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Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive, fatal motor neuron disease with a variable natural history. There are no accurate models that predict the disease course and outcomes, which complicates risk assessment... more
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive, fatal motor neuron disease with a variable natural history. There are no accurate models that predict the disease course and outcomes, which complicates risk assessment and counselling for individual patients, stratification of patients for trials, and timing of interventions. We therefore aimed to develop and validate a model for predicting a composite survival endpoint for individual patients with ALS. We obtained data for patients from 14 specialised ALS centres (each one designated as a cohort) in Belgium, France, the Netherlands, Germany, Ireland, Italy, Portugal, Switzerland, and the UK. All patients were diagnosed in the centres after excluding other diagnoses and classified according to revised El Escorial criteria. We assessed 16 patient characteristics as potential predictors of a composite survival outcome (time between onset of symptoms and non-invasive ventilation for more than 23 h per day, tracheostomy...
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BackgroundDysregulation of iron homeostasis is one possible pathophysiological mechanism involved in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). SLC11A2 gene encodes the divalent metal transport 1 (DMT1) mediating... more
BackgroundDysregulation of iron homeostasis is one possible pathophysiological mechanism involved in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). SLC11A2 gene encodes the divalent metal transport 1 (DMT1) mediating iron transport in cerebral endosomal compartments. The objective of the study was to analyze DMT1 as a possible risk or modulating factor in sporadic ALS (SALS).
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Research Interests: Quality of life, France, Comorbidity, Amyotrophic Lateral Sclerosis, Prospective studies, and 15 moreHumans, Female, Pulmonary Embolism, Pneumonia, Male, Clinical Sciences, Hospice Care, Aged, Middle Aged, Neurosciences, Prospective Study, Heart Diseases, Cause of death, Asphyxia, and Respiratory insufficiency
Isolated paralysis of the serratus anterior (SA) muscle had been reported, especially in athletes. During SA fascial flap dissections, we observed that fascial and vascular structures can mechanically constrain the thoracic portion of the... more
Isolated paralysis of the serratus anterior (SA) muscle had been reported, especially in athletes. During SA fascial flap dissections, we observed that fascial and vascular structures can mechanically constrain the thoracic portion of the long thoracic nerve (LTN). Here, we assess the results of neurolysis of the thoracic segment of the LTN. A prospective multicenter study was conducted between December 1999 and June 2004. Every case of isolated palsy of the SA was included, after a Parsonage-Turner syndrome has been ruled out. Eighteen consecutive cases underwent such neurolysis. There were 14 men and 4 women. Their mean age was 30 years (17 to 49). The operation took place 16.4 months (range, 4-72 months) after the onset of palsy. Pain relief usually occurred during the first postoperative month. At the longest follow-up most patients had recovered completely. In the absence of spontaneous recovery from traumatic palsy, surgical release of the distal segment of the LTN is a minima...
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... Letters. The relationship of SMN to amyotrophic lateral sclerosis. Thomas O. Crawford MD,; Richard L. Skolasky Jr. MA. Article first published online: 22 NOV 2002. DOI: 10.1002/ana. 10378. Copyright © 2002 Wiley-Liss, Inc. Issue.... more
... Letters. The relationship of SMN to amyotrophic lateral sclerosis. Thomas O. Crawford MD,; Richard L. Skolasky Jr. MA. Article first published online: 22 NOV 2002. DOI: 10.1002/ana. 10378. Copyright © 2002 Wiley-Liss, Inc. Issue. Annals of Neurology. ...
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We report on a patient with a 30-year history of left temporal lobe epilepsy who presented with ictal bradycardia followed by cardiac asystole. The EEG during the ictal period was documented and analyzed. Clinical features and therapeutic... more
We report on a patient with a 30-year history of left temporal lobe epilepsy who presented with ictal bradycardia followed by cardiac asystole. The EEG during the ictal period was documented and analyzed. Clinical features and therapeutic considerations are discussed.
