Papers by Philippe Corcia
Expert Review of Neurotherapeutics, Sep 20, 2016
Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disord... more Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder affecting both upper and lower motor neurons. Despite much research and effort, no clear insights into a unifying hypothesis for the pathogenesis has so far emerged for this disease. Areas covered: We review the main pathophysiological hypotheses and the potential therapeutic targets in ALS, as well as the management of these patients (in order to improve their survival and quality of life). Expert commentary: ALS is a complex neurodegenerative disease, these days considered as a multisystem disorder with predominant motor symptoms (and various clinical forms). Further comprehension of the pathophysiology of this disease is required, although pathophysiological mechanisms (such as TDP-43) show promise in the search for new therapies. There is still no curative treatment for ALS, but the emergence of multidisciplinary specialized ALS clinics has increased both the quality of life and the survival of these patients.
Neural Regeneration Research, 2017
Amyotrophic lateral sclerosis (ALS), identified as a distinct clinical entity by Charcot since th... more Amyotrophic lateral sclerosis (ALS), identified as a distinct clinical entity by Charcot since the end of the nineteenth century, is a devastating and fatal neurodegenerative disorder that affects motor neurons in the brain, brainstem and spinal cord. Survival of patients with ALS is associated with several factors such as clinical phenotype, age at onset, gender, early presence of respiratory failure, weight loss and treatment with Riluzole (the only disease-modifying drug approved for this disease). Nowadays, there is still no curative treatment for ALS: palliative care and symptomatic treatment are therefore essential components in the management of these patients. Nevertheless, the scientific knowledge in the field of ALS motor neuron degeneration is growing, with the prospect of new treatments. Based on this physiopathological knowledge, several new therapeutic targets are being studied, involving various mechanisms such as excitotoxicity, neuroinflammation, mitochondrial dysfunction, oxidative stress, RNA metabolism and other attractive concepts. Moreover, it is also important to identify reliable biomarkers that will be essential components for future therapeutic development and study design in ALS. In this review, we present the main recent advances and promising therapeutics and biomarkers in the field of ALS.
Epilepsy & Behavior, Aug 1, 2016
The purpose of this study was to evaluate the effectiveness and safety of PER as add-on treatment... more The purpose of this study was to evaluate the effectiveness and safety of PER as add-on treatment in patients with severe refractory epilepsy with a particular focus on patients with learning disability and/or psychiatric comorbidity. Method: We pooled retrospective data from adult patients with refractory epilepsy prescribed perampanel from a tertiary center in France between 1st May 2014 and 3rd June 2015. Data collection was done on February 2016. Results: One hundred and one patients were included (mean age: 41.2 years, 37.6% with learning disability and 49.5% with psychiatric comorbidity). Mean retention was 8.1 months (range: 14 days to 17 months). On final evaluation, a N50% reduction in seizure frequency was reached in 41.6% of patients, and 7 patients (6.9%) became seizure-free. Sixty-three patients (62.4%) experienced adverse effects. The most common adverse effects were irritability, asthenia, aggression, and sedation. Efficacy, retention of treatment, and safety were equally similar in patients with learning disability or psychiatric comorbidity as for those without. The only significant difference was in percentage of seizure-free patients: 11.1% in the group without learning disability compared with 0% in the group with (p = 0.043). Conclusion: Adjunctive PER can achieve clinically meaningful improvement, or even seizure freedom, in more than one-third of patients suffering from severe refractory epilepsies. It seems similarly safe and effective in the subgroup of these patients with learning disability or with psychiatric comorbidity. However, the rate of psychiatric side effects is high,; of note, we asked both patient and caregivers at each visit especially focusing on psychiatric side effects. Patients, caregivers, and families should be informed of potential psychiatric/behavioral risks associated with taking perampanel especially during the initial titration period.
Neurobiology of Aging, Apr 1, 2012
Mutations in UBQLN2 encoding ubiquilin-2 have recently been identified in families with dominant ... more Mutations in UBQLN2 encoding ubiquilin-2 have recently been identified in families with dominant X-linked juvenile and adult-onset amyotrophic lateral sclerosis (ALS) and ALS/dementia. Ubiquilin-2 is a component of the ubiquitin inclusions detected in degenerating neurons in ALS patients. All the previously reported UBQLN2 mutations were localized in 1 of the 12 PXX domains of ubiquilin-2 protein. We sequenced UBQLN2 in 130 French patients with familial ALS (FALS) and absence of male-to-male transmission and the PXX domain in 240 more patients with sporadic ALS (SALS). We identified, at the heterozygote state, the c.1500_1508delCATAGGCCC, p.Gly502_Ile504del, in 1 affected woman. This deletion presumably leads to the in-frame deletion of 1 PXX repeat in the protein. This variant did not segregate with the disease in the corresponding family and was also detected in 1/380 control subject. Our results suggest that UBQLN2 gene mutations are rare in French ALS.
