PubMed Health⌕ Search

Biomedical subjects

B Fontaine

Publications and source records attributed to B Fontaine.

At least 19 recordsLinked to original sources
PubMed2006

PADI4 gene in multiple sclerosis: a family-based association study.

In multiple sclerosis (MS) MBP is heavily citrullinated by peptidylarginine deiminase (PAD). This post-translational modification may be crucial for its pathogenesis. PADI4 is the isoform expressed in inflammatory infiltrates. The aim of this study was to analyse the role of PADI4 gene in conferring susceptibility to MS, by means of a family-based association study, testing three SNPs by RFLP. No association was found either with single SNPs or haplotypes. Similarly no significant association was detected partitioning the patients according to DRB1*15 positivity or disease severity. These results do not support a major role of the PADI4 gene, but further studies may contribute to clarify the genetic factors that regulate deimination.

Adult↗
PubMed2006

Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia.

BACKGROUND: Mutations in the SPG7 gene, which encodes paraplegin, are responsible for an autosomal recessive hereditary spastic paraplegia (HSP). OBJECTIVE: To screen the SPG7 gene in a large population of HSP families compatible with autosomal recessive transmission. METHODS: The authors analyzed 136 probands with pure or complex HSP for mutations in the SPG7 using denaturation high-performance liquid chromatography and direct sequencing. RESULTS: The authors identified 47 variants including 6 mutations, 27 polymorphisms, and 14 changes with unknown effects. In one family from Morocco, compound c.850_851delTTinsC and c.1742_1744delTGG heterozygous mutations were shown to be causative. This family had complex HSP with cerebellar impairment. Progression of the disease was rapid, resulting in a severe disease after 8 years of duration. Also detected were 20 families with one heterozygous mutation that was not found in a large control population. The mutations produced highly defective proteins in four of these families, suggesting that they were probably causative. Direct sequencing of all exons and reverse transcription PCR experiments demonstrated the absence of a second mutation. However, the p.Ala510Val missense substitution previously described as a polymorphism was shown to be significantly associated with HSP, suggesting that it had a functional effect. CONCLUSION: SPG7 mutations account for less than 5% of hereditary spastic paraplegia (HSP) families compatible with autosomal recessive inheritance. Cerebellar signs or cerebellar atrophy on brain imaging were the most frequent additional features in patients with SPG7 HSP. Rare nucleotide variants in SPG7 are frequent, complicating routine diagnosis.

ATPases Associated with Diverse Cellular Activitie↗
PubMed2005

The primary periodic paralyses: diagnosis, pathogenesis and treatment.

Periodic paralyses (PPs) are rare inherited channelopathies that manifest as abnormal, often potassium (K)-sensitive, muscle membrane excitability leading to episodic flaccid paralysis. Hypokalaemic (HypoPP) and hyperkalaemic PP and Andersen-Tawil syndrome are genetically heterogeneous. Over the past decade mutations in genes encoding three ion channels, CACN1AS, SCN4A and KCNJ2, have been identified and account for at least 70% of the identified cases of PP and several allelic disorders. No prospective clinical studies have followed sufficiently large cohorts with characterized molecular lesions to draw precise conclusions. We summarize current knowledge of the clinical diagnosis, molecular genetics, genotype-phenotype correlations, pathophysiology and treatment in the PPs. We focus on unresolved issues including (i) Are there additional ion channel defects in cases without defined mutations? (ii) What is the mechanism for depolarization-induced weakness in Hypo PP? and finally (iii) Will detailed electrophysiological studies be able to correctly identify specific channel mutations? Understanding the pathophysiology of the potassium-sensitive PPs ought to reduce genetic complexity, allow subjects to be stratified during future clinical trials and increase the likelihood of observing true clinical effects. Ideally, therapy for the PPs will prevent attacks, avoid permanent weakness and improve quality of life. Moreover, understanding the skeletal muscle channelopathies will hopefully lead to insights into the more common central nervous system channel diseases such as migraine and epilepsy.

