Biomedical subjects

Jean Pouget

Publications and source records attributed to Jean Pouget.

16 recordsLinked to original sources

PubMed2006

Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay.

ANT1, TWINKLE and POLG genes affect mtDNA stability and are involved in autosomal dominant PEO, while mutations in POLG are responsible for numerous clinical presentations, including autosomal recessive PEO, sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO), spino-cerebellar ataxia and epilepsy (SCAE) or Alpers syndrome. In this study, we report on the mutational analysis of ANT1, TWINKLE and POLG genes in 15 unrelated patients, using a dHPLC-based protocol. This series of patients illustrates the large array of clinical presentations associated with mtDNA stability defects, ranging from isolated benign PEO to fatal Alpers syndrome. A total of seven different mutations were identified in six of 15 patients (40%). Six different recessive mutations were found in POLG, one in TWINKLE while no mutation was identified in ANT1. Among the POLG mutations, three are novel and include two missense and one frameshift changes. Seventeen neutral changes and polymorphisms were also identified, including four novel neutral polymorphisms. Overall, this study illustrates the variability of phenotypes associated with mtDNA stability defects, increases the mutational spectrum of POLG variants and provides an efficient and reliable detection protocol for ANT1, TWINKLE and POLG mutational screening.

Adenine Nucleotide Translocator 1↗

PubMed2006

Cortical versus spinal dysfunction in amyotrophic lateral sclerosis.

Little is known about the possible link between cortical and spinal motor neuron dysfunction in amyotrophic lateral sclerosis (ALS). We correlated the characteristics of the responses to transcranial magnetic stimulation (TMS) with the electromechanical properties and firing pattern of single motor units (MUs) tested in nine ALS patients, three patients with Kennedy's disease, and 15 healthy subjects. In Kennedy's disease, 19 of 22 MUs were markedly enlarged with good electromechanical coupling and discharged with great variability. Their excitatory responses increased with MU size. In ALS, 17 of 34 MUs with excitatory responses behaved as in Kennedy's disease. By contrast, 28 MUs with nonsignificant responses showed poor electromechanical coupling and high firing rates, whereas 28 MUs with inhibitory responses showed moderate functional alterations. This result indicates that in ALS as in Kennedy's disease, sprouting of corticospinal axons may occur on surviving motoneurons. A clear relationship exists between the responsiveness of MUs to TMS and their functional state.

Adolescent↗

PubMed2006

Platelet-endothelial cell adhesion molecule-1 and CD146: soluble levels and in situ expression of cellular adhesion molecules implicated in the cohesion of endothelial cells in idiopathic inflammatory myopathies.

OBJECTIVE: Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of diseases characterized by chronic inflammation of muscles. We investigated the role of cellular adhesion molecules implicated in the cohesion of endothelial cells in IIM. METHODS: In 22 patients with IIM we investigated plasma concentrations of soluble junctional adhesion molecules [platelet-endothelial cell adhesion molecule (sPECAM-1) and sCD146] and cellular adhesion molecules [sP-selectin, sE-selectin, intercellular adhesion molecule (sICAM-1), and vascular cell adhesion molecule (sVCAM-1)] implicated in leukocyte/endothelial cell interactions. Results were compared to a control group. Muscle biopsy samples from 8 out of 22 IIM patients were studied by immunohistochemistry for tissue expression of these molecules and compared to normal muscle samples. PECAM-1 and CD146 expression was also studied using immunoblots from muscle biopsies from 5 patients and 2 controls. RESULTS: We observed distinct patterns of soluble levels and in situ expression between dermatomyositis (DM), polymyositis (PM), and sporadic inclusion body myositis (s-IBM). PM samples showed significantly increased levels of sCD146, sPECAM-1, and s-ICAM1 and increased expression of CD146, CD31, and ICAM-1 in endothelial cells, whereas CD146 and ICAM-1 were also recorded in some muscle fibers. In DM, sE-selectin, sP-selectin, and sPECAM-1 were significantly increased, with abnormal expression of ICAM-1 in endothelial cells and perifascicular muscle fibers. In the small group of s-IBM samples, results were similar to PM, but the only significant increase was the level of sPECAM-1. Immunoblots confirmed increased expression of PECAM-1 and CD146 in all IIM muscles in comparison to controls, with the highest expression in PM and IBM samples. CONCLUSION: We observed abnormal increases of soluble levels of adhesion molecules implicated in endothelial cell junctions in PM (sCD146, sPECAM-1) and to a lesser extent in DM and s-IBM (sPECAM-1). We conclude that the distinctly different profiles between PM/s-IBM and DM reflect differences in the pathophysiological background of these diseases.