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This study aims to develop a cellular metabolomics model that reproduces the pathophysiological conditions found in amyotrophic lateral sclerosis in order to improve knowledge of disease physiology. We used a co-culture model combining... more
This study aims to develop a cellular metabolomics model that reproduces the pathophysiological conditions found in amyotrophic lateral sclerosis in order to improve knowledge of disease physiology. We used a co-culture model combining the motor neuron-like cell line NSC-34 and the astrocyte clone C8-D1A, with each over-expressing wild-type or G93C mutant human SOD1, to examine amyotrophic lateral sclerosis (ALS) physiology. We focused on the effects of mutant human SOD1 as well as oxidative stress induced by menadione on intracellular metabolism using a metabolomics approach through gas chromatography coupled with mass spectrometry (GC-MS) analysis. Preliminary non-supervised analysis by Principal Component Analysis (PCA) revealed that cell type, genetic environment, and time of culture influenced the metabolomics profiles. Supervised analysis using orthogonal partial least squares discriminant analysis (OPLS-DA) on data from intracellular metabolomics profiles of SOD1(G93C) co-cul...
Research Interests: Cognitive Science, Principal Component Analysis, Metabolomics, Oxidative Stress, Quality Control, and 14 moreMolecular Neurobiology, Amyotrophic Lateral Sclerosis, Cell line, Discriminant Analysis, Humans, Reactive Oxygen Species, Superoxide Dismutase, Time Factors, Gas Chromatography/mass Spectrometry, Reproducibility of Results, Cell Survival, Neurosciences, Vitamin K, and coculture techniques
Résumé: Les événements non épileptiques psychogènes (ENEP) survenant chez les sujets âgés ont une fréquence sous-estimée. L'enregistrement vidéo-EEG des épisodes cliniques permet d'affirmer le diagnostic. Des travaux récents... more
Résumé: Les événements non épileptiques psychogènes (ENEP) survenant chez les sujets âgés ont une fréquence sous-estimée. L'enregistrement vidéo-EEG des épisodes cliniques permet d'affirmer le diagnostic. Des travaux récents indiquent que les ENEP ...
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Cognitive disorders have been described in amyotrophic lateral sclerosis, but usually after the diagnosis has ben established. A 57-year-old man was intubated for acute respiratory distress subsequent to pneumonia and diaphragm palsy. He... more
Cognitive disorders have been described in amyotrophic lateral sclerosis, but usually after the diagnosis has ben established. A 57-year-old man was intubated for acute respiratory distress subsequent to pneumonia and diaphragm palsy. He had a 2-year history of drug-resistant depression and deterioration of cognitive functions. A pyramidal syndrome associated with biopsy-proven chronic neurogenic atrophy led to the diagnosis of amyotrophic lateral sclerosis. The electromyogram did not contribute to diagnosis. Brain MRI only evidenced moderate bilateral frontal-temporal atrophy. Brain SPECT demonstrated major perfusion defects in the frontal lobes. This patient had amyotrophic lateral sclerosis and frontal-temporal dementia with an unusually late onset clinical presentation: cognitive disorder was the inaugural sign. Brain SPECT and muscle biopsy enabled us to identify the cortical and peripheral motor neurone involvement in this uncooperative intensive care patient totally dependent on mechanical ventilation.
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ALS is likely to be a disorder of multifactorial origin. Among all the factors that may increase the risk of ALS, environmental ones are being studied for many years, but in the recent years, several advances have pointed to a new... more
ALS is likely to be a disorder of multifactorial origin. Among all the factors that may increase the risk of ALS, environmental ones are being studied for many years, but in the recent years, several advances have pointed to a new interest in their potential involvement in the disease process, especially for the cyanotoxin BMAA. Food containing BMAA has been found on Guam, a well-known focus of ALS/parkinsonism/dementia and high levels of BMAA have been identified into the brain of these patients. The BMAA cyanotoxin is potentially ubiquitous and have also been found into the food of patients who died from ALS both in Europe and USA. BMAA can be wrongly integrated into the protein structure during mRNA traduction, competing with serine. This may induce abnormal protein folding and a subsequent cell death. Heavy metals, such as lead or mercury may be directly toxic for neuronal cells. Several works have suggested an increased risk of ALS in individuals chronically exposed to these me...
