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Biomedical subjects

B Fontaine

Publications and source records attributed to B Fontaine.

At least 109 records · Page 6Linked to original sources
PubMed1997

Juvenile-onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene.

Progressive proximal muscle weakness is present both in spinal muscular atrophy (SMA) type III (Kugelberg-Welander disease) and in GM2 gangliosidosis, diseases that segregate in an autosomal recessive fashion. The SMN gene for SMA and the HEXA gene for GM2 gangliosidosis were investigated in a woman with progressive proximal muscle weakness, long believed to be SMA type III (Kugelberg-Welander type). She and her family underwent biochemical studies for GM2 gangliosidosis. Analysis of SMN excluded SMA. Biochemical studies on GM2 gangliosidosis showed deficiency in hexosaminidase A activity and increased GM2 ganglioside accumulation in the patient's fibroblasts. The HEXA gene was first analyzed for the Gly269-->Ser mutation characteristic for adult GM2 gangliosidosis. Since the patient was carrying the adult mutation heterozygously, all 14 exons and adjacent intron sequences were analyzed. A novel mutation in exon 1 resulting in an A-to-T change in the initiation codon (ATG to TTG) was identified. The adult patient is a compound heterozygote, with each allele containing a different mutation. Although mRNA was transcribed from the novel mutant allele, expression experiments showed no enzyme activity, suggesting that neither the TTG nor an alternative codon serve as an initiation codon in the HEXA gene.

Adult↗
PubMed1997

Diseases caused by voltage-gated ion channels.

Ion channels regulate the transfer of ions between the outer and the inner surface of the cell membrane. The opening of ion channels may be triggered by the binding of a ligand or variations in the membrane potential. Voltage-gated ion channels are an important class of such channels, that are involved in the generation and propagation of action potentials and play a key role in cell to cell communication. As a consequence of cloning and sequencing of ion channel genes, their role in diseases affecting excitable tissues such as the nervous system, heart and skeletal muscle has been examined, and a new class of diseases has emerged. We will review disorders caused by mutations in voltage-gated ion channels affecting these excitable tissues as well as non-excitable tissues such as the kidney. The clinician should be aware of this new class of diseases because pharmacological agents modulating channel functions are available. Characterization of these gene defects should lead to better treatment of these disorders.

Animals↗
PubMed1997

[Influence of the transfer mode on short-term outcome in neonates with high perinatal risk].

BACKGROUND: Transferring in utero children with high perinatal risk has been widely recommended in France over the last few years. The purpose of this study is to describe the different transfer modes for children less than 32 weeks GA or less than 1,500 g birthweight and analyse their impact on death and severe neurological lesion. POPULATION AND METHODS: This retrospective study concerned live births in a definite geographic area (Lorraine, France). Four hundred and twenty-seven children born alive between 1989 and 1992 and hospitalized in eight neonatology units were recruited. Multivariate analysis (logistic regressions) were performed to assess the influence of transfer mode on death or severe neurological lesion. RESULTS: Sixty-two percent of the children were born in the level 3 maternity, 19% in a level 1 maternity and 19% in a level 2 maternity. One hundred and twenty-one children (28%) were transferred in utero and 116 (27%) were transferred extra muros. Thirty children died during the hospital stay. Multivariate analysis does show that neonatal extra muros transfer plays a significative role on neonatal death after adjustment for other risks factors (OR = 3.3 (1.1-9.91). Thirty-one children presented a severe neurological lesion. In comparison with neonates born in the level 3 maternity without transfer, extra muros transfer appears to be a very significant risk factor (P = 0.0008): OR for transfer from level 2 and level 1 maternity is 15.8 (3.8-66.5), and 5.6 (1.3-24) respectively. There is no significant increased risk for children born after maternal transfer or born in a level 2 maternity without transfer. CONCLUSION: These data are consistent with data from the literature and confirm the risk related to extra muros transfer in premature babies less than 32 weeks GA or less than 1,500 g birthweight.