CD146 Antigen↗

PubMed2005

Dysferlin mutations in LGMD2B, Miyoshi myopathy, and atypical dysferlinopathies.

DYSF encoding dysferlin is mutated in Miyoshi myopathy and Limb-Girdle Muscular Dystrophy type 2B, the two main phenotypes recognized in dysferlinopathies. Dysferlin deficiency in muscle is the most relevant feature for the diagnosis of dysferlinopathy and prompts the search for mutations in DYSF. DYSF, located on chromosome 2p13, contains 55 coding exons and spans 150 kb of genomic DNA. We performed a genomic analysis of the DYSF coding sequence in 34 unrelated patients from various ethnic origins. All patients showed an absence or drastic decrease of dysferlin expression in muscle. A primary screening of DYSF using SSCP or dHPLC of PCR products of each of 55 exons of the gene was followed by sequencing whenever a sequence variation was detected. All together, 54 sequence variations were identified in DYSF, 50 of which predicting either a truncated protein or one amino-acid substitution and most of them (34 out of 54) being novel. In 23 patients, we identified two pathogenic mutations, while only one was identified in 11 patients. These mutations were widely spread in the coding sequence of the gene without any mutational "hotspot."

Child↗

PubMed2005

Lewis-Sumner syndrome and multifocal motor neuropathy.

We compared the clinical, electrophysiological, laboratory, and pathological features of 13 patients with Lewis-Sumner syndrome (LSS) with those of 20 patients with multifocal motor neuropathy (MMN). LSS and MMN patients have several common clinical features: age at onset, weakness in the distribution of individual peripheral nerves, mild wasting, cramps and fasciculations, partial areflexia, and frequent stepwise disease course. Cerebrospinal fluid protein level was normal or slightly elevated, but always less than 100 mg/dl. Conduction blocks are the electrophysiological hallmarks of these two neuropathies, and no differences in distribution and number of blocks were found. Contrary to MMN, lower-limb involvement at onset was frequent in LSS but extension to the upper limbs was a frequent later feature of the disease. Cranial nerve involvement was noted in 4 LSS patients during relapses and absent in all MMN patients. The major distinguishing features were the clinical and electrophysiological sensory involvement in LSS, and the lack of anti-GM1 antibodies in LSS, whereas IgM anti-GM1 were found in 40% of MMN patients. Some LSS patients responded to steroid therapy, whereas this was ineffective in MMN. From these features, LSS can be considered an entity distinct from MMN, with its own clinical, laboratory, and electrophysiological characteristics, and as an intermediate link between chronic inflammatory demyelinating polyneuropathy and MMN.

Action Potentials↗

PubMed2005

Functional sparing of intrafusal muscle fibers in muscular dystrophies.

In a previous study, we showed that patients with muscular dystrophies (MDs) perceive passive movements, experience sensations of illusory movement induced by muscle tendon vibration, and have proprioceptive-regulated sways in response to vibratory stimulation applied to the neck and ankle muscle tendons. These findings argue for preserved proprioceptive functions of muscle spindles. However, it is unclear whether the function of intrafusal muscle fibers is spared, i.e., whether they retain their ability to contract when submitted to a fusimotor drive. To answer this question, we analyzed the effects of reinforcement maneuvers (mental computation and the Jendrassik maneuver) that are known to increase muscle spindle sensitivity via fusimotor drive in healthy subjects. Nine patients with different MDs participated in the study. Reinforcement maneuvers increased both the mean amplitude of the Achilles tendon reflex (187 +/- 52.9% of the mean control amplitude) and the sensitivity of muscle spindle afferents to imposed movements of the ankle. The same reinforcement maneuvers failed to alter the amplitude of the Hoffmann reflex in the triceps surae muscle. These results suggest that the intrafusal muscle fibers preserve their contractile abilities in slowly progressive MDs. The reasons for a differential impairment of intrafusal and extrafusal muscle fibers and the clinical implications of the present results are discussed.

Achilles Tendon↗

PubMed2005

Magnetic stimulation using a triple-stimulation technique in patients with multifocal neuropathy without conduction block.

It has been suggested previously that multifocal motor neuropathy (MMN) without conduction block (CB) or other features of demyelination is axonal in nature. Conventional transcranial magnetic stimulation (TMS) and the triple-stimulation technique (TST) performed on 10 MMN patients without CB revealed a proximal focal CB in 4 patients. In 3 other patients, the amplitude ratio obtained in response to conventional TMS was abnormally low, but the area ratio was normal. The TST amplitude ratio and area ratio were normal in these 3 patients. This pattern suggested the occurrence of temporal dispersion without CB. The occurrence of temporal dispersion or CB was associated with a relatively satisfactory response to intravenous immunoglobulins. These findings suggest that some forms of MMN previously thought to be axonal are in fact proximal variants of MMN with CB.

