Form Of Motor Neuron Disease Research Articles

Amyotrophic lateral sclerosis: an emerging era of collaborative gene discovery.

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND). It is currently incurable and treatment is largely limited to supportive care. Family history is associated with an increased risk of ALS, and many Mendelian causes have been discovered. However, most forms of the disease are not obviously familial. Recent advances in human genetics have enabled genome-wide analyses of single nucleotide polymorphisms (SNPs) that make it possible to study complex genetic contributions to human disease. Genome-wide SNP analyses require a large sample size and thus depend upon collaborative efforts to collect and manage the biological samples and corresponding data. Public availability of biological samples (such as DNA), phenotypic and genotypic data further enhances research endeavors. Here we discuss a large collaboration among academic investigators, government, and non-government organizations which has created a public repository of human DNA, immortalized cell lines, and clinical data to further gene discovery in ALS. This resource currently maintains samples and associated phenotypic data from 2332 MND subjects and 4692 controls. This resource should facilitate genetic discoveries which we anticipate will ultimately provide a better understanding of the biological mechanisms of neurodegeneration in ALS.

Occupational exposures to magnetic fields and neurodegenerative disease risks

Occupational exposures to magnetic fields and neurodegenerative disease risks

TDP-43 in differential diagnosis of motor neuron disorders

Motor neuron disorders are clinically and pathologically heterogeneous. They can be classified into those that affect primarily upper motor neurons, lower motor neurons or both. The most common disorder to affect both upper and lower motor neurons is amyotrophic lateral sclerosis (ALS). Some forms of motor neuron disease (MND) affect primarily motor neurons in the spinal cord or brainstem, while others affect motor neurons at all levels of the neuraxis. A number of genetic loci have been identified for the various motor neuron disorders. Several of the MND genes encode for proteins important for cytoskeletal stability and axoplasmic transport. Despite these genetic advances, the relationship of the various motor neuron disorders to each other is unclear. Except for rare familial forms of ALS associated with mutations in superoxide dismutase type 1 (SOD1), which are associated with neuronal inclusions that contain SOD1, specific molecular or cellular markers that differentiate ALS from other motor neuron disorders have not been available. Recently, the TAR DNA binding protein 43 (TDP-43) has been shown to be present in neuronal inclusions in ALS, and it has been suggested that TDP-43 may be a specific marker for ALS. This pilot study aimed to determine the value of TDP-43 in the differential diagnosis of MND. Immunohistochemistry for TDP-43 was used to detect neuronal inclusions in the medulla of disorders affecting upper motor neurons, lower motor neurons or both. Medullary motor neuron pathology also was assessed in frontotemporal lobar degeneration (FTLD) that had no evidence of MND. TDP-43 immunoreactivity was detected in the hypoglossal nucleus in all cases of ALS, all cases of FTLD-MND and some of cases of primary lateral sclerosis (PLS). It was not detected in FTLD-PLS. Surprisingly, sparse TDP-43 immunoreactivity was detected in motor neurons in about 10% of FTLD that did not have clinical or pathologic features of MND. The results suggest that TDP-43 immunoreactivity is useful in differentiating FTLD-MND and ALS from other disorders associated with upper or lower motor neuron pathology. It also reveals subclinical MND in a subset of cases of FTLD without clinical or pathologic evidence of MND.

A mutation in human VAP-B–MSP domain, present in ALS patients, affects the interaction with other cellular proteins

Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset Motor Neuron Disease (MND), characterized by motor neurons death in the cortex, brainstem and spinal cord. Ten loci linked to Familial ALS have been mapped. ALS8 is caused by a substitution of a proline by a serine in the Vesicle-Associated Membrane Protein-Associated protein-B/C ( VAP-B/C). VAP-B belongs to a highly conserved family of proteins implicated in Endoplasmic Reticulum—Golgi and intra-Golgi transport and microtubules stabilization. Previous studies demonstrated that the P56S mutation disrupts the subcellular localization of VAP-B and that this position would be essential for Unfolded Protein Response (UPR) induced by VAP-B. In the present work we expressed and purified recombinant wild-type and P56S mutant VAP-B–MSP domain for the analysis of its interactions with other cellular proteins. Our findings suggest that the P56S mutation may lead to a less stable interaction of this endoplasmic reticulum protein with at least two other proteins: tubulin and GAPDH. These two proteins have been previously related to other forms of neurodegenerative diseases and are potential key points to understand ALS8 pathogenesis and other forms of MND. Understanding the role of these protein interactions may help the treatment of this devastating disease in the future.