Journal of Neurology, Neurosurgery, and Psychiatry, Jan 6, 2021
ObjectivesTo determine whether the familial clustering of amyotrophic lateral sclerosis (ALS) cas... more ObjectivesTo determine whether the familial clustering of amyotrophic lateral sclerosis (ALS) cases and the phenotype of the disease may help identify the pathogenic genes involved.MethodsWe conducted a targeted next-generation sequencing analysis on 235 French familial ALS (FALS), unrelated probands to identify mutations in 30 genes linked to the disease. The genealogy, that is, number of cases and generations with ALS, gender, age, site of onset and the duration of the disease were analysed.ResultsRegarding the number of generations, 49 pedigrees had only one affected generation, 152 had two affected generations and 34 had at least three affected generations. Among the 149 pedigrees (63.4%) for which a deleterious variant was found, an abnormal G4C2 expansion in C9orf72 was found in 98 cases as well as SOD1, TARBP or FUS mutations in 30, 9 and 7 cases, respectively. Considering pedigrees from the number of generations, abnormal G4C2 expansion in C9orf72 was more frequent in pedigrees with pairs of affected ALS cases, which represented 65.2% of our cohort. SOD1 mutation involved all types of pedigrees. No TARDBP nor FUS mutation was present in monogenerational pedigrees. TARDBP mutation predominated in bigenerational pedigrees with at least three cases and FUS mutation in multigenerational pedigrees with more than seven cases, on average, and with an age of onset younger than 45 years.ConclusionOur results suggest that familial clustering, phenotypes and genotypes are interconnected in FALS, and thus it might be possible to target the genetic screening from the familial architecture and the phenotype of ALS cases.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of... more Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Across environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for pert...
Amyotrophic lateral sclerosis & frontotemporal degeneration, 2018
Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the most frequent motor... more Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the most frequent motor neuron disorders in adulthood and infancy, respectively. There is a growing literature supporting common pathophysiological patterns between those disorders. One important clinical issue for that is the co-occurrence of both diseases within a family. To collect families in which ALS and SMA patients co-exist and describe the phenotype and the genotype of ALS patients. Nine families with co-occurrence of SMA and ALS have been gathered over the last 15 years. Epidemiological, phenotype and genetic status were collected. Out of the nine families, six corresponded to the criteria of familial ALS (FALS). Clinical data were available for 11 patients out of the 15 ALS cases. Mean age of onset was 58.5 years, site of onset was lower limbs in nine cases (81.8%), median duration was 22 months. Four ALS patients carried a mutation: three mutations in SOD1 gene (G147N in two cases and one with E121...
Neuron, Jan 21, 2018
To identify novel genes associated with ALS, we undertook two lines of investigation. We carried ... more To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis o...
Neural regeneration research, 2017
Amyotrophic lateral sclerosis (ALS), identified as a distinct clinical entity by Charcot since th... more Amyotrophic lateral sclerosis (ALS), identified as a distinct clinical entity by Charcot since the end of the nineteenth century, is a devastating and fatal neurodegenerative disorder that affects motor neurons in the brain, brainstem and spinal cord. Survival of patients with ALS is associated with several factors such as clinical phenotype, age at onset, gender, early presence of respiratory failure, weight loss and treatment with Riluzole (the only disease-modifying drug approved for this disease). Nowadays, there is still no curative treatment for ALS: palliative care and symptomatic treatment are therefore essential components in the management of these patients. Nevertheless, the scientific knowledge in the field of ALS motor neuron degeneration is growing, with the prospect of new treatments. Based on this physiopathological knowledge, several new therapeutic targets are being studied, involving various mechanisms such as excitotoxicity, neuroinflammation, mitochondrial dysfu...
