Biomedical subjects

J M Warter

Publications and source records attributed to J M Warter.

At least 55 records · Page 3Linked to original sources

PubMed1998

[Hereditary neurological diseases caused by amplification of triplet repetitions].

NEW TYPE OF MUTATION: Repeated sequences of nucleotide triplets can cause two groups of diseases. GROUP I DISEASES: These diseases result from an expansion of a noncoding portion of a gene which may be repeated more than 1000 times. This group includes several multisystem diseases such as the fragile X syndrome and its variants, Steinert's disease and Friedreich's disease in which nervous system disorders are not always predominant. The molecular mechanism of the cellular disorder is probably related to a nonfunctional abnormal protein. GROUP II DISEASES: Huntington's disease, spinobulbar amyotrophy or Kennedy's disease, dentato-rubo-pallidolusian atrophy and spinocerebellar ataxias 1, 2, 3, 6, and 7 are characterized by local expansion of the coding part of a gene. This low-amplitude expansion always involves the CAG triplet and leads to expression of a protein with an abnormal number of glutamines, producing typical neurodegenerative disease almost exclusively limited to the nervous system. The underlying mechanism of the neuronal suffering is probably the production of an abnormal but functional protein. The causes of this type of mutation remain unclear. PERSPECTIVES: Positive diagnosis is now possible with DNA sequencing. While antenatal diagnosis offers essential information for family genetic counselling there is no perspective of therapeutic propositions for the near future. The problems raised by presymptomatic diagnosis must not be underestimated.

DNA Mutational Analysis↗

PubMed1998

High signal in the adenohypophysis on T1-weighted images presumably due to manganese deposits in patients on long-term parenteral nutrition.

Hypermanganesaemia is reported in patients on long-term parenteral nutrition. Deposition of manganese, giving high signal on T1-weighted images, may involve the basal ganglia. MRI in nine patients (mean age 51 years, range 31-75 years) on long-term parenteral nutrition (mean duration 30 months, range 6-126 months), demonstrated high signal in the anterior pituitary gland on T1-weighted sagittal and coronal images. The gland appeared normal on T2-weighted images. Signal intensity in the basal ganglia on T1-weighted images was increased in all patients. Endocrine assessment showed no significant abnormality. Neurological examination showed a mild parkinsonian movement disorder in one patient. Hypermanganaesemia was present in all nine (1.3-2.8 micromol/l, mean 1.87 micromol/l). The high signal in the anterior pituitary gland was probably related to deposition of paramagnetic substances, especially manganese.

Adult↗

PubMed1998

The effect of the nonpeptide neurotrophic compound SR 57746A on the progression of the disease state of the pmn mouse.

1. The progressive motor neuronopathy (pmn) mouse is an autosomal recessive mutant, in which the homozygotes suffer caudio-cranial degeneration of motor axons and die several weeks after birth. This strain provides the opportunity of testing potential therapeutic strategies for the treatment of motor neurone diseases such as amyotrophic lateral sclerosis. We have performed a study of the effects on the pmn mouse of SR 57746A, an orally-active, non-peptide compound which has been found to exhibit neurotrophic effects in vitro and in vivo. In order to treat the affected mice from birth, the mothers were administered 2.5 mg kg(-1). p.o., SR 57746A every two days until the weaning of the offspring (at day 20); then the offspring were given every two days a dose of 30 microg kg(-1), p.o., until their death. 2. Affected mice treated with SR 57746A had a lifespan 50% longer than that of the vehicle-treated mice (P=0.01). Compared to vehicle-treated pmn mice, SR 57746A improved the performance of the pmn mice in three different behavioural tasks. SR 57746A also maintained the amplitude of the motor evoked response of the gastrocnemius muscle, reduced the distal motor latency, and delayed the occurrence of the spontaneous denervation activity in this muscle. Histological studies indicated that at 20 days of age the mean surface areas of the fibres of the sciatic nerve were higher in SR 57746A-treated than in vehicle-treated mice. 3. At present, SR 57746A is the only orally active, nonpeptide compound known to be capable of delaying the progression of the motor neurone degeneration in pmn mice.