Clinical patterns in progressive muscular atrophy (PMA): A prospective study

Progressive muscular atrophy (PMA) is a form of motor neuron disease, but its outcome is not well defined, and the aim was to study the pattern of clinical progression in PMA. We studied 10 patients prospectively for 12 months. None showed clinical signs of upper motor neuron involvement at presentation or during follow-up, and all had normal transcranial magnetic stimulation studies. Four had upper limb onset, four lower limb onset and two axial onset. We used neurophysiological and strength measurements and a clinical rating scale (ALS-FRS). Seven other patients presenting with a PMA syndrome developed upper motor neuron signs during a one-year period of observation and were excluded from the study. The rate of progression was variable. At six months, only motor unit number estimation (MUNE) and ALS-FRS had decreased significantly. The Neurophysiological Index (NI) and M-wave amplitude measurements decreased at 12 months. Two patients with axial-onset disease progressed rapidly to respiratory failure. Overall the pattern of change resembled that of ALS, although some patients progressed very slowly. Axial onset, however, predicts the early onset of respiratory failure, and a poor prognosis.

Biomarkers for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease. ALS is a fatal neurodegenerative disease and clinical diagnosis typically takes many months to complete. Early disease diagnosis through the use of biomarkers may aid in correct clinical management of patients and possibly delay time to ventilator and morbidity. This review explores the progress of biomarker discovery efforts for ALS and the many challenges that remain. Included are different technologies utilized in biomarker discovery efforts (proteomic, genomic and metabolomic) and putative biomarkers uncovered using these techniques. These studies have discovered genetic mutations leading to familial forms of ALS, and specific protein alterations that occur in biological fluids (cerebrospinal fluid and blood) and/or tissues of ALS subjects. More recent high-throughput technologies have revealed panels of proteomic or metabolic biomarkers that can discriminate between ALS and control groups. The identification of disease-specific biomarkers will provide opportunities to develop early diagnostic measures as well as surrogate markers to monitor disease progression and test drug efficacy in clinical trials.

No association ofDYNC1H1with sporadic ALS in a case‐control study of a northern European derived population: A tagging SNP approach

The cytoplasmic dynein-dynactin complex has been implicated in the aetiology of motor neuron degeneration in both mouse models and human forms of motor neuron disease. We have previously shown that mutations in the cytoplasmic dynein 1 heavy chain 1 gene (Dync1h1) are causal in a mouse model of late-onset motor neuron degeneration but have found no association of the homologous sites in human DYNC1H1 with human motor neuron disease. Here we extend these analyses to investigate the DYNC1H1 genomic locus to determine if it is associated with sporadic amyotrophic lateral sclerosis (ALS) in a northern European-derived population. Among the 16 single nucleotide polymorphisms (SNPs) we examined, just two SNPs (rs2251644 and rs941793) were sufficient to tag the majority of haplotypic variation (r2 > or = 0.85) and these were tested in a case-control association study with 266 North American sporadic ALS patients and 225 matched controls. We found no association between genetic variation at DYNC1H1 and sporadic ALS (rs2251644; p = 0.538, rs941793; p = 0.204, haplotype; p = 0.956). In addition we investigated patterns of diversity at DYNC1H1 in Japanese and Cameroonian populations to establish the evolutionary history for this gene and observed reduced genetic diversity in the northern Europeans suggestive of selection at this locus.

A case of presumptive primary lateral sclerosis with upper and lower motor neurone pathology

Motor Neurone Disease (MND) is one of the commonest neurodegenerative disorders of adulthood. MND characteristically presents with a combination of both upper and lower motor neurone features. Primary Lateral Sclerosis (PLS) is thought to be a variant of MND presenting with purely upper motor neurone signs. Debate continues over whether PLS constitutes a distinct pathological entity or whether it is part of the spectrum of motor neurone diseases that present as an upper motor neurone-predominant form of MND. We present a case of MND with purely upper motor neurone features and a prominent pain component. A pre-mortem diagnosis of PLS was made, however autopsy findings demonstrated both upper and lower motor neurone involvement. We believe these findings support the view that PLS is not a discrete pathological entity, but that it is a part of the range of motor neurone diseases that present with predominant but not exclusive upper motor neurone involvement. This case also highlights the feature that pain may be associated with MND even though it is not appreciated to have a sensory pathology.