Expert Review of Neurotherapeutics, 2016
Revue Neurologique, 2007
Introduction Decrite depuis environ 15 ans, l’anarthrie progressive (AnP) est une atrophie cortic... more Introduction Decrite depuis environ 15 ans, l’anarthrie progressive (AnP) est une atrophie corticale focale (ACF) rare, caracterisee par un trouble arthrique avec apraxie bucco-faciale evoluant vers un mutisme avec syndrome frontal. Objectifs Analyser les caracteristiques cliniques, neuropsychologiques et paracliniques de patients atteints d’une AnP pour en preciser le cadre nosographique. Methodes Cette etude retrospective porta sur 5 patients AnP avec recueil de l’âge d’apparition des symptomes, l’âge du diagnostic, le motif de la premiere consultation et des donnees cliniques et neuropsychologiques initiales. Les resultats de l’electromyogramme (EMG), de l’IRM cerebrale, de la scintigraphie cerebrale de perfusion furent analyses. Le caractere evolutif fut evalue grâce a l’examen clinique et les bilans neuropsychologiques. Resultats L’âge de debut moyen etait de 75,2 ± 5,8 ans. Les patients consultaient a 11,2 ± 3 mois d’evolution en consultation memoire (n = 3) ou orientee motoneurone (n = 2). La dysarthrie etait associee a un syndrome dysexecutif et parfois, en cours d’evolution, a des troubles de la comprehension. L’EMG etait normal. Une atrophie temporale et/ou frontale gauche etait presente sur l’IRM cerebrale (n = 3). La scintigraphie cerebrale de perfusion montrait un hypodebit frontal ou temporal gauche (n = 4). Discussion L’orientation initiale vers le specialiste est variable avec un delai diagnostique relativement long pour un handicap social important. Les examens paracliniques permettent d’ecarter une pathologie du motoneurone et d’argumenter le diagnostic d’ACF. A la phase initiale, l’absence de trouble du langage et l’existence d’un syndrome dysexecutif amenent a considerer l’AnP comme une forme d’ACF touchant l’opercule frontal. Conclusion L’AnP presente des caracteristiques cliniques et neuropsychologiques qui en font une entite particuliere au sein des atrophies corticales focales.
Revue Neurologique, 2009
International audienc
Neurology, 2012
To describe the phenotype and phenotype-genotype correlations in patients with amyotrophic latera... more To describe the phenotype and phenotype-genotype correlations in patients with amyotrophic lateral sclerosis (ALS) with TARDBP gene mutations. French TARDBP+ patients with ALS (n = 28) were compared first to 3 cohorts: 737 sporadic ALS (SALS), 192 nonmutated familial ALS (FALS), and 58 SOD1 + FALS, and then to 117 TARDBP+ cases from the literature. Genotype-phenotype correlations were studied for the most frequent TARDBP mutations. In TARDBP+ patients, onset was earlier (p = 0.0003), upper limb (UL) onset was predominant (p = 0.002), and duration was longer (p = 0.0001) than in patients with SALS. TARDBP+ and SOD1+ groups had the longest duration but diverged for site of onset: 64.3% UL onset for TARDBP+ and 74.1% on lower limbs for SOD1+ (p < 0.0001). The clinical characteristics of our 28 patients were similar to the 117 cases from the literature. In Caucasians, 51.3% of had UL onset, while 58.8% of Asians had bulbar onset (p = 0.02). The type of mutation influenced survival (p < 0.0001), and the G298S1, lying in the TARDBP super rich glycine-residue domain, was associated with the worst survival (27 months). Differences in phenotype between the groups as well as the differential influence of TARBDP mutations on survival may help physicians in ALS management and allow refining the strategy of genetic diagnosis.
Journal of the Neurological Sciences, 2010
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. During the course of th... more Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. During the course of the illness, malnutrition can occur and may shorten survival. The aim of our study was to determine whether clinical nutritional parameters that are used in daily practice are associated with prognosis and whether they can help guide therapeutic decisions. We retrospectively reviewed a cohort of ALS patients in our institution between January 2002 and January 2006. Clinical and demographic outcomes were compiled. To evaluate predictors of survival, we analyzed several clinical nutritional parameters available in daily practice (body mass index, weight loss exceeding 10% of premorbid weight at the time of diagnosis and during the course of the disease and the use of technical supports such as percutaneous endoscopic gastrostomy (PEG) and non-invasive ventilation). Sixty-three patients were retrospectively studied. Thirteen patients had weight loss exceeding 10% of premorbid weight at the time of diagnosis and thirty patients had weight loss meeting this criterion at final examination. Weight loss exceeding 10% at the time of diagnosis was associated with a shorter duration of disease (17±6months versus 35±26months; p=0.002). A linear correlation was found between mean disease duration and time between onset and diagnosis (p<0.0001). The subgroup of patients with a PEG had a longer survival time than the other subgroup of patients (p=0.02). In ALS patients, early and marked weight loss significantly predicts a worse prognosis. The percentage of premorbid weight loss is a suitable and useful measure that can be used in daily practice to identify patients with a poor prognosis.