Animals↗

PubMed1998

Novel muscle chloride channel (CLCN1) mutations in myotonia congenita with various modes of inheritance including incomplete dominance and penetrance.

Autosomal-dominant and -recessive myotonia congenita are caused by mutations in the skeletal muscle voltage-gated chloride channel gene (CLCN1). We searched for mutations in this gene in 20 unrelated families with myotonia congenita. We identified 11 different mutations in 10 families. Two of five new mutations (Ala313Thr and Ile556Asn) were both autosomal recessive and dominant with either reduced penetrance or incomplete dominance. Mutations in the CLCN1 gene do not therefore necessarily behave in a classic Mendelian manner.

Adult↗

PubMed1998

[Spinal cord MRI in multiple sclerosis: comparison of turbo-spin echo sequences and turbo-MRI].

UNLABELLED: To compare T2-weighted turbo spin-echo (turboSE) and turbo inversion recovery magnitude (turboIRM) sequences in the detection of multiple sclerosis of the spinal cord. METHODS: 28 patients with clinically confirmed multiple sclerosis and signs of cervical cord involvement were examined on a 1.5 tesla MR system. Sagittal T2-weighted turboSE sequences were followed by sagittal turboIRM sequences. 24 patients also underwent a cranial study. RESULTS: Using turboIRM sequence, all the patients showed at least one spinal cord plaque with a total of 91 plaques. Using turboSE sequence, 61 lesions were identified in 25 patients. Spinal plaques were seen best on turboIRM sequences with a higher contrast between the lesion and the normal spinal cord. In 10 patients with cord plaques in both sequences, the cranial study was normal or non conclusive. CONCLUSIONS: The turboIRM sequences detect more cord lesions and with a better contrast than the turboSE sequence. This results confirm those described in other studies and demonstrate the inadequacy of the fast spin echo sequences. Assessment of spinal plaques is particularly important when MR findings of the brain are negative or non conclusive.

Adult↗

PubMed1998

[Gerstmann-Straüssler-Scheinker syndrome].

The Gerstmann-Sträussler-Scheinker syndrome, is a disease transmitted by autosomal dominant inheritance characterized by nonsense mutations of the prion protein associated with specific neuropathological lesions-multicentric amyloid plaques labelled by antibodies directed against the prion protein. This restrictive definition justifies retaining the name of Gerstmann-Sträussler-Scheinder syndrome and excludes observations of hereditary prion diseases without multicentric amyloid plaques and sporadic forms with multicentric plaques. The main feature of these different observations is their polymorphous clinical presentation which varies not only between families with the same mutation but also with a given family. The underlying mechanisms of the phenotypic polymorphism remain uncertain.

Brain↗

PubMed1997

Progressive motor neuron impairment in an animal model of familial amyotrophic lateral sclerosis.

Mutations of Cu,Zn superoxide dismutase cause an autosomal dominant form of familial amyotrophic lateral sclerosis. An animal model of the disease has been produced by expressing mutant human SOD1 in transgenic mice (G93A). In order to quantify the dysfunction of the motor unit in transgenic mice, electromyographic recordings were performed during the course of the disease. The first alterations in neuromuscular function appeared between P63 and P90. The deficits became even more striking after P100; compound muscle action potentials in the hindlimb decreased by 80% of initial value. Spontaneous fibrillation potentials were measured in more than 50% of transgenic mice. The number of motor units in the gastrocnemius muscle was progressively reduced over time, down to 18% of the control value at P130. Moreover, distal motor latencies increased after P120. These data suggest that the initial dysfunctions of motor unit are related to a severe motor axonal degeneration, which is followed at later periods by myelin alteration.

Amyotrophic Lateral Sclerosis↗

PubMed1997

Degeneration of cocultures of spinal muscular atrophy muscle cells and rat spinal cord explants is not due to secreted factors and cannot be prevented by neurotrophins.

We have shown recently that cocultures of muscle cells from infantile spinal muscular atrophy (SMA) patients innervated by motoneurons of normal rat spinal cord explants undergo a degeneration process, suggesting that muscle may play a role in this atrophy, which previously has been considered to be a pure motoneuron disease. Conditional media of SMA cocultures did not affect control healthy nerve muscle cocultures. Conversely, conditioned media of control cocultures were unable to prevent degeneration of SMA cocultures. Moreover, neurotrophic factors, thought to be of help in motoneuron disease treatment, did not protect SMA cocultures from premature death. Our results suggest that the abnormal phenotype observed in nerve-muscle coculture (1) is not due to the release of a toxic factor nor to the lack of a secreted survival factor, and (2) does not respond to neurotrophin treatment.