Distal spinal and bulbar muscular atrophy caused by dynactin mutation

Impaired axonal transport has been postulated to play a role in the pathophysiology of multiple neurodegenerative disorders. In this report, we describe the results of clinical and neuropathological studies in a family with an inherited form of motor neuron disease caused by mutation in the p150Glued subunit of dynactin, a microtubule motor protein essential for retrograde axonal transport. Affected family members had a distinct clinical phenotype characterized by early bilateral vocal fold paralysis affecting the adductor and abductor laryngeal muscles. They later experienced weakness and atrophy in the face, hands, and distal legs. The extremity involvement was greater in the hands than in the legs, and it had a particular predilection for the thenar muscles. No clinical or electrophysiological sensory abnormality existed; however, skin biopsy results showed morphological abnormalities of epidermal nerve fibers. An autopsy study of one patient showed motor neuron degeneration and axonal loss in the ventral horn of the spinal cord and hypoglossal nucleus of the medulla. Immunohistochemistry showed abnormal inclusions of dynactin and dynein in motor neurons. This mutation of dynactin, a ubiquitously expressed protein, causes a unique pattern of motor neuron degeneration that is associated with the accumulation of dynein and dynactin in neuronal inclusions.

Metabolomic analysis and signatures in motor neuron disease

Motor neuron diseases (MND) are a heterogeneous group of disorders that includes amyotrophic lateral sclerosis (ALS) and result in death of motor neurons. These diseases may produce characteristic perturbations of the metabolome, the collection of small-molecules (metabolites) present in a cell, tissue, or organism. To test this hypothesis, we used high performance liquid chromatography followed by electrochemical detection to profile blood plasma from 28 patients with MND and 30 healthy controls. Of 317 metabolites, 50 were elevated in MNDpatients and more than 70 were decreased (p < 0.05). Among the compounds elevated, 12 were associated with the drug Riluzole. In a subsequent study of 19 subjects with MND who were not taking Riluzole and 33 healthy control subjects, six compounds were significantly elevated in MND, while the number of compounds with decreased concentration was similar to study 1. Our data also revealed a distinctive signature of highly correlated metabolites in a set of four patients, three of whom had lower motor neuron (LMN) disease. In both datasets we were able to separate MND patients from controls using multivariate regression techniques. These results suggest that metabolomic studies can be used to ascertain metabolic signatures of disease in a non-invasive fashion. Elucidation of the structures of signature molecules in ALS and other forms of MND should provide insight into aberrant biochemical pathways and may provide diagnostic markers and targets for drug design.

Loss of synaptophysin‐positive boutons on lumbar motor neurons innervating the medial gastrocnemius muscle of the SOD1G93A G1H transgenic mouse model of ALS

Amyotrophic lateral sclerosis (ALS) is a common form of motor neuron disease (MND) that involves both upper and lower nervous systems. In the SOD1G93A G1H transgenic mouse, a widely used animal model of human ALS, a significant pathology is linked to the degeneration of lower motor neurons in the lumbar spinal cord and brainstem. In the current study, the number of presynaptic boutons immunoreactive for synaptophysin was estimated on retrogradely labeled soma and proximal dendrites of alpha and gamma motor neurons innervating the medial gastrocnemius muscle. No changes were detected on both soma and proximal dendrites at postnatal day 60 (P60) of alpha and gamma motor neurons. By P90 and P120, however, alpha motor neuron soma had a reduction of 14 and 33% and a dendritic reduction of 19 and 36%, respectively. By P90 and P120, gamma motor neuron soma had a reduction of 17 and 41% and a dendritic reduction of 19 and 35%, respectively. This study shows that levels of afferent innervation significantly decreased on surviving alpha and gamma motor neurons that innervate the medial gastrocnemius muscle. This finding suggests that the loss of motor neurons and the decrease of synaptophysin in the remaining motor neurons could lead to functional motor deficits, which may contribute significantly to the progression of ALS/MND.

Association between CYP1A2 activity and riluzole clearance in patients with amyotrophic lateral sclerosis

Riluzole is used in a fixed dosing schedule of 50 mg twice daily to treat patients with amyotropic lateral sclerosis (ALS), one form of motor neurone disease. The large variability in the pharmacokinetics of riluzole may be a factor contributing to its limited therapeutic benefit. Riluzole is assumed to be mainly metabolized by the cytochrome P450 enzyme 1A2 (CYP1A2). The aim of the study was to investigate the relationship between CYP1A2 activity and riluzole clearance with a view to optimize drug treatment. A group of 30 ALS patients participated in the study. In each patient the CYP1A2 activity was determined using caffeine as a metabolic probe. Riluzole clearance was estimated from serum drug concentration measurements followed by Bayesian fitting. Riluzole clearance and the serum paraxanthine : caffeine (P/C) ratio showed a positive correlation (r = 0.693; P = 0.0002). Linear regression analysis identified the P/C ratio (beta: 1.16) and height (beta: 0.027) as independent predictors of riluzole clearance (adjusted r2 = 0.369). The P/C ratio, used as measure of CYP1A2 activity, significantly correlated with the riluzole clearance, although only 37% of the observed variability could be explained.

