and suggest pNfH could serve as a biomarker to differentiate the two diseases. Further, this finding is in agreement with recent evidence showing that primary muscle damage is a crucial feature in SBMA.

Electro Clinical Profiles of Motor Neuron Disease and Atypical Motor Neuron Disorders: A Case Series

Amyotrophic lateral sclerosis (ALS) is the commonest MND phenotype. Although many of the atypical motor neuron disorders share some features with ALS, they often can be distinguished by their clinical and electrophysiologic characteristics. Here we present five different cases with varied clinical findings. All the patients were referred from outpatient department to neurophysiology laboratory where electrodiagnostic (EDX) correlations helped to come to a conclusion. The nerve conduction study protocol for a suspected atypi¬cal motor neuron disorder is the same as that for ALS. Akin to the nerve conduction studies, the EMG evaluation of patients with suspected atypical motor neuron disorders is similar to that of ALS. An extensive study is indicated, often of all four limbs, the paraspinal muscles, and the bulbar muscles to reach a possible diagnosis. History, clinical findings and electrophysiological correlation often help to differentiate these atypical motor neuron disorders. Correct diagnosis is needed for further evaluation and prognosis. In this case series five (5) cases have described who are referred from outpatient department to neurophysiology laboratory for electrodiagnostic (EDX) correlations.Journal of National Institute of Neurosciences Bangladesh, 2017;3(1): 57-61