Amyotrophic Lateral Sclerosis, 2008
Death represents the main hallmark of amyotrophic lateral sclerosis (ALS). Despite its importance... more Death represents the main hallmark of amyotrophic lateral sclerosis (ALS). Despite its importance in clinical care and phase III trials, many uncertainties remain on the cause of death due to the lack of post-mortem verifications. To provide a more robust approach to these causes, we performed a retrospective pathological study on a large cohort of patients. 100 ALS patients referred for a deterioration of their clinical condition and who died in the ALS clinic of Salpétrière had a complete macroscopic and microscopic post-mortem analysis. The clinical causes of death reported on medical records were compared to the results of autopsy. The concordance between clinical and pathological conclusions was insufficient (20%) to consider clinical assessment as a reliable marker of causes of death. At autopsy, broncho-pneumonia and pneumonia were the main causes of death. Heart failure, representing 10% of deaths, was two times more frequent in bulbar than in spinal ALS. Pulmonary embolism representing 6% of death was exclusively found in spinal onset patients and is related to lower limbs disability. An effort has to be made for a better understanding of the causes of deterioration of ALS patients. A more proactive attitude to treat respiratory infections could have a significant impact on survival.
Amyotrophic Lateral Sclerosis, 2010
Our objectives were to analyse carbohydrate metabolism in a series of ALS patients and to examine... more Our objectives were to analyse carbohydrate metabolism in a series of ALS patients and to examine potential association with parameters of lipid metabolism and clinical features. Glucose tolerance was assessed by the oral glucose tolerance test in 21 non-diabetic ALS patients and compared with 21 age- and sex-matched normal subjects. Lipids and lactate/pyruvate ratio, levels of pro-inflammatory cytokines (tumour necrosis factor-alpha and interleukin-6) and adipocytokines (leptin and adiponectin) were also measured in ALS patients. Mann-Whitney U-tests analysed continuous data and Fisher's exact tests assessed categorical data. Blood glucose determined 120 min after the glucose bolus was significantly higher in patients with ALS (7.41 mmol/l+/-1.68) compared to controls (6.05+/-1.44, p=0.006). ALS patients with impaired glucose tolerance (IGT) according to WHO criteria (n=7, 33%) were more likely to have elevated free fatty acids (FFA) levels compared to patients with normal glucose tolerance (0.77 nmol/l+/-0.30 vs. 0.57+/-0.19, p=0.04). IGT was not associated with disease duration or severity. In conclusion, patients with ALS show abnormal glucose tolerance that could be associated with increased FFA levels, a key determinant of insulin resistance. The origin of glucose homeostasis abnormalities in ALS may be multifactorial and deserves further investigation.
Journal of Medical Genetics, 2010
Background. Mutations in SOD1, ANG, VAPB, TARDBP and FUS genes have been identified in amyotrophi... more Background. Mutations in SOD1, ANG, VAPB, TARDBP and FUS genes have been identified in amyotrophic lateral sclerosis (ALS). Methods. We estimated the relative contributions of the different mutations to ALS by systematically screening a cohort of 162 families enrolled in France and 500 controls (1000 chromosomes) using molecular analysis techniques and performing phenotype-genotype correlations. Results. We found 31 pathogenic missense mutations in 36 patients (20 SOD1, 1 ANG, 1 VAPB, 7 TARDBP and 7 FUS). Surprisingly two FUS mutation carriers also harbored ANG variants. We identified one family of Japanese origin with the P56S VAPB mutation. Seven novel mutations (3 in SOD1, 2 in TARDBP, 2 in FUS) were found. None of them was detected in controls. Segregation of detected mutations with the disease was confirmed in 11 families including 5 pedigrees carrying the novel mutations. Clinical comparison of SOD1, TARDBP, FUS and other FALS patients (with no mutation in the screened genes) revealed differences in site of onset (predominantly lower limbs for SOD1 and upper limbs for TARDBP mutations), age of onset (younger with FUS mutations) and in life span (shorter for FUS carriers). One third of SOD1 patients survived more than 7 years: these patients had earlier disease-onset than those presenting with more typical course. Differences were also observed among FUS mutations, with the R521H FUS mutation being associated with longer disease duration. Conclusions. This study identifies new genetic associations with ALS and provides phenotype-genotype correlations with both previously reported and novel mutations.
