Showing papers by "Vincent Meininger published in 2011"
TL;DR: The coding exons of OPTN were sequenced in 126 French patients with familial ALS and it was found that the nonsense c.382_383insAG variant led to a loss of function and the latter did not cause protein accumulation, but the results do not confirm the contribution of OPTn in ALS.
77 citations
TL;DR: In vivo and in vitro investigation of skeletal muscle in ALS suggests that SC function is altered in ALS, which could limit the efficacy of compensatory processes and therefore contribute to the progression of muscle atrophy and weakness.
Abstract: Amyotrophic lateral sclerosis (ALS) is characterized by progressive denervation leading to muscle atrophy prevented, during the early phase, by compensatory reinnervation. Little is known about muscle fibre regeneration capacity in ALS. We have carried out in vivo and in vitro investigation of skeletal muscle in ALS. Seven ALS patients underwent a deltoid muscle biopsy. Immunohistochemical analysis revealed various degrees of denervation- and reinnervation-related changes in the ALS muscle biopsies including satellite cells (SCs) activation and regenerating fibres. Only 3/7 primary cultures of ALS muscle cells were successfully established and had sufficient myogenicity, as assessed by desmin positivity, to be used without further purification. This was in contrast with the cultures derived from control muscles, predominantly desmin-positive cells. Although capable to proliferate in vitro, ALS-derived SCs presented an abnormal senescent-like morphology. Markers of senescence, including senescent-associated (SA)-βGal activity and p16 expression, were increased. Furthermore, ALS-derived SCs were also unable to fully differentiate in vitro as shown by abnormal myotubes morphology and reduced MHC isoform expression, compared to control myotubes. Our study suggests that SC function is altered in ALS. This could limit the efficacy of compensatory processes and therefore could contribute to the progression of muscle atrophy and weakness.
74 citations
TL;DR: Key issues related to the pathophysiology, preclinical studies and clinical trials that should be addressed in the future include the relationships between different disease mechanisms, the challenges presented by the heterogeneity of the disease, and the need for early intervention, optimal dose selection and effective biomarkers.
Abstract: Since the approval of riluzole for the treatment of amyotrophic lateral sclerosis (ALS) 17 years ago, more than 30 large clinical trials have been conducted, but none has proved successful. The failure to translate positive preclinical results into the clinical setting raises questions about the validity of the rodent model that is used to study ALS, and about the quality of both preclinical and clinical studies. However, the greatest challenge is the disease itself as, with rare exceptions, the causes are unknown. In this Perspectives article, we highlight key issues related to the pathophysiology, preclinical studies and clinical trials that should be addressed in the future. These areas include the relationships between different disease mechanisms, the challenges presented by the heterogeneity of the disease, and the need for early intervention, optimal dose selection and effective biomarkers.
54 citations
TL;DR: FUS gene mutations are rare in SALS, with four new FUS variants identified in five different SALS cases, two of which are located in the carboxy terminal of the protein where the previously reported variants were mostly clustered.
Abstract: Mutations in the FUS gene have been recently associated with amyotrophic lateral sclerosis (ALS). While most of the variants have been identified in patients with a family history of the disease, a few mutations were also found in sporadic patients. Considering this, we wanted to evaluate the frequency of mutations in the coding region of the FUS gene in a sporadic ALS (SALS) cohort compared to a control population. We tested 475 SALS cases of European origin and 475 matched controls for coding variations in the 15 exons of the FUS gene. Rare novel variants were identified in a total of five SALS patients: one missense, one deletion, one frameshift, and one nonsense substitution. Two of the four variants are located in the carboxy terminal of the protein where the previously reported variants were mostly clustered. In conclusion, FUS gene mutations are rare in SALS, with four new FUS variants identified in five different SALS cases. These findings will help evaluate the proportion of FUS variation...
35 citations
TL;DR: The findings support an implication for iron metabolism in ALS and suggest that the genotype of the SLC11A2 gene could modulate the duration of the disease in French SALS patients.
33 citations
TL;DR: Mortality rates for MND increased between 1968 and 2007, and more rapidly in women than men, and this increase was better explained by the birth-cohort of individuals than by period effects.
Abstract: The incidence and mortality of motor neuron disease (MND) increase with age and appear to have increased with time. The examination of period and cohort effects using age-period-cohort (APC) models can help characterize temporal trends. Our objective was to describe mortality from MND in France (1968-2007), and to examine the role of age, period of death, and birth-cohort on changes in mortality. The number of people who died from MND and population statistics (1968-2007) were extracted from French national records. Annual standardized (age/sex) mortality ratios (SMRs) were computed. Using Poisson regression, APC models examined the relationship between mortality rates and age, period of death, and birth-cohort in subjects aged 40-89 years. Deviance/degrees-of-freedom ratios evaluated model fit; ratios close to one indicated adequate fit. Between 1968 and 2007, 38,863 individuals died from MND (mortality rate = 1.74/100,000); 37,624 were aged 40-89 years. SMRs increased from 54 (95% CI = 49-59) in 1968 to 126 (120-132) in 2007. Male-to-female ratios declined from 1.80 in 1968 to 1.45 in 2007. Changing mortality rates were best explained by cohort effects (deviance/degrees-of-freedom = 1.09). The relative risk of dying from MND increased markedly for persons born between 1880 and 1920, and more slowly after 1920. In conclusion, mortality rates for MND increased between 1968 and 2007, and more rapidly in women than men. This increase was better explained by the birth-cohort of individuals than by period effects. Changing environmental exposures may be a possible explanation and these findings warrant the continued search for environmental risk factors for MND.