Animals↗

PubMed1997

Neurofibrillary tangles in Gerstmann-Sträussler-Scheinker syndrome with the A117V prion gene mutation.

One patient of a French family with Gerstmann-Sträussler-Scheinker syndrome with the mutation in codon 117 of the prion protein (PrP) gene displayed unexpected neuritic degeneration around PrP plaques and numerous diffuse neurofibrillary tangles, whereas other members did not. The tau profile in this patient's brain was analysed and compared with one from another member of the Gerstmann-Sträussler-Scheinker family as well as with the Alzheimer's tau profile. A panel of well characterised antibodies against both normal tau protein and paired helical filaments-tau protein was used on immunoblots of brain proteins resolved by mono and two dimensional gels. The tau profile in the patient with Gerstmann-Sträussler-Scheinker syndrome without neurofibrillary tangles was normal. The tau profile from the patient with Gerstmann-Sträussler-Scheinker syndrome and neurofibrillary tangles was characterised by a hyperaggregation state of tau protein. This case illustrates the phenotypic heterogeneity of the GSS117 mutation not only from one family to another, but also between members of the same family. In this family, the presence of neurofibrillary tangles is still unexplained, but could be correlated with either the protracted duration of the disease or the old age of the patient.

Adult↗

PubMed1997

Clinical and molecular features of spinocerebellar ataxia type 6.

The mutation involved in spinocerebellar ataxia type 6 (SCA6) is a small CAG expansion in the alpha-1A subunit of the voltage-dependent calcium channel gene. We looked for this mutation in 91 families with autosomal-dominant cerebellar ataxias and found that SCA6 is a minor locus in our series (2%) and is rare in France (1%). Furthermore, we did not detect the SCA6 mutation on 146 sporadic cases with isolated cerebellar ataxia or olivopontocerebellar atrophy. The normal and expanded alleles ranged from 4 to 15 and 22 to 28 CAG repeats, respectively, and age at onset was correlated to CAG repeat length (r = -0.87). In contrast with other SCA, the expanded allele was stable during transmission. Clinically, SCA6 patients (n = 12) presented with moderate to severe cerebellar ataxia with a lower frequency of associated signs compared with other SCA and a mean age at onset of 45 +/- 14 years (range, 24 to 67). MRI showed extensive cerebellar atrophy but not of the brainstem or cerebral cortex.

Adult↗

PubMed1997

Characterization of new polyclonal antibodies specific for 40 and 42 amino acid-long amyloid beta peptides: their use to examine the cell biology of presenilins and the immunohistochemistry of sporadic Alzheimer's disease and cerebral amyloid angiopathy cases.

BACKGROUND: In Alzheimer's disease (AD), the main histological lesion is a proteinaceous deposit, the senile plaque, which is mainly composed of a peptide called A beta. The aggregation process is thought to occur through enhanced concentration of A beta 40 or increased production of the more readily aggregating 42 amino acid-long A beta 42 species. MATERIALS AND METHODS: Specificity of the antibodies was assessed by dot blot, Western blot, ELISA, and immunoprecipitation procedures on synthetic and endogenous A beta produced by secreted HK293 cells. A beta and p3 production by wild-type and mutated presenilin 1-expressing cells transiently transfected with beta APP751 was monitored after metabolic labeling and immunoprecipitation procedures. Immunohistochemical analysis was performed on brains of sporadic and typical cerebrovascular amyloid angiopathy (CAA) cases. RESULTS: Dot and Western blot analyses indicate that IgG-purified fractions of antisera recognize native and denaturated A beta s. FCA3340 and FCA 3542 display full specificity for A beta 40 and A beta 42, respectively. Antibodies immunoprecipitate their respective synthetic A beta species but also A beta s and their related p3 counterparts endogenously secreted by transfected human kidney 293 cells. This allowed us to show that mutations on presenilin 1 triggered similar increased ratios of A beta 42 and its p 342 counterpart over total A beta and p3. ELISA assays allow detection of about 25-50 pg/ml of A beta s and remain linear up to 750 to 1500 pg/ml without any cross-reactivity. FCA18 and FCA3542 label diffuse and mature plaques of a sporadic AD case whereas FCA3340 only reveals the mature lesions and particularly labels their central dense core. In a CAA case, FCA18 and FCA3340 reveal leptomeningeal and cortical arterioles whereas FCA3542 only faintly labels such structures. CONCLUSIONS: Polyclonal antibodies exclusively recognizing A beta 40 (FCA 3340) or A beta 42 (FCA3542) were obtained. These demonstrated that FAD-linked presenilins similarly affect both p342 and A beta 42, suggesting that these mutations misroute the beta APP to a compartment where gamma-secretase, but not alpha-secretase, cleavages are modified. Overall, these antibodies should prove useful for fundamental and diagnostic approaches, as suggested by their usefulness for biochemical, cell biological, and immunohistochemical techniques.