Female↗
PubMed1997

Hypokalemic periodic paralysis: an autosomal dominant muscle disorder caused by mutations in a voltage-gated calcium channel.

Hypokalemic periodic paralysis (hypoPP) is an autosomal dominant disorder characterized by acute attacks of muscle weakness concomitant to a drop in blood potassium levels. Recent molecular work has shown that hypoPP is due to mutations in a skeletal muscle voltage-gated calcium channel: the dihydropyridine receptor (DHP receptor). Mutations affect segments S4 of domains II and IV, changing an arginine in position 528 and 1239 into an histidine, or an histidine or a glycine respectively. Surprisingly, expressing in vitro mutants channels in a non-muscular environment resulted in functional calcium channels with minor modifications in electrophysiological properties. Expressing mutant channels in a muscular environment or transgenic mice might help to bridge the gap between the knowledge of the molecular defect and the understanding of the pathophysiology of the disease.

Animals↗
PubMed1997

Identification of a Val 145 Ile substitution in the human myelin oligodendrocyte glycoprotein: lack of association with multiple sclerosis. The Réseau de Recherche Clinique INSERM sur la Susceptibilité Génétique à la Sclérose en Plaques.

Myelin/oligodendrocyte glycoprotein (MOG) is a major target antigen in experimental autoimmune encephalomyelitis and it has been suggested that it may as well play a key role in the demyelination process in multiple sclerosis (MS). As MOG variants could be pathogenic in autoimmune demyelinating diseases of the central nervous system, we analysed the coding sequence of MOG in MS patients and described a G-->A transition occurring in exon 3 of the human MOG gene. The mutation predicts that isoleucine substitutes for a valine at codon 145 (Val 145 Ile) in the transmembrane region of the protein. This is the first aminoacid substitution reported in human MOG. The polymorphism can be detected by restriction enzyme digestion of genomic DNA or reverse-transcribed PCR amplified products, making it a simple tool to detect a potential implication of MOG alleles in susceptibility to MS by association study. The analysis of 83 unrelated MS patients and 82 unrelated healthy controls showed that the polymorphism is found in similar proportions in MS patients (18%) and controls (14.6%). It is therefore unlikely that the MOG Val 145 Ile variant is responsible for genetic susceptibility to MS.

Amino Acid Sequence↗
PubMed1997

Hereditary thermosensitive neuropathy: an autosomal dominant disorder of the peripheral nervous system.

We report the clinical and electrophysiologic characteristics of eight patients (four men and four women) with a hereditary neuropathy with probable thermosensitivity (HTN) of autosomal dominant inheritance. Patients presented reversible episodes of ascending muscle weakness, paresthesiae, and areflexia apparently triggered by an elevation of body temperature over 38.5 degrees C. Mean age at onset was 13 +/- 12 (SD; range 6 to 43). Four patients had suffered up to five attacks. EMG and pathologic findings were compatible with a reversible demyelinating neuropathy such as Guillain-Barré syndrome. We excluded loci causing other hereditary demyelinating neuropathies, such as Charcot-Marie-Tooth disease type I (CMT type I) and hereditary neuropathy with liability to pressure palsies (HNPP), by linkage analysis; thus, HTN is not allelic to either CMT type I or to HNPP.

Adult↗
PubMed1997

Commonly prescribed salt intake in continuous ambulatory peritoneal dialysis patients is too restrictive: results of a double-blind crossover study.

Salt restriction in continuous ambulatory peritoneal dialysis (CAPD) patients is widely prescribed and thereby may reduce quality of life. It is presumed that this has a beneficial effect on BP and reduces the need for hypertonic dialysate. However, this has never been formally evaluated. A double-blind crossover study of placebo versus sodium chloride pills (60 mEq of sodium per day) is presented in 20 stable CAPD patients, 10 of whom were hypertensive. Dietary sodium was quantified throughout the study by 3-d dietary histories and remained unaltered throughout. There was a clinically unimportant but statistically significant rise in BP with added salt: 135/77 to 144/82 (P < 0.05). No rise in BP occurred in the hypertensive patients. Weights, use of hypertonic dialysate, and BP medications remained unaltered throughout the study. In conclusion, 200 mEq of sodium per day, i.e., a normal sodium intake, is easily tolerated in stable CAPD patients, and the recommended sodium intake commonly prescribed is too restrictive.