Animals↗
PubMed2005

[Intravenous ketoprofen for severe lithium-induced polyuria].

INTRODUCTION: Although lithium has a narrow therapeutic range, it is widely used in psychiatry because of its antipsychotic and antidepressant properties. During long-term treatment, the onset of nephrogenic diabetes insipidus is common, but few cases of severe hypotonic polyuria, which would be an aggravating factor, have been reported. Appropriate treatment in such cases is an open question. CASE: We report a case of acute lithium poisoning in a 42-year-old man, due to chronic lithium treatment (plasma lithium=2.6 mmol/L). This patient, admitted to our intensive care unit, presented neurological disorders complicated by the early emergence of severe nephrogenic diabetes insipidus. After perfusion of hypotonic solution and intravenous treatment with ketoprofen (100 mg x 3/24 h), the polyuria improved rapidly. COMMENTS: The beneficial action of nonsteroidal antiinflammatory drugs lies in their capacity to inhibit prostaglandin synthesis. Lithium causes excess production of prostaglandins, which decrease the ability of kidneys to reabsorb free water. Some publications report indomethacin to be effective in this case. Because it is available only in oral or rectal forms, however, its effect may be delayed. Our case suggests that intravenous ketoprofen, with its rapid onset of action, is effective in the treatment of severe lithium-induced nephrogenic diabetes insipidus. Rehydration must be strictly monitored because of the risk of renal failure connected with nonsteroidal antiinflammatory drugs.

Adult↗
PubMed2005

Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases.

BACKGROUND: SPG4 encodes spastin, a member of the AAA protein family, and is the major gene responsible for autosomal dominant spastic paraplegia. It accounts for 10-40% of families with pure (or eventually complicated) hereditary spastic paraparesis (HSP). OBJECTIVE: To assess the frequency of SPG4 mutation in patients with spastic paraplegia but without family histories. METHODS: 146 mostly European probands with progressive spastic paraplegia were studied (103 with pure spastic paraplegia and 43 with additional features). Major neurological causes of paraplegia were excluded. None had a family history of paraplegia. DNA was screened by DHPLC for mutations in the 17 coding exons of the SPG4 gene. Sequence variants were characterised by direct sequencing. A panel of 600 control chromosomes was used to rule out polymorphisms. RESULTS: The overall rate of mutations was 12%; 19 different mutations were identified in 18 patients, 13 of which were novel. In one family, where both parents were examined and found to be normal, the mutation was transmitted by the asymptomatic mother, indicating reduced penetrance. The parents of other patients were not available for analysis but were reported to be normal. There was no evidence for de novo mutations. The mutations found in these apparently isolated patients were mostly of the missense type and tended to be associated with a less severe phenotype than previously described in patients with inherited mutations. CONCLUSIONS: The unexpected presence of SPG4 gene mutations in patients with sporadic spastic paraplegia suggests that gene testing should be done in individuals with pure or complicated spastic paraplegia without family histories.

Adenosine Triphosphatases↗
PubMed2005

Human skeletal muscle sodium channelopathies.

Ion channels are transmembrane proteins that allow ions to flow in or out of the cell. Sodium and potassium channel activation and inactivation are the basis of action potential's production and conduction. During the past 15 years, ion channels have been implicated in diseases that have come to be known as the channelopathies. Over 30 mutations of the muscle channel gene SCN4A, which encodes the muscle voltage-gated sodium channel, have been described and associated with neuromuscular disorders like hypo- and hyper-kalaemic periodic paralyses (hypoPP and hyperPP), paramyotonia congenita, sodium channel myotonias and congenital myasthenic syndrome. Different mutations within the same gene (SCN4A) cause distinct clinical disorders, while mutations in different channel genes may result in similar phenotypes. In addition, identical sodium channel mutations can result in different clinical phenotypes (hyperPP or paramyotonia) in different members of the same family, suggesting that the genetic background and perhaps other epigenetic factors may influence the clinical expression of a particular mutation. This article reviews the clinical features of the skeletal muscle sodium channel diseases and highlights the phenotypic or genetic overlap in these disorders.