Monmelic Amyotrophy Hirayama’s Dissease

INTRODUCTION The patient presenting with weakness and wasting of one limb, usually the arm, can be a considerable diagnostic challenge for the neurologist. While the spectre of the amyotrophic lateral...

Analysis of the Glutathione S-Transferase P1 Gene Ile105Val Polymorphism in the Patients with Sporadic Motor Neuron Disease from Russia

Ile105Val polymorphism in exon 5 of glutathione S-transferase (GSTP1) gene was examined in a group of patients with motor neuron disease (MND) and control sample. No statistically significant differences in the allele and genotype frequency distributions between the samples examined were demonstrated. We conclude that Ile105Val polymorphism is not associated with the risk of the disease development in the patients from Russia with sporadic form of MND.

A polymorphism in the poliovirus receptor gene differs in motor neuron disease.

Poliovirus has been implicated in the etiology of sporadic motor neuron disease. DNA polymorphisms in the poliovirus receptor gene (PVR) are associated with persistent poliovirus infection in cell culture. PVR DNA polymorphisms were therefore studied in 110 cases of amyotrophic lateral sclerosis, 30 cases of progressive muscular atrophy (a disorder of lower motor neurons) and 280 normal controls. In exon 2 of PVR the heterozygous Ala67Thr change was detected in 20.0% of progressive muscular atrophy, 11.8% of amyotrophic lateral sclerosis and 6.8% of control subjects. The frequency of the polymorphism was significantly higher in patients with progressive muscular atrophy than in controls. Differences in the poliovirus receptor gene may result in slowly progressive viral cytopathic effects that lead to lower motor neuron forms of motor neuron disease.

Amyotrophic lateral sclerosis: progress and prospects for treatment.

Fifteen years ago, a role for excitotoxic damage in the pathology of amyotrophic lateral sclerosis (ALS) was postulated. This stimulated the development of riluzole, the only available treatment for the disease. Since then, the identification of abnormal forms of superoxide dismutase as the genetic basis of certain familial forms of ALS has provided a huge impetus to the search for new effective treatments for this devastating disease. Transgenic mouse models have been developed expressing these aberrant mutants that develop a form of motor neurone disease the progress of which can be slowed by riluzole. Studies in these mice have provided evidence for a role for excitotoxic, apoptotic and oxidative processes in the development of pathology. The mice can be used for testing molecules targeting these processes as potential therapies, to allow the most promising to be evaluated in humans. Several such agents are currently in clinical trials. Many previous clinical trials in ALS were insufficiently powered to demonstrate any relevant effect on disease progression. This situation has been to some extent remedied in the more recent trials, which have recruited many hundreds of patients. However, with the exception of studies with riluzole, the results of these have been disappointing. In particular, a number of large trials with neurotrophic agents have revealed no evidence for efficacy. Nonetheless, the need for large multinational trials of long duration limits the number that can be carried out and makes important demands on investment. For this reason, surrogate markers that can be used for rapid screening in patients of potential treatments identified in the transgenic mice are urgently needed.

Enfermedad de la motoneurona asociada a hipernefroma. Presentación de un caso

Paraneoplastic motor neuron disease are rare among patients with renal cell carcinoma.Present the clinical and electrophysiological evolution of a patient with a motor neuron disease and hypernephrome.A 60 years old woman, affected only by high level pressure since 10 years ago. She noticed sudden palsy of the left leg and 10 months later an abdominal ultrasound showed a renal cell carcinoma, discovered without other symptoms than neurologic. After radical nephrectnomy, the patient was treated with recombinant interferon alpha 2b. The neurologic damage advanced and she has a flaccid weakness and muscle atrophy in the legs and brisk reflexes, also in wasted limbs. There is Babinski, fasciculations, light flaccid dysarthria and laryngospasm. Peripheral nerve conduction studies are within normal limits. The electromyogram show positive sharp waves in both legs and left hand. Recruitment patterns are decreased and there are fasciculations in the tongue, upper and lower limbs. The magnetic resonance of the brain and spinal cord is normal. There are not evidence of metastasis. The question of whether or not this is a paraneoplastic form of motor neuron disease remain unclear.This case suggest the need to consider a renal cell carcinoma in the course of a motor neuron disease.