Aged↗
PubMed1996

Electrophysiological properties of the hypokalaemic periodic paralysis mutation (R528H) of the skeletal muscle alpha 1s subunit as expressed in mouse L cells.

Hypokalaemic periodic paralysis (HypoPP) is an autosomal dominant muscle disease which has been linked to point mutations in the skeletal muscle L-type calcium channel alpha 1 subunit (alpha 1s). Here, we have introduced one of the point mutations causing HypoPP (R528H) into cDNA of the rabbit alpha 1s. Expression of either the wild-type alpha 1s or the mutant R528H alpha 1s (alpha 1s-R528H) subunits was obtained in mouse Ltk- cells using a selectable expression vector. The alpha 1s-R528H subunit led to the expression of functional L-type Ca2+ channels. Corresponding whole-cell Ba2+ currents exhibit very slow activation and inactivation kinetics, typical for recombinant skeletal Ca2+ channel currents. Voltage-dependent activation and inactivation properties were similar for alpha 1s- and alpha 1s-R528H, as well as their sensitivity to the dihydropyridine agonist Bay K 8644. Differences in alpha 1s- and alpha 1s-R528H-directed channels reside in the Ba2+ current density, which was significantly reduced 3.2 fold in cells expressing alpha 1s-R528H. It was concluded that the R528H mutation af alpha 1s results in minor differences in the electrophysiological properties but significantly reduces the whole-cell Ca2+ channel current in its amplitude.

Animals↗
PubMed1996

Recessive Schwartz-Jampel syndrome (SJS): confirmation of linkage to chromosome 1p, evidence of genetic homogeneity and reduction of the SJS locus to a 3-cM interval.

Schwartz-Jampel syndrome (SJS), or chondrodystrophic myotonia, is a rare autosomal recessive disorder characterized by generalized myotonia resulting in a particular, recognizable facies and osteoarticular abnormalities. Some of us have recently shown genetic linkage of SJS to a locus on 1p34-p36.1 in five families. Here, we show by homozygosity mapping and segregation analysis that eight new families are most likely linked to the SJS locus on chromosome 1, confirming the localization of SJS to chromosome 1p and suggesting genetic homogeneity. Recombination events reduced the SJS locus from a genetic interval of 8 to 3 cM, which should facilitate the identification of the SJS gene. Low clinical variability was observed between the studied families, except for osteoarticular abnormalities. Since the severity and the location of osteoarticular abnormalities varied from one individual to another, even in the same families, other factors than the SJS gene itself, genetic or epigenetic, might contribute to the phenotype.

Alleles↗
PubMed1996

Paramyotonia congenita: genotype to phenotype correlations in two families and report of a new mutation in the sodium channel gene.

Sodium channel disorders include hyperkalemic periodic paralysis (hyperPP), paramyotonia congenita (PC) and potassium-aggravated myotonia (PAM). PC is a myotonic syndrome characterized by cold-induced muscle stiffness and weakness. In this paper, we report two families. The first is affected by PC with cold-induced stiffness and no weakness, in addition to hyperPP. This family displays the Arg1448Cys mutation in the sodium channel gene originally described in pure PC families. The fact that families with the same mutation present distinct phenotypes indicates that other factors, genetic or environmental, may modulate the expression of the disease in sodium channel disorders. The second family was unusual because patients presented cold-induced weakness without stiffness. A mutation was found in the sodium channel gene that changed an isoleucine into a threonine at position 693. These two families demonstrate that sodium channel mutations may cause either cold-induced stiffness or weakness.

Adult↗
PubMed1996

Phenotype of autosomal dominant spastic paraplegia linked to chromosome 2.