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Vitamin D deficiency has been associated with poorer prognosis in ALS. Better understanding of the role of vitamin D in ALS is needed to determine whether trials of systematic supplementation are justified. Our aim was to report vitamin D... more
Vitamin D deficiency has been associated with poorer prognosis in ALS. Better understanding of the role of vitamin D in ALS is needed to determine whether trials of systematic supplementation are justified. Our aim was to report vitamin D levels during the course of ALS and to evaluate its relationship with clinical parameters at diagnosis and with disease progression. We prospectively collected vitamin D serum concentrations from 125 consecutive ALS patients. Cox proportional hazard models analyzed the relationship between vitamin D concentrations, clinical parameters, and survival. The mean vitamin D concentration was below our laboratory's lower limit of normal (P < 0.0001) and did not change during the course of the disease. The concentrations were higher in patients with bulbar onset (P = 0.003) and were negatively associated with body mass index (BMI) (P = 0.0095). Models with ALSFRS-R (ALS Functional Rating Scale-Revised) and BMI as a covariates showed that vitamin D concentrations predicted worse prognosis. The distribution of vitamin D concentrations in our cohort was consistent with previous reports. Surprisingly, we noted a negative effect of higher vitamin D levels on prognosis in ALS. More detailed research is warranted to determine whether manipulation of vitamin D could be beneficial to patients.
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Amyotrophic lateral sclerosis is sporadic (SALS) in 90% of cases and has complex environmental and genetic influences. Nogo protein inhibits neurite outgrowth and is overexpressed in muscle in ALS. Our aims were to study the reticulon 4... more
Amyotrophic lateral sclerosis is sporadic (SALS) in 90% of cases and has complex environmental and genetic influences. Nogo protein inhibits neurite outgrowth and is overexpressed in muscle in ALS. Our aims were to study the reticulon 4 receptor gene RTN4R which encodes Nogo 1 receptor (NgR1) in SALS, to test if the variants were associated with variable expression of the gene and whether NgR1 protein expression was modified in a transgenic mouse model of ALS. We genotyped three single nucleotide polymorphisms (SNPs; rs701421, rs701427, and rs1567871) of the RTN4R gene in 364 SALS French patients and 430 controls. We examined expression of RTN4R mRNA by quantitative PCR in control post mortem human brain tissue. We determined the expression of NgR1 protein in spinal motor neurons from a SOD1 G86R ALS mouse model. We observed significant associations between SALS and RTN4R alleles. Messenger RNA expression from RTN4R in human cortical brain tissue correlated significantly with the ge...
Research Interests: Immunohistochemistry, France, Amyotrophic Lateral Sclerosis, Brain, Humans, and 15 moreMice, Female, Animals, Spinal Cord, Male, Superoxide Dismutase, Aged, Middle Aged, Adult, Myelin Proteins, European Continental Ancestry Group, Case Control Studies, Motor Neurons, alleles, and reverse transcriptase polymerase chain reaction
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Numerous biomarkers studies in ALS used targeted and non-targeted approaches, to help for the diagnosis, the prognosis or to identify new pathophysiological ways. The emerging approaches such as "omics" studies are very... more
Numerous biomarkers studies in ALS used targeted and non-targeted approaches, to help for the diagnosis, the prognosis or to identify new pathophysiological ways. The emerging approaches such as "omics" studies are very promising, but the practical and technical limits do not enable their optimization. Even if some biomarkers such as cystatin C or glutamate are highlighted in ALS, to date, no biomarker is currently used in routine practice. Diffusion-based neuroimaging has emerged as a tool to identify the involvement of the central neuron, but a recent meta-analysis shows a poor sensitivity and specificity. Spinal cord imaging has the advantage of simultaneoulsy investigating both the corticospinal tract and the peripheral motor neurons in the anterior horns of the spinal cord. Its interest to provide biomarkers in ALS is illustrated by recent studies that used a multiparametric approach. The limits of biomarkers studies are principally based on small cohorts, involving a...