Adult↗

PubMed2005

[Pathophysiological characterization of congenital myasthenic syndromes: the example of mutations in the MUSK gene].

Congenital myasthenic syndromes (CMS) are rare genetic diseases affecting the neuromuscular junction (NMJ) and are characterized by a dysfunction of the neurotransmission. They are heterogeneous at their pathophysiological level and can be classified in three categories according to their presynaptic, synaptic and postsynaptic origins. We report here the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding a postsynaptic molecule, the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified two heteroallelic mutations, a frameshift mutation (c.220insC) and a missense mutation (V790M). The muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the neuromuscular junction and severe decrease in acetylcholine receptor (AChR) epsilon-subunit and MuSK expression. In vitro and in vivo expression experiments were performed using mutant MuSK reproducing the human mutations. The frameshift mutation led to the absence of MuSK expression. The missense mutation did not affect MuSK catalytic kinase activity but diminished expression and stability of MuSK leading to decreased agrin-dependent AChR aggregation, a critical step in the formation of the neuromuscular junction. In electroporated mouse muscle, overexpression of the missense mutation induced, within a week, a phenotype similar to the patient muscle biopsy: a severe decrease in synaptic AChR and an aberrant axonal outgrowth. These results strongly suggest that the missense mutation, in the presence of a null mutation on the other allele, is responsible for the dramatic synaptic changes observed in the patient.

Animals↗

PubMed2004

MUSK, a new target for mutations causing congenital myasthenic syndrome.

We report the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified two heteroallelic mutations, a frameshift mutation (c.220insC) and a missense mutation (V790M). The muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the neuromuscular junction and severe decrease in acetylcholine receptor (AChR) epsilon-subunit and MuSK expression. In vitro and in vivo expression experiments were performed using mutant MuSK reproducing the human mutations. The frameshift mutation led to the absence of MuSK expression. The missense mutation did not affect MuSK catalytic kinase activity but diminished expression and stability of MuSK leading to decreased agrin-dependent AChR aggregation, a critical step in the formation of the neuromuscular junction. In electroporated mouse muscle, overexpression of the missense mutation induced, within a week, a phenotype similar to the patient muscle biopsy: a severe decrease in synaptic AChR and an aberrant axonal outgrowth. These results strongly suggest that the missense mutation, in the presence of a null mutation on the other allele, is responsible for the dramatic synaptic changes observed in the patient.

Adult↗

PubMed2004

Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2.

Ataxia-ocular apraxia 2 (AOA2) was recently identified as a new autosomal recessive ataxia. We have now identified causative mutations in 15 families, which allows us to clinically define this entity by onset between 10 and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia and elevated alpha-fetoprotein (AFP). Ten of the fifteen mutations cause premature termination of a large DEAxQ-box helicase, the human ortholog of yeast Sen1p, involved in RNA maturation and termination.

Cerebellar Ataxia↗

PubMed2004

Is muscle spindle proprioceptive function spared in muscular dystrophies? A muscle tendon vibration study.

Muscular dystrophies (MDs) are characterized by the degeneration of skeletal muscle fibers. The aim of the present study was to determine whether the intrafusal fibers of muscle spindles are also affected in MD. The functional integrity of muscle spindles was tested by analyzing their involvement in the perception of body segment movements and in the control of posture. Twenty MD patients (4 with dystrophinopathy, 5 with myotonic dystrophies, 5 with fascioscapulohumeral MD, and 6 with limb-girdle dystrophies) and 10 healthy subjects participated in the study. The MD patients perceived passive movements and experienced illusory movements similar to those perceived by healthy subjects in terms of their direction and velocity. Vibratory stimulation applied to the neck and ankle muscle tendons induced postural responses in MD patients with spatial and temporal characteristics similar to those produced by healthy subjects. These results suggest that the proprioceptive function of muscle spindles is spared in muscular dystrophies.

Adult↗

PubMed2003

A clustering of conjugal amyotrophic lateral sclerosis in southeastern France.

BACKGROUND: The origin of amyotrophic lateral sclerosis (ALS) remains largely unknown but seems to be multifactorial. We believe that ALS clusters may help clinicians understand or analyze the role of environmental factors in ALS pathogenesis. OBJECTIVE: To describe a cluster of conjugal ALS in southeastern France. PATIENTS: We describe 9 couples in which both spouses were affected by ALS. Eight of the 9 had lived in southeastern France. In all cases, the spouses were married for more than 10 years. Three couples lived in the same département and 2 of them in the same city. RESULTS: To our knowledge, such a large cluster of conjugal ALS cases has not been previously reported. No precise environmental factors could be identified at the origin of these conjugal cases. CONCLUSIONS: We suggest that genetic and environmental factors, or both, may explain the occurrence of this cluster of ALS.