Humans↗
PubMed2005

[Adult onset hereditary leukoencephalopathies].

In clinical practice, the term "genetic leukoencephalopathy" refers to a group of genetic diseases whose common point is to give an aspect of diffuse leukoencephalopathy on MRI. With progress in diagnostic techniques including radiology, biochemistry or genetics, a large number of hereditary diseases causing leukoencephalopathy have been identified. Although generally beginning in childhood, these diseases often have more insidious clinical forms which can begin in adulthood. These forms remain poorly known. Some are accessible to treatment so their diagnosis appears essential. The diagnostic steps must be guided by clinical examination (neurological, ophthalmological and systemic), electromyography and MRI. The purpose of this review is to propose a classification of the genetic leukoencephalopathies and to give a progress report applicable in neurological practice.

Age of Onset↗
PubMed2005

[Smoking and breastfeeding: how can we help mothers stop smoking?].

The study of nicotine metabolism shows that nicotine has a half-life of 60 to 90 min, and that nicotine concentration in human breast milk is 2.9 times higher than in the plasma. Smokers are less likely to choose breastfeeding. The duration of breastfeeding is shorter and there is less milk production amongst smokers who decide to breastfeed. Breastfeeding diminishes the infant's respiratory problems that are linked to smoking. During the breastfeeding period, in addition to psychological support, nicotine replacement therapy should be proposed, preferring gums or 2 mg tablets with a short half-life taken after feeding. For those who continue to smoke, the number of cigarettes should be limited and smoking should be done after feeding and outside of living quarters.

Breast Feeding↗
PubMed2005

[Pregnancy and smoking: the occupational physician's point of view].

It has become urgent to initiate preventive measures to avoid occupation exposure of pregnant women to smoking. Tobacco smoke is a recognized cause of respiratory cancer and a large number of workers are exposed to substances classified as cancerogenic agents. The occupational physician can provide information on risks, measure biological markers (CO in ambient air, serum markers such as CO in expired air, carboxyhemoglobin or cotinine), counsel the employer concerning elimination of the secondary smoke current or the management of toxic materials, and propose modifications of the ventilation system. The current legislation (Evin law) should be included in the house rules. In the event a non-smoking pregnant woman is exposed to passive smoking, the work post should be adapted or changed. Smoking women should be encouraged to stop smoking and provided with the necessary support to achieve cessation. The woman's individual maternity book let should include information on the risk of smoking and encourage contact with the primary care physician, the gynecologist, or the anti-smoking care center. The occupational physician should search for addictive or occupational co-exposures.

Female↗
PubMed2005

Schwartz-Jampel syndrome and perlecan deficiency.

Schwartz-Jampel syndrome (SJS) is a rare autosomal recessive disorder characterized by the association of myotonia with chondrodysplasia. A positional cloning strategy allowed the localization and the identification of perlecan as the disease causing gene. Another human recessive disorder, the Dyssegmental Dysplasia, Silverman-Handmaker type (DDSH), is caused by functional null mutations of the perlecan gene. A gene-dosage effect seems to account for the correlation between the phenotype and the mutations within the gene: SJS would be associated with hypomorph mutations of the perlecan gene and DDSH would be due to the absence of functional perlecan. Perlecan is the major heparan sulfate proteoglycan of extracellular matrix and basement membranes that displays various functions. Based on these functions, several hypotheses are evoked to explain chondrodysplasia and the unusual myotonia in SJS. Mouse models are invaluable tools to explore these hypotheses. Since knock-out mice develop a phenotype similar to DDSH, we have developed a SJS mouse model by reproducing the hypomorph effect of SJS perlecan mutation in this species. The characterization of this mouse model will help to understand the pathophysiological mechanism leading to this multisystemic human disorder.