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Neurologic disorders represent the most severe complications of acute intermittent porphyria (AIP). Cognitive disturbances, bulbar and spinal weakness appear as the most critical neurological complications as they may lead to death or... more
Neurologic disorders represent the most severe complications of acute intermittent porphyria (AIP). Cognitive disturbances, bulbar and spinal weakness appear as the most critical neurological complications as they may lead to death or definitive motor weakness. A 38-year-old woman was admitted for an acute and painful tetra paresis occurring after a laparoscopy for an ovarian cyst. She also complained of abdominal pain treated with noramidopyrine, tachycardia, hypertension and hyponatremia. The electrophysiological examination showed a motor axonal neuropathy. The increase of Urine ALA at 268 micromol/l (N<38) and of at 235 micromol/l (N<5) strongly suggested AIP that was further confirmed by PBG desaminase deficiency in red cells. Thanks to the prescription of heme arginate (HA) at the dose of 3 mg/kg/day for 4 days, pain resolved immediately and motor function began to improve since the second day of treatment concurrently to a dramatic decrease of both urine ALA and PBG con...
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Our objective was to examine the strength of evidence in support of the paraneoplastic syndrome (PNS) as one cause of ALS and, if the association appears more likely than chance, determine which features of ALS imply concurrent... more
Our objective was to examine the strength of evidence in support of the paraneoplastic syndrome (PNS) as one cause of ALS and, if the association appears more likely than chance, determine which features of ALS imply concurrent malignancy. We reviewed the literature on concurrent ALS and neoplasia assessing the strength of evidence for the association. Most accounts of ALS and neoplasm are case reports or small uncontrolled series. In order of strength of evidence, three clinical situations that support a paraneoplastic aetiology for ALS are: 1) laboratory evidence of well-characterized onconeuronal antibodies, most often anti-Hu, anti-Yo or anti-Ri; 2) co-occurrence of ALS and a neoplasm known to cause PNS, usually lymphoma or cancer of the breast; and 3) combined ALS and a neoplasm not classically associated with PNS, without detectable onconeuronal antibodies. Clinical features that warrant evaluation of neoplasm include upper motor neuron disease in elderly females, rapid progre...
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Hematological malignancies include several diseases that may affect the peripheral nervous system (PNS) through various mechanisms. A common and challenging situation is represented by the occurrence of an active peripheral neuropathy in... more
Hematological malignancies include several diseases that may affect the peripheral nervous system (PNS) through various mechanisms. A common and challenging situation is represented by the occurrence of an active peripheral neuropathy in a patient with a supposed inactive hematological disorder.We report clinical, electrophysiological, biological, and pathological data of 8 patients with latent malignant hemopathies (most were considered in remission): B-cell chronic lymphocytic leukemia in 3 patients, B-cell lymphoma in 1 patient, low-grade non-Hodgkin&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s lymphoma in 1 patient, Waldenström&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s macroglobulinemia in 1 patient, smoldering multiple myeloma in 1 patient, and monoclonal gammopathy of undetermined significance in 1 patient.In all these cases, the nerve biopsy (NB) helped to diagnose the hematological relapse or detect a pathological mechanism linked to the hematological disorder: epineurial lymphocytic infiltration in 5 patients (including one with antimyelin-associated glycoprotein antibodies), cryoglobulin deposits in 1 patient, chronic inflammatory demyelinating polyneuropathy in 1 patient, and necrotizing vasculitis in 1 patient. In each case, pathological findings were crucial to select the adequate treatment, leading to an improvement in the neurological and biological manifestations.These observations illustrate the value of NB and the need for active collaboration between neurologists and hematologists in such cases.
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The SOD1 gene encoding the superoxide dismutase 1 (SOD1) protein is mutated in approximately 15% of familial amyotrophic lateral sclerosis (ALS) and 3% of sporadic ALS. We identified a novel mutation in SOD1 in a man who presented at age... more
The SOD1 gene encoding the superoxide dismutase 1 (SOD1) protein is mutated in approximately 15% of familial amyotrophic lateral sclerosis (ALS) and 3% of sporadic ALS. We identified a novel mutation in SOD1 in a man who presented at age 49 with lower limb stiffness, and at age 53, a spastic paraparesia with distal muscular atrophy in the lower limbs and fasciculations in the quadriceps. A diagnosis of ALS was established. Eleven years after disease onset his condition continues gradually and slowly to deteriorate. The heterozygous mutation observed in exon 2 resulted in a valine to alanine substitution at position 31 in the β-barrel domain of the SOD1 protein. Functional analysis in NSC34 cells showed that the overexpression of the mutant form of SOD1(V31A) induced aggregates and decreased cell viability. This mutation is located outside of the regions carrying most of the ALS-related mutations (i.e., the catalytic center, the region of dimerization, and the loops between the β-str...