Alzheimer Disease↗

PubMed1996

[Neuronal ceroid lipofuscinosis. An unknown overload disease].

Neuronal ceroid lipofuscinosis comprises a group of lysosomal diseases transmitted by autosomal recessive inheritance. Often unrecognized, this disease should be evoked in children or adolescents with blindness due to retinal pigmentation, dementia and myoclonal seizures. Retinal pigmentation is lacking in adults. The characteristic feature is an accumulation of fluorescent lipopigments deposited within cells, especially neurons. Histology examination gives the diagnosis based on the ultrastructure of skin biopsies and identification of the disease-specific lysosomal inclusions. The disease can also be identified in children by identification of mutations on genes CLN1, CLN3 and CLN5. The pathophysiology of these diseases remains unknown and treatment is limited to symptomatic care.

Adult↗

PubMed1996

Electromyographical and motor performance studies in the pmn mouse model of neurodegenerative disease.

The mouse autosomal recessive mutation progressive motor neuronopathy (pmn) results in early onset motor neuron disease with rapidly progressive hindlimb paralysis, severe muscular wasting, and death at around 6 weeks of age. This mutant provides opportunities for testing novel therapeutic strategies, including the administration of trophic factors, to prevent the degeneration of diseased neurons. The construction of a strain expressing the pmn and the Extra-toe (Xt) phenotypes allows the detection, and therefore the treatment, of affected progeny before the onset of the clinical weakness. Electromyography is the most appropriate technique for a longitudinal study in which a given individual is examined repeatedly. We present the results of an electrophysiological and behavioral exploration of the pmn disease and show that electromyography is a powerful tool for following the course of the disease and evaluating potential therapies relevant to motor neuron diseases.

Action Potentials↗

PubMed1996

Neurotrophins increase motoneurons' ability to innervate skeletal muscle fibers in rat spinal cord--human muscle cocultures.

Neurotrophins, nerve growth factor (NGF), neurotrophin-3 (NT-3), neurotrophin-5 (NT-5) and brain-derived neurotrophic factor (BDNF), were studied in vitro in a coculture model of human skeletal muscle myotubes and rat embryo spinal cord explants, which enables the different steps of functional innervation to be followed, including neurite outgrowth, synapse formation and induction of contractile activity. We found that NT-3, NT-5, BDNF, but not NGF simultaneously induced a significant increase in the number and length of neurites emerging from spinal cord explants, the number of endplates per muscle fiber, and the area of innervated muscle fibers around each spinal cord explant. These results suggest that neurotrophins NT-3, NT-5 and BDNF enhance spinal cord motoneurons potential of innervation.

Animals↗

PubMed1996

Percutaneous laser disk decompression under CT and fluoroscopic guidance: indications, technique, and clinical experience.