Animals↗
PubMed2004

New mutations of SCN4A cause a potassium-sensitive normokalemic periodic paralysis.

BACKGROUND: Periodic paralysis is classified into hypokalemic (hypoPP) and hyperkalemic (hyperPP) periodic paralysis according to variations of blood potassium levels during attacks. OBJECTIVE: To describe new mutations in the muscle sodium channel gene SCN4A that cause periodic paralysis. METHODS: A thorough clinical, electrophysiologic, and molecular study was performed of four unrelated families who presented with periodic paralysis. RESULTS: The nine affected members had episodes of muscle weakness reminiscent of both hyperPP and hypoPP. A provocative test with potassium chloride was positive in two patients. However, repeated and carefully performed tests of blood potassium levels during attacks resulted in normal potassium levels. Remarkably, two patients experienced hypokalemic episodes of paralysis related to peculiar provocative factors (corticosteroids and thyrotoxicosis). Similarly to hyperPP, electromyography in nine patients revealed increased compound muscle action potentials after short exercise and a delayed decline during rest after long exercise as well as myotonic discharges in one patient. With use of molecular genetic analysis of the gene SCN4A, three new mutations were found affecting codon 675. They resulted in an amino acid substitution of a highly conserved arginine (R) to either a glycine (G), a glutamine (Q), or a tryptophan (W). Interestingly, hypoPP is caused by both mutations affecting nearby codons as well as the change of an arginine into another amino acid. CONCLUSION: A potassium-sensitive and normokalemic type of periodic paralysis caused by new SCN4A mutations at codon 675 is reported.

Acetazolamide↗
PubMed2004

A second-generation genomic screen for multiple sclerosis.

Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disorder. Despite substantial evidence for polygenic inheritance of the disease, the major histocompatibility complex is the only region that clearly and consistently demonstrates linkage and association in MS studies. The goal of this study was to identify additional chromosomal regions that harbor susceptibility genes for MS. With a panel of 390 microsatellite markers genotyped in 245 U.S. and French multiplex families (456 affected relative pairs), this is the largest genomic screen for MS conducted to date. Four regions met both of our primary criteria for further interest (heterogeneity LOD [HLOD] and Z scores >2.0): 1q (HLOD=2.17; Z=3.38), 6p (HLOD=4.21; Z=2.26), 9q (HLOD; Z=2.71), and 16p (HLOD=2.64; Z=2.05). Two additional regions met only the Z score criterion: 3q (Z=2.39) and 5q (Z=2.17). Further examination of the data by country (United States vs. France) identified one additional region demonstrating suggestive linkage in the U.S. subset (18p [HLOD=2.39]) and two additional regions generating suggestive linkage in the French subset (1p [HLOD=2.08] and 22q [HLOD=2.06]). Examination of the data by human leukocyte antigen (HLA)-DR2 stratification identified four additional regions demonstrating suggestive linkage: 2q (HLOD=3.09 in the U.S. DR2- families), 6q (HLOD=3.10 in the French DR2- families), 13q (HLOD=2.32 in all DR2+ families and HLOD=2.17 in the U.S. DR2+ families), and 16q (HLOD=2.32 in all DR2+ families and HLOD=2.13 in the U.S. DR2+ families). These data suggest several regions that warrant further investigation in the search for MS susceptibility genes.

Chromosome Mapping↗
PubMed2004

[Quality assurance program for pain management after obstetrical perineal injury].