Sleep Medicine, 2009
Sleep disorders have been well studied in prion disease, particularly in fatal familial insomnia ... more Sleep disorders have been well studied in prion disease, particularly in fatal familial insomnia (FFI) [1], but not in variant Creutzfeldt-Jakob disease (vCJD). We report the case of a 32year-old French woman with neuropathologically confirmed vCJD who underwent five polysomnographies. She was homozygous for methionine at codon 129 on the prion protein gene. The first polysomnography was performed 8 months after the onset because she complained of insomnia. It showed a dramatic reduction in total sleep time (106 min). Only residual spindles were found. Six months later another polysomnography showed a normal total sleep time (409 min) with only one slow-wave sleep period and a single and short REM sleep period. In the second part of night, sleep became fragmented with increased interspersed wakefulness. One month later polysomnography was performed during two consecutive nights and one day. Total sleep time was reduced (315 and 225 min in nights, 71 min in day). It showed almost lack of sleep spindles, slow-wave sleep and difficulty maintaining sleep. Only short REM sleep periods persisted. Thus, polysomnographic features were comparable to those observed in FFI [1,2], sporadic fatal insomnia [3] and familial CJD with methionine homozygous at PRNP codon 129 [4]. The codon-129 polymorphism constitutes a determinant of sleep characteristics and seems to be associated with more damage in the thalamus [2]. These diseases are characterized by predominant damage of the thalamus particularly in anterior and dorsomedian nuclei, which are the recognised source of spindle activity [5]. The loss of spindling should also explain other sleep recording features such as reduction of slow-wave sleep and REM sleep. In normal sleep, spindle activity precedes the onset of both slow wave and REM sleep and marks the progressive transition to a deeper stage of sleep [2].
Neurology, 2009
Background: Amyotrophic lateral sclerosis (ALS) is the most serious form of degenerative motor ne... more Background: Amyotrophic lateral sclerosis (ALS) is the most serious form of degenerative motor neuron disease in adults, characterized by upper and lower motor neuron degeneration, skeletal muscle atrophy, paralysis, and death. High prevalence of malnutrition and weight loss adversely affect quality of life. Moreover, two thirds of patients develop a hypermetabolism of unknown cause, leading to increased resting energy expenditure. Inasmuch as lipids are the major source of energy for muscles, we determined the status of lipids in a population of patients with ALS and investigated whether lipid contents may have an impact on disease progression and survival. Methods: Blood concentrations of triglycerides, cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were measured in a cohort of 369 patients with ALS and compared to a control group of 286 healthy subjects. Postmortem histologic examination was performed on liver specimens from 59 other patients with ALS and 16 patients with Parkinson disease (PD). Results: The frequency of hyperlipidemia, as revealed by increased plasma levels of total cholesterol or LDL, was twofold higher in patients with ALS than in control subjects. As a result, steatosis of the liver was more pronounced in patients with ALS than in patients with PD. Correlation studies demonstrated that bearing an abnormally elevated LDL/HDL ratio significantly increased survival by more than 12 months. Conclusions: Hyperlipidemia is a significant prognostic factor for survival of patients with amyotrophic lateral sclerosis. This finding highlights the importance of nutritional intervention strategies on disease progression and claims our attention when treating these patients with lipidlowering drugs. Neurology ® 2008;70:1004-1009 GLOSSARY AD ϭ Alzheimer disease; ALS ϭ amyotrophic lateral sclerosis; ALS-FRS ϭ ALS functional rating scale; BMI ϭ body mass index; HDL ϭ high-density lipoprotein; LDL ϭ low-density lipoprotein; PD ϭ Parkinson disease. Amyotrophic lateral sclerosis (ALS) is a chronic, adult-onset neurodegenerative disorder affecting both the lower motor neurons in the spinal cord and brainstem and the upper motor neurons in the motor areas of the cerebral cortex and leading to death within 2 to 5 years of onset through failure of the respiratory muscles. 1 Despite the traditional view of ALS as a pure motor neuron disorder, growing evidence suggests that the disease is, in fact, a multisystem disorder with additional extramotor neurologic manifestations. Beyond the nervous system, intriguing metabolic alterations have also been observed in association with the course of the disease. 2 In particular, recent studies revealed that two thirds of patients with ALS present with a stable hyper
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Papers by Philippe Corcia