We report the clinical features of 12 families with autosomal dominant spastic paraplegia (ADSP) linked to the SPG4 locus on chromosome 2p, the major locus for this disorder that accounts for approximately 40% of the families. Among 93 gene carriers, 32 (34%) were unaware of symptoms but were clinically affected. Haplotype reconstruction showed that 90% of the asymptomatic gene carriers presented increased reflexes and/or extensor plantar responses independent of age at examination. The mean age at onset was 29 years, ranging from 1 to 63 years. Intra- as well as inter-familial variability of age at onset was important, but did not result from anticipation. Phenotype-genotype correlations and comparison with SPG3 and SPG5 families indicated that despite the variability of age at onset, SPG4 is a single genetic entity but no clinical features distinguish individual SPG4 patients from those with SPG3 or SPG5 mutations.

Adolescent↗
PubMed1996

Determination of clozapine in serum by radioreceptor assay versus high-performance liquid chromatography: possible detection of hydroxy-metabolites.

Clozapine is an antipsychotic drug with few extra-pyramidal motor side-effects, used to treat schizophrenia which is resistant to classical neuroleptic therapy. This report shows that norclozapine but not clozapine-N-oxide has the same D2 receptor affinity as clozapine. Assay results suggest a bimodal distribution which may be explained by CYP1A2 polymorphism. Extensive metabolizers could produce other active metabolites, probably other hydroxy-clozapine derivatives.

Animals↗
PubMed1995

Skeletal muscle DHP receptor mutations alter calcium currents in human hypokalaemic periodic paralysis myotubes.

1. Mutations in the gene encoding the alpha 1-subunit of the skeletal muscle dihydropyridine (DHP) receptor are responsible for familial hypokalaemic periodic paralysis (HypoPP), an autosomal dominant muscle disease. We investigated myotubes cultured from muscle of patients with arginine-to-histidine substitutions in putative voltage sensors, IIS4 (R528H) and IVS4 (R1239H), of the DHP receptor alpha 1-subunit. 2. Analysis of the messenger ribonucleic acid (mRNA) in the myotubes from such patients indicated transcription from both the normal and mutant genes. 3. In control myotubes, the existence of the slow L-type current and of two rapidly activating and inactivating calcium current components (T-type with a maximum at about -20 mV and 'third type' with a maximum at +10 to +20 mV) was confirmed. In the myotubes from patients with either mutation, the third-type current component was seen more frequently and, on average, with larger amplitude. 4. In myotubes with the IVS4 mutation (R1239H) the maximum L-type current density was smaller than control (-0.53 +/- 0.31 vs. -1.41 +/- 0.71 pA pF-1). The voltage dependence of activation was normal, and hyperpolarizing prepulses to -120 mV for 20 s did not increase the reduced current amplitude during test pulses. 5. In myotubes with the IIS4 mutation (R528H) the L-type current-voltage relation, determined at a holding potential of -90 mV, was normal. However, the voltage dependence of inactivation was shifted by about 40 mV to more negative potentials (voltage at half-maximum inactivation, V1/2 = -41.5 +/- 8.2 vs. -4.9 +/- 4.3 mV in normal controls).(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1995

Exclusion of the candidate locus FSP1 in six families with late-onset autosomal dominant spastic paraplegia.

Hereditary spastic paraplegias are neurological hereditary conditions of unknown aetiology. In pure spastic paraplegia, most of the pedigrees display an autosomal dominant mode of inheritance. A gene for pure autosomal dominant spastic paraplegia (ADSP), termed FSP1, was mapped to chromosome 14q in a large pedigree with early-onset disease. This locus was tested by linkage analysis in six large French kindreds of ADSP with late-onset disease, using four microsatellites spanning a 9 cM interval including FSP1. FSP1 could be excluded in five of the six families, while no evidence for linkage was found in the remaining family. These results suggest that FSP1 is not involved in late onset ADSP, at least in the six families studied.

Adolescent↗