Age of Onset↗

PubMed2002

Neurological involvement in acute Q fever: a report of 29 cases and review of the literature.

BACKGROUND: Q fever is characterized by its clinical polymorphism; neurological involvement has occasionally been described. In the course of acute Q fever, neurological manifestations may include aseptic meningitis, encephalitis or encephalomyelitis, and peripheral neuropathy. OBJECTIVE: To review and evaluate cases of acute Q fever with neurological symptoms diagnosed in our laboratory. METHODS: A total of 1269 acute Q fever cases were recorded from January 1985 to January 2000 in our laboratory and were reviewed for neurological complications. Patients were considered to have acute Q fever when serological procedures showed Coxiella burnetii phase II titers of 1:200 or higher for IgG and 1:50 or higher for IgM. Those patients who underwent a lumbar puncture for cerebrospinal fluid analysis or who had abnormal neurological symptoms were selected for this study. We describe the clinical, epidemiological, and biological features of these cases. We also review the literature and compare our cases with those previously reported. RESULTS: Among the 45 patients selected, 14 were excluded because they had normal cerebrospinal fluid and no neurological symptoms. Two were excluded because there were no clinical or epidemiological data. Three major clinical syndromes were observed: meningoencephalitis or encephalitis in 17 cases; meningitis in 8; and myelitis and peripheral neuropathy in 4. Encephalitic signs were not specific, but behavior or psychiatric disturbances were common. CONCLUSIONS: Q fever should be included in the differential diagnosis of acute neurological disease in a patient with a fever. Serological testing should be performed in cases of meningoencephalitis, lymphocytic meningitis, and peripheral neuropathy, including Guillain-Barré syndrome and myelitis.

Acute Disease↗

PubMed2002

A sensitive flow cytometry method for anti-GM1 antibodies detection.

High-affinity anti-GM1 antibodies are frequently described in several nervous system diseases, mainly in multifocal motor neuropathy (MMN) and some acute neuropathies. These antibodies are currently detected using enzyme-linked immunosorbent assay (ELISA) and immuno-thin-layer-chromatography (immuno-TLC) methods. We report in this article a new method based on the incorporation of exogenous GM1 in a selected cell line to detect anti-GM1 antibodies using flow cytometry (FC). This method is evaluated on 80 sera from normal blood donors (NBD) and patients suffering various nervous system diseases. It appears to be as sensitive as our method ELISA for the diagnosis of some motor neuron syndromes.

Autoantibodies↗

PubMed2002

Increased visual dependence in Parkinson's disease.

The present study tested the hypothesis that there is increased visual dependence perceptually in patients with Parkinson's disease. We also evaluated whether the visual control of posture and locomotion was related to perceptual visual field dependence. 21 patients with idiopathic Parkinson's disease and 22 age-matched normal subjects were compared on judgment of the visual vertical using the Rod-and-Frame test with visual perturbations in the frontal plane with a tilted frame. Patients had significantly larger errors than controls in the estimation of the subjective vertical. In the same experiment, we performed a posture and a gait analysis in both groups. Posturographic evaluation did not indicate significant differences in unsteadiness between patients and controls. Gait analysis indicated a typical pattern of reduced velocity, shortened stride length, and normal step width. A significant correlation of .89 was found only in the Parkinsonian group between their errors in estimating subjective visual vertical and the Romberg quotient evaluating visual contribution to postural control. No specific locomotor pattern was correlated with visual dependence. Considering our results and previous reports on the visual control of posture, we conclude that patients with Parkinson's disease showed a significantly increased dependence upon visual information both perceptually and motorically, with an increased perceptual visual dependence in the patients being predictive of an equivalent visual dependence or visual control of posture and equilibrium.

Aged↗

PubMed2002

[Dysferlinopathy. Example of a new myopathy].

Over the past 10 years, the impact of modern microscopic pathology and molecular genetics on the knowledge of myopathies has been enormous. Dysferlinopathy is a good example. Dysferlin is a surface membrane protein without homology with known mammalian protein excepted otoferlin. It is encoded by a gene on chromosome 2. Miyoshi myopathy and limb girdle muscular dystrophy 2B have been reported to arise from defects in the same genetic locus (chromosome 2p 13). Some personal different examples are presented with typical features, high level of creatine kinase. Gene mutations, immunoblot and immunohistochemistry allow the diagnosis. Three clinical phenotypes are separated: distal myopathy, proximal myopathy, entire lower limbs posterior compartment amyotrophy. Structural changes are mild. Inflammation is not unusual and leads to the diagnosis of polymyositis. There are no correlation genotype-phenotype.

Dysferlin↗