The aim of percutaneous laser disk decompression (PLDD) is to vaporize a small portion of the nucleus pulposus of an intervertebral disk, thereby reducing the volume and pressure of a diseased disk. This minimally invasive technique can be performed in patients who need surgical intervention for disk herniation with leg pain. PLDD is usually performed under fluoroscopic guidance with or without diskoscopy. However, it can also be performed under dual computed tomographic (CT) and fluoroscopic guidance as an outpatient procedure. CT and fluoroscopic guidance increases the safety and accuracy of PLDD, with high precision of instrument guidance, direct visualization of nucleus pulposus vaporization, and reduced risk of complications. Of 119 patients with lumbar disk herniation treated with PLDD under CT and fluoroscopic guidance, 91 (76.5%) had a good or fair response. PLDD performed with CT and fluoroscopic guidance appears to be a safe and effective treatment for herniated intervertebral disks.

Adolescent↗

PubMed1996

[Amyloidosis, protein conformation dynamics and neurologic diseases].

The abnormal protein which accumulates in the extracellular space in the central nervous system in Alzheimer's disease and prion diseases could result from similar mechanisms. Many studies have demonstrated that the abnormal protein is resistant to proteolytic agents. This resistance is correlated with a modification in the conformation of the protein, inverting the ratio of alpha and beta helix structures. This change in conformation could be the cause of the central nervous system lesions. The mechanism of the modification in conformation could be related to a process of hydrophobisation of the protein resulting from mutation. A hydrophilic amino acid would be replaced by a hydrophobic amino acid or in sporadic forms, modifications in the environment of the peptide may lead to physical and chemical aggressions. Hydrophobisation of the two proteins could later lead to formation of polymers and then insoluble aggregates with the physical and chemical characteristics of the amyloid substance. Polymerisation could be triggered by the formation of protein dimers which would be, in one case, an endogenous protein, PrP, and in the other exogenous proteins coming from the environment.

Alzheimer Disease↗

PubMed1996

[Abnormal central nervous conduction in long-term treatments with retinoids].

INTRODUCTION: Neurological manifestations are uncommon among the undesirable effects of systemic retinoid therapy. We observed a case of axial rigidity imputable to acitretine. Somesthesic evoked potentials were also altered. We therefore searched for such abnormal findings in patients given long-term systemic retinoid therapy. PATIENTS AND METHODS: A neurological exploration was performed in two groups of patients, G1 and G2, with psoriasis and no neurological complaint. The exploration included a physical examination, a study of the somesthesic evoked potentials of all 4 limbs and an electromyogram in case of abnormal findings. There were 8 patients (3 women, 5 men, mean age 56 years, age range 39-71) in G1 treated with systemic retinoids for a mean 140 months (80-185). Cumulative dose was 50 to 280 g with a daily dose of 0.2 to 0.6 mg/kg/day, i.e 20 to 50 mg/d of etretinate or acitretine. In G2, there were 5 subjects (mean age 42 years, range 21-52) with psoriasis (mean duration 20 years range 14-25) who had never been treated with systemic retinoids. RESULTS: Alterations in somesthesic evoked potentials were observed in 7 of the 8 patients in G1. Bilateral disturbances were seen in 6 cases, demonstrating abnormal lemniscal central nervous conduction in the dorsal and/or cervical level in 3 cases and the cervical level alone in 3 cases. There was one asymmetrical case involving the lumbar level on the right and the dorsal and/or cervical level on the right. Only one of the 5 controls in G2 had a minimal unilateral reduction in somesthesic evoked potentials involving the lower limb. Direct effect of systemic retinoids was retained in absence of any other cause due to metabolic, toxic or deficient disorders or spinal compression. CONCLUSION: Long-term use of systemic retinoids induces frequent latent neurological anomalies expressed as lemniscal central nervous conduction. It is hypothesized that pathogenesis involves changes in the lipid composition of the nervous membranes.

Adult↗

PubMed1995

Constitutive muscular abnormalities in culture in spinal muscular atrophy.

To explore the cause of spinal muscular atrophy (SMA), we used an in-vitro model of nerve-muscle co-cultures in which motoneurons were normal and satellite cells were obtained from SMA patients. In co-cultures initiated with satellite cells from type I and type II SMA patients only, we observed degeneration of the innervated fibres after 1-3 weeks of nerve-muscle co-culture. This process involved vacuolisation, disorganisation, and death of the innervated muscle fibres. This observation points to a muscular implication in the severe forms of SMAs.

Culture Techniques↗