31 citations
TL;DR: The protein muscle expression of TDP-43 and FUS in s-IBM compared to sporadic amyotrophic lateral sclerosis patients (including one patient with TARDBP gene mutation) and controls is investigated and abnormal FUS and T DP-43 fragments in s -IBM and TARD BP -linked disease are reported.
Abstract: Abnormal protein deposits are observed in the cytoplasm of sporadic inclusion body myositis (s-IBM) muscle. A number of proteins known to be included in s-IBM aggregates have also been described in various neurodegenerative diseases, including ubiquitin, β amyloid peptide, α -synuclein, phosphorylated τ and TAR DNA-binding protein (TDP-43).
In the central nervous system (CNS), TDP-43 aggregates are characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive neuronal inclusions. Numerous dominant mutations in the TARDBP gene encoding TDP-43 protein have been reported in ALS cases, demonstrating that TDP-43 abnormalities could directly trigger neurodegeneration. The recent discovery of mutations in the gene encoding Fused in Sarcoma (FUS) protein, which shares functional and structural homology with TDP-43, has strengthened the prominence of gene expression-mediating proteins in ALS pathogenesis. Whether muscle TDP-43 aggregates observed in s-IBM are just trashed protein, or whether they are pathogenic, particularly trough RNA metabolism disturbances, remains unknown.
We hypothesised that FUS protein could be altered in TDP-43 positive muscles of s-IBM. For this purpose, we investigated the protein muscle expression of TDP-43 and FUS in s-IBM compared to sporadic amyotrophic lateral sclerosis (SALS) patients (including one patient with TARDBP gene mutation) and controls. We report abnormal FUS and TDP-43 fragments in s-IBM and TARDBP -linked disease.
Five patients with s-IBM, five patients with …
29 citations
TL;DR: HPN is an alternative procedure to PEG in advanced ALS patients and a prospective study comparing HPN and radiologic inserted gastrostomy (RIG) would allow comparison of the relative risk-benefit and survival of these procedures.
Abstract: We carried out a retrospective multicentre study to assess the safety of home parenteral nutrition (HPN) in patients with ALS. We reviewed the case records of patients from French ALS centres treated with HPN by central venous catheter (CVC) using an implantable port between January 2005 and October 2009. Seventy-three patients received HPN for a total of 11,908 catheter days. Twenty-seven patients experienced a total of 37 CVC related complications resulting in an incidence rate of 3.11 CVC complications/1000 catheter days, including 1.93 septic complications and 1.09 mechanical complications/1000 catheter days. Metabolic complications were frequent but without serious consequences on mortality. The use of the catheter for intravenous therapies in addition to HPN was identified as a septicaemia's risk factor (relative risk (RR) = 2.54, confidence interval (CI) 1.56–4.14, p = 0.04). In conclusion, HPN is an alternative procedure to PEG in advanced ALS patients. The incidence of complications appea...
25 citations
TL;DR: Whether intersecting basic, pre-clinical and clinical knowledge of ALS may lead to a coherent novel scenario allowing to translate basic findings into clinical practice is investigated.
Abstract: A B S T R A C T Introducing ALS at present times leads to re-define the concept of motor neuron selectivity which characterizes this disorder. In fact, multiple systems including skin, liver, and bone marrow are altered in ALS patients. The motor neuron is still the focus of the disorder and the extended pathology did not modify the concept of ALS as a devastating disorder based on motor neuron loss. Nonetheless, the involvement of non-motor neurons as well as areas outside the central nervous system leads to a different perspective to understand the causes, pathophysiology and therapy of ALS. For this reason a specific issue is dedicated to understand whether intersecting basic, pre-clinical and clinical knowledge of ALS may lead to a coherent novel scenario allowing to translate basic findings into clinical practice. Several pre-clinical issues described in this volume appear robust enough to indicate that we should modify a number of approaches when designing future therapeutic strategies. Similarly, novel investigations based on altered cell to cell communication are needed to further progress in understanding amyotrophic lateral sclerosis.
6 citations
01 Jan 2011
TL;DR: The finding of persistent multifocal conduction block confined to motor nervefibres raises questions about the nature and the importance ofthissyndrome and the existence of a distinct entity.
Abstract: Twentyfourpatients withpuremotor neuropathy arereported. The chronic motorinvolvement associated withfasciculations andcramps,mainlyinthearms, led,inmostpatients, toaninitial diagnosisofmotorneurondisease. In some patients (nineof24),therewasnoappreciable muscleatrophy. Tendonreflexes wereoftenabsent orweak.Thefinding of persistent multifocal conduction block confined to motor nervefibres raises questions aboutthe natureand the importance ofthissyndrome. Segmental reduction ofmotorconduction velocity occurred atthesiteoftheblock, butsignificant slowing ofmotornerveconductionwasnotfoundoutside thissite. The responsetointravenous IVIgtreatment seemstobecorrelated withtheabsence ofamyotrophy. Patients withlittle orno amyotrophy hadaninitial andsustained responsetoIVIg,anddidnotdevelop amyotrophy duringthefollow up study. Theycouldbeconsidered tohaveavariantofchronicinflammatory demyelinatingpolyneuropathy. Patientswith pronounced amyotrophy independent of thedisease duration didnotrespondas wellto IVIgtreatment, suggesting the existence ofa distinct entity. Among the patients treated abouttwothirds whohad aninitial goodresponse toIVIghadhigh orsignificant antiganglioside GM1 (antiGM1) antibody titres, buttherewas no correlation betweenthehightitres before treatmentandlonglasting responseto IVIgtreatment. (JNeurol Neurosurg Psychiatry 1995;59:38-44)