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Amyotrophic lateral sclerosis (ALS) is an age-related neurodegenerative disorder that is believed to have complex genetic and environmental influences in the pathogenesis, but etiologies are unidentified for most patients. Until the major... more
Amyotrophic lateral sclerosis (ALS) is an age-related neurodegenerative disorder that is believed to have complex genetic and environmental influences in the pathogenesis, but etiologies are unidentified for most patients. Until the major causes are better defined, drug development is directed at downstream pathophysiological mechanisms, themselves incompletely understood. For nearly 30 years, glutamate-induced excitotoxicity has lain at the core of theories behind the spiraling events, including mitochondrial dysfunction, oxidative stress, and protein aggregation, that lead to neurodegenerative cell death. One drug, riluzole, which possesses anti-glutamatergic properties, is approved as neuroprotective for ALS. Following the achievement of the riluzole trials, numerous other agents with similar mechanisms have been tested without success. This article provides an overview of excitotoxicity in ALS, focusing on the events that contribute to excess glutamate, how the excess might damage nerve cells, and how this information is being harnessed in the development of potential new neuroprotective agents. The work highlights clinical trials of drugs that have targeted the glutamate system, comments on the potential role of glutamate as a biomarker and concludes with a section on future directions for the field. As research uncovers elusive etiologies and brings clarity to pathophysiological mechanisms, the success of new interventions will increasingly depend on the design of agents that target particular mechanisms for specific individuals. The heady future of personalized drug regimens for ALS rests with medicinal chemists, the scientists whose ideas and work produce these designer drugs.
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Somatosensory evoked potentials (SEPs) offer complementary results to those of nerve conduction studies and contribute to the electrodiagnostic criteria of chronic inflammatory demyelinating polyradiculoneuropathy. We performed nerve... more
Somatosensory evoked potentials (SEPs) offer complementary results to those of nerve conduction studies and contribute to the electrodiagnostic criteria of chronic inflammatory demyelinating polyradiculoneuropathy. We performed nerve conduction studies and SEPs in patients with symmetrical motor weakness, areflexia, and/or sensory disturbances lasting for at least 8 weeks. We determined two groups according to the electrodiagnostic criteria of the European Federation of Neurological Societies. Group 1 included patients who met the definite or probable electrodiagnostic criteria, and group 2 included patients who met the possible electrodiagnostic criteria. We also compared SEPs results with those of controls (group of healthy subjects). Sixteen patients (14 men; mean age, 59 ± 17.3 years) were included in the study. The latencies of potentials N9, N13, N7, and N22 and the intervals N9-N13 and N7-N22 were significantly increased in patients compared with controls. The N9/iP14 amplitude ratio was significantly lower in patients. There was no significant difference in the latencies of SEPs between the two groups of patients. We confirm the contribution of SEPs as complementary information to nerve conduction studies in chronic inflammatory demyelinating polyradiculoneuropathy diagnosis. In addition to the usual abnormalities, a decrease in the N9/iP14 amplitude ratio could potentially be used as an electrodiagnostic criterion.