INTRODUCTION: A quality insurance program has been set up in order to improve the relief of pain in patients with perineal injury after childbirth. PATIENTS AND METHODS: The program has been developed according to the French standards of accreditation. After elaboration of a referential, a first study (103 patients) allowed to evaluate the ongoing practices and to appreciate the pain intensities. After analysis of the results, an action strategy has been elaborated, with a brand new therapeutic standard and a pain-monitoring program for nurses. Six months later, a second study (105 patients) measured the efficiency of the accomplished actions. The statistic analysis used chi2 and Kruskal-Wallis tests and a multivariate analyse (p <0.05). RESULTS: Several indicators led to conclude to the success of this program: analgesics prescribed systematically and earlier, best observance, larger utilisation of the NSAI, decrease of the analgesics requests, improvement of the satisfaction referred to the relief of pain. The multivariate analyse showed a risk twice as little as in the second study to have a 36th hour VAS score superior to four (p =0.03). CONCLUSION: The apply of this quality insurance program allowed to improve the analgesia after obstetric perineal injuries. A few adaptations are needed, and also more formations of the medical and paramedical staff. The durability of the accomplished actions shall be evaluated in the future.

Adult↗
PubMed2004

[Muscular genetic disorders caused by abnormal membrane excitability].

Ion channels are transmembrane proteins which enable ion exchanges between the inner and the outer part of the cell. During evolution, the property of ligand- or voltage-gating conferred cell excitability which permitted intercellular communication. The study of muscle diseases, periodic paralysis and myotonia, has led to the discovery of mutations in the genes encoding ion channels. The analysis of the functional consequences on muscle membrane gave insight into pathophysiology. A loss of function of sodium or calcium channels leads to hypokalaemic periodic paralysis. A gain of function of sodium channel results in hyperkalaemic periodic paralysis or paramyotonia, depending of its level. It is also known that mutations in other genes can cause membrane excitatibility such as the gene encoding perlecan (Schwartz-Jampel syndrome). The study of muscle channelopathies has opened a new field in neurological disorders. Molecular diagnosis is now possible and the efficacy of treatments is better understood.

Humans↗
PubMed2004

[Negative impact of cigarette smoking on male fertility: from spermatozoa to the offspring].

Cigarette smoking has negative effects on male fertility. Recent studies showed an active transfer of several components of cigarettes through the blood-testis barrier. The presence of these components in the seminal plasma may induce a degradation of sperm parameters and nuclear quality of spermatozoa, and compromise the chances of pregnancy. Moreover, smoking may have a negative impact on the smokers'offspring: poor quality embryos, development of childhood cancers. Oxidative stress-induced DNA damage seems to be one of the major causes of sperm quality alteration. Several methods are now available to analyze the degree of DNA fragmentation. In order to optimize the success rate of assisted reproduction technologies, the deleterious effects of smoking on male fertility and the necessity of cessation have to be explained in detail to these patients.

Blood-Testis Barrier↗
PubMed2004

A vulnerability locus to multiple sclerosis maps to 7p15 in a region syntenic to an EAE locus in the rat.

Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease of the central nervous system. Evidence from family studies indicates a strong genetic component. Despite many studies of candidate genes, only an association with the HLA-DRB1*1501-DQB1*0602 haplotype has been generally detected, and HLA linkage established by transmission disequilibrium testing. A genome-wide scan revealed suggestive linkage of MS with markers on chromosome 7p15 in HLA-DR15-nonsharing British families, in a region syntenic to a locus predisposing to experimental autoimmune encephalomyelitis in the rat. We therefore tested the 7p15 region as a candidate region for genetic susceptibility to MS in 104 French families with at least two affected siblings. We found evidence suggestive of a predisposing locus in families in which only one affected sibling or none of them carry the HLA-DR15 allele. Comparison of the results of the British and French groups suggests that the region of interest can be narrowed to a 2.45-cM interval.

Alleles↗
PubMed2003

Lack of association of the potassium channel-associated peptide MiRP2-R83H variant with periodic paralysis.

A missense variant (R83H) of the gene (KCNE3) encoding a potassium channel-associated peptide, MinK-related peptide 2 (MiRP2), has been reported in periodic paralysis patients. In the current study, no difference in the frequency of the MiRP2-R83H variant between periodic paralysis patients and healthy individuals was found. Furthermore, there was no segregation of this gene variant with the disease. These observations weaken the proposal that MiRP2-R83H causes periodic paralysis.

Adult↗