Neurolathyrism: mitochondrial dysfunction in excitotoxicity mediated by l-β-oxalyl aminoalanine

β- N-Oxalyl amino- l-alanine ( l-BOAA); synonym β- N-oxalyl-α,β-diaminopropionic acid (β-ODAP) is a naturally occurring non-protein amino acid present in the chickling pea from the plant Lathyrus sativus grown in drought prone areas. Ingestion of l-BOAA as a staple diet results in a progressive neurodegenerative condition, neurolathyrism, a form of motor neuron disease which affects the upper motor neurons and anterior horn cells of the lumbar spinal cord. l-BOAA is an excitatory acid and acts as an agonist at the AMPA receptor. One of the primary effects of l-BOAA toxicity is the inhibition of mitochondrial complex I selectively in the motor cortex and lumbar spinal cord. Recent evidence has suggested that the mitochondrial dysfunction is a consequence of oxidation protein thiol groups as a result of generation of reactive oxygen species. Mitochondrial complex I is highly to vulnerable to inactivation through oxidation of vital sulfhydryl groups. Thiol antioxidants such as α-liopic acid offer a method of protecting mitochondrial function. A common mechanism involving oxidation of protein thiol groups may underlie neurodegeneration occurring through mitochondrial dysfunction induced by excitatory amino acid.

Ubiquitin immunoreactivity in presumed spinal interneurones in motor neurone disease.

Previous studies have demonstrated the presence of ubiquitin-immunoreactivity (Ub-IR) as inclusions and skeins in motor neurones of both the familial and sporadic forms of motor neurone disease (MND). There is evidence that interneurones also degenerate in MND, but Ub-IR in ventral horn spinal interneurones has not been studied previously. Here, Ub-IR was investigated in 1445 presumed interneurones and 1086 presumed motor neurones counted in three random 20-microm sections of the ventral horn of the third lumbar segment of the spinal cord of each of seven controls and seven patients with MND. The ventral horn was divided into four quadrants; the dorsomedial quadrant contains almost exclusively interneurones and the ventrolateral quadrant largely motor neurones. The neurones were also classified by morphological and size criteria into presumed interneurones (< 25 microm) and presumed motor neurones (>or= 25 microm). Ub-IR was classified as inclusions, skeins and dispersed cytoplasmic and nuclear staining. Ub-IR inclusions or skeins were not observed in the controls but 6.6% of neurones (motor neurones and interneurones) showed the presence of dispersed cytoplasm staining and nuclear staining. The incidence of Ub-IR cytoplasmic and nuclear staining was significantly greater in both motor neurones and interneurones of MND patients than controls. Ub-IR was less frequent in MND cases in which a great loss of neurones was observed. Ub-IR was significantly more frequent in motor neurones than interneurones, both in patients and controls. Ub-IR inclusions and skeins were only observed in motor neurones from MND patients. Ub-IR inclusions were not observed in presumed spinal interneurones, while skeins were only seen in three out of 565 of these cells (two of them in the dorsomedial quadrant) in two out of seven patients. Thus, although presumed spinal interneurones occasionally revealed Ub-IR features similar to motor neurones, the rare staining of Ub-IR skeins and the lack of Ub-IR inclusions in interneurones in MND suggests that these neurones only occasionally form ubiquitin-protein conjugates. Neuronal size, rather than type, may be important in determining whether ubiquitin-protein conjugates form in the ventral horn neurones in MND.

Motor Neuron Disease

Motor neuron disease refers to a spectrum of disorders resulting from degeneration of the upper or lower motor neurons or both. Amyotrophic lateral sclerosis is the most common form of motor neuron disease, in which patients demonstrate evidence of both anterior horn cell (lower motor neuron) and corticospinal tract (upper motor neuron) dysfunction. Several theories regarding the pathogenesis of amyotrophic lateral sclerosis have emerged, including glutamate excitotoxicity, free radical oxidative stress, cytoskeletal abnormalities, a deficiency of neurotrophic factor, autoimmunity, apoptosis, and viral infection. Numerous clinical trials have been completed based on these possible mechanisms of the disease propagation including treatment with antiglutamate agents, anti-oxidants, immunosuppressants, and neurotrophic factors. Several of these trials have shown modest effects in slowing the disease course. None, however, have yielded marked benefit in arresting disease progression. The most significant effect in abating disease progression has been our use and understanding of aggressive symptomatic therapy to reduce disability, enhance quality of life, and improve prognosis.