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We evaluated clinical and bioelectrical impedance (BIA) parameters at the time of diagnosis and during follow-up and associated these parameters with survival in amyotrophic lateral sclerosis (ALS) patients. One hundred seventeen patients... more
We evaluated clinical and bioelectrical impedance (BIA) parameters at the time of diagnosis and during follow-up and associated these parameters with survival in amyotrophic lateral sclerosis (ALS) patients. One hundred seventeen patients were enrolled and were evaluated prospectively every 3 months. All patients underwent at least 1 BIA-based assessment, and 73 underwent at least 2 assessments. Data regarding the site of onset, age at onset, weight, body mass index (BMI), amyotrophic lateral sclerosis functional rating scale score (ALSFRS), fat-free mass (FFM), fat mass (FM), and phase angle (PA) were collected. At the time of diagnosis, weight loss exceeding 5% of the premorbid weight and low PA were poor prognostic factors. During follow-up, a decrease of PA and FFM were associated with shorter survival, regardless of weight loss. These results confirm that BIA is useful to identify poor prognostic factors at the time of diagnosis and during follow-up and thus could be used to monitor patients during follow-up. Early identification of poor prognostic factors enables nutritional management and might improve patient survival. Muscle Nerve 51: 479-484, 2015.
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ABSTRACT Although the pathophysiology of amyotrophic lateral sclerosis remains currently unknown, involvement of genetic factors is worldwide accepted as a key clue in the motor neuron death. Since 1993 and the discovery of mutation in... more
ABSTRACT Although the pathophysiology of amyotrophic lateral sclerosis remains currently unknown, involvement of genetic factors is worldwide accepted as a key clue in the motor neuron death. Since 1993 and the discovery of mutation in the SOD1 gene, number of genes linked to or promoting ALS had always growing. Among them, only four (SOD1, TARDBP, FUS and C9ORF72 genes) are unanimously recognized as convincing causative genetic factors for more than 60% of familial and probably 10% of sporadic ALS cases. Geographic origin of the studied populations tends to become one of the major items in the gene–ALS relationship: this was extremely stressed for C9ORF72. Concerning susceptibility genes factors, an increase of the risk of ALS is clearly shown for SMN1 and ATXN2 genes and accepted for some VEGF haplotypes. Finally, some modulating effects might also exist as underline for the relationships between ApoE and ALS that differ between European and North American studies. In inherited ALS, The European Federation of Neurological Societies (EFNS) edited rules that gave a legal frame to situations for which research of mutations were justified. Progress in the field of genetic raises major questions concerning the relevance of genetic studies from asymptomatic relatives. This first implies that the mutation identified in the proband case is perfectly characterized as a pathogenic mutation.
ALS is likely to be a disorder of multifactorial origin. Among all the factors that may increase the risk of ALS, environmental ones are being studied for many years, but in the recent years, several advances have pointed to a new... more
ALS is likely to be a disorder of multifactorial origin. Among all the factors that may increase the risk of ALS, environmental ones are being studied for many years, but in the recent years, several advances have pointed to a new interest in their potential involvement in the disease process, especially for the cyanotoxin BMAA. Food containing BMAA has been found on Guam, a well-known focus of ALS/parkinsonism/dementia and high levels of BMAA have been identified into the brain of these patients. The BMAA cyanotoxin is potentially ubiquitous and have also been found into the food of patients who died from ALS both in Europe and USA. BMAA can be wrongly integrated into the protein structure during mRNA traduction, competing with serine. This may induce abnormal protein folding and a subsequent cell death. Heavy metals, such as lead or mercury may be directly toxic for neuronal cells. Several works have suggested an increased risk of ALS in individuals chronically exposed to these metals. Exposure to pesticides has been suggested to be linked to an increased risk of developing ALS. The mechanism of their toxicity is likely to be mediated by paraoxonases. These proteins are in charge of detoxifying the organism from toxins, and particularly organophosphates. To date, there are insufficient scientific data to suggest that exposure to electromagnetic fields may increase the risk of having ALS. We are particularly missing longitudinal cohorts to demonstrate that risk.
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Mutations in the SOD1 gene encoding the Cu/Zn superoxide dismutase-1 protein are responsible for amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. To date a large number of mutations have been reported in SOD1, but... more
Mutations in the SOD1 gene encoding the Cu/Zn superoxide dismutase-1 protein are responsible for amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. To date a large number of mutations have been reported in SOD1, but only few of them have been studied and validated by functional studies. We present a novel mutation in SOD1 in a female suffering from slowly progressive ALS. This dominant mutation (c.365A > G) in exon 5 resulted in a substitution of a highly conserved amino acid (p.E121G) of the protein. Functional studies in the motor neuronal cell line NSC34 and in primary culture of mouse motor neurons revealed that this mutation p.E121G induced aggregates positive for SOD1 and ubiquitin, as well as reduced cell viability. These findings identified a novel causal mutation in ALS in close proximity with one of the three histidine residues (H120) of SOD1 interacting with copper.
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ABSTRACT Introduction Les mutations du gène TARDBP ont été récemment décrites à la fois dans la SLA familiale et sporadique. Si l’effet modulateur des mutations du gène SOD1 sur le phénotype de la SLA, a été clairement démontré, celui des... more
ABSTRACT Introduction Les mutations du gène TARDBP ont été récemment décrites à la fois dans la SLA familiale et sporadique. Si l’effet modulateur des mutations du gène SOD1 sur le phénotype de la SLA, a été clairement démontré, celui des mutations du gène TARDBP n’a pas été encore étudié sur une grande série. Objectifs Étudier les relations entre les mutations du gène TARDBP et le phénotype des patients atteints de SLA familiale et sporadique. Matériel et méthodes Les caractéristiques cliniques de 28 patients SLA français liés à une mutation du gène TARDBP ont été analysées et comparées à celles de trois autres cohortes de patients SLA : 1) 737 SLA sporadiques ; 2) 323 SLA familiales ; et 3) la population des SLA avec mutation TARDBP de la littérature internationale, soit 108 patients. Cette analyse a été complétée par l’étude phénotypique plus détaillée des 5 mutations TARDBP les plus souvent rapportées. Résultats Il existait dans le groupe TARDBP une prédominance significative du site de début aux membres supérieurs (p = 0,0000007), une tendance à une évolution plus lente et aucune différence concernant l’âge de début. L’étude génotype-phénotype centrée sur les 5 mutations TARDBP les plus fréquentes montrait des variations dans l’âge de début et dans la durée d’évolution selon les mutations. Discussion Le tableau clinique d’une SLA avec mutation TARDBP, se distingue des autres SLA par un début plus fréquent aux membres supérieurs et une évolution plus lente. Certaines mutations sont associées à un profil plus spécifique mais la corrélation génotype-phénotype nécessitera des groupes plus importants pour une analyse plus fine. Conclusion Ces différences pourraient aider le clinicien à privilégier l’analyse d’un gène ou d’un autre (SOD1 ou TARDBP) en fonction du phénotype, les mutations SOD1 débutant, elles, plus souvent aux membres inférieurs.
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ABSTRACT
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ABSTRACT Neurologic disorders represent the most severe complications of acute intermittent porphyria (AIP). Cognitive disturbances, bulbar and spinal weakness appear as the most critical neurological complications as they may lead to... more
ABSTRACT Neurologic disorders represent the most severe complications of acute intermittent porphyria (AIP). Cognitive disturbances, bulbar and spinal weakness appear as the most critical neurological complications as they may lead to death or definitive motor weakness. A 38-year-old woman was admitted for an acute and painful tetra paresis occurring after a laparoscopy for an ovarian cyst. She also complained of abdominal pain treated with noramidopyrine, tachycardia, hypertension and hyponatremia. The electrophysiological examination showed a motor axonal neuropathy. The increase of Urine ALA at 268 μmol/l (N&lt;38) and of at 235 μmol/l (N&lt;5) strongly suggested AIP that was further confirmed by PBG desaminase deficiency in red cells. Thanks to the prescription of heme arginate (HA) at the dose of 3 mg/kg/day for 4 days, pain resolved immediately and motor function began to improve since the second day of treatment concurrently to a dramatic decrease of both urine ALA and PBG concentrations. Motor recovery was complete after 12 months of evolution. This case illustrates the potential severity of acute porphyric neuropathy when precipitating factors (noramidopyrine, surgery) are present in previously undiagnosed AIP. Moreover, motor neuronal function improved while HA therapy was initiated 22 days after the clinical onset of weakness. This tempts us to propose HA therapy at any stage of acute porphyric neuropathy.