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Biomedical subjects

J M Warter

Publications and source records attributed to J M Warter.

At least 37 records · Page 2Linked to original sources
PubMed2000

Homogeneous phenotype of the gypsy limb-girdle MD with the gamma-sarcoglycan C283Y mutation.

OBJECTIVE: To characterize the clinical phenotype of LGMD2C in gypsies. BACKGROUND: Limb-girdle muscular dystrophy (LGMD) in gypsies of Western Europe is caused by a homozygous C283Y mutation on the same haplotype, suggesting a founder effect. METHODS: We performed clinical, laboratory, and muscle imaging studies of 40 patients. RESULTS: Mean age at onset was 5.3 years. One half of the patients had loss of ambulation by the age of 12; 13% still could walk after age 16. Calf hypertrophy, scapular winging, macroglossia, and lumbar hyperlordosis were common. Girdle, trunk, and proximal limb flexor muscles had earlier and more severe involvement. Cardiomyopathy was not observed. Five patients in the third decade of life required mechanical ventilation. Scoliosis was common in the nonambulatory stage. CONCLUSIONS: LGMD2C in gypsy patients with C283Y mutation presents a rather homogeneous phenotype, characterized by an initial Duchenne-like progressive course followed by a more prolonged survival rate possibly due to the absence of early respiratory impairment and cardiac failure.

Adolescent↗
PubMed2000

Prevention of mutant SOD1 motoneuron degeneration by copper chelators in vitro.

An animal model of familial amyotrophic lateral sclerosis (FALS) has been generated by overexpression of human CuZn superoxide dismutase (SOD1) containing a substitution of glycine to alanine at position 93 in transgenic G93A mice. The loss of motoneurons shown in this model has been attributed to a dominant gain of function of this mutated enzyme, which might be due to copper toxicity. This hypothesis was tested in purified spinal motoneurons cultures originating from G93A transgenic embryos. Spinal motoneurons were isolated from E13 embryos by several steps including density gradient centrifugation. The effect of copper chelators on survival and neurite growth of motoneurons was investigated. Survival of G93A motoneurons was decreased by 46% as compared to wild-type motoneurons. Moreover, G93A motoneurons showed reduced neurite outgrowth. Copper chelators strikingly increased viability of G93A motoneurons (by over 200%) but had no effect on wild-type cells. Presence of DDC in the medium increases the length of neurites from G93A motoneurons. The present results suggest the capacity of copper chelators to reduce the effect of reverse function of mutated SOD1 on motoneurons.

Amyotrophic Lateral Sclerosis↗
PubMed2000

MRI in multiple sclerosis of the spinal cord: evaluation of fast short-tan inversion-recovery and spin-echo sequences.

We compared the sensitivity of T2-weighted spin-echo (FSE) and fast short-tau inversion-recovery (fSTIR) sequences in detection of multiple sclerosis of the spinal cord in 100 consecutive patients with clinically confirmed multiple sclerosis (MS); 86 patients underwent also brain MRI. In all, 310 focal lesions were detected on fSTIR and 212 on T2-weighted FSE, spinal cord lesions were seen better on fSTIR images, with a higher contrast between the lesion and the normal spinal cord. In 24 patients in whom cord plaques were shown with both sequences, the cranial study was normal or inconclusive. Assessment of spinal plaques can be particularly important when MRI of the brain is inconclusive, and in there situations fSTIR can be helpful.

Adult↗
PubMed2000

Is clonidine growth hormone stimulation a good test to differentiate multiple system atrophy from idiopathic Parkinson's disease?

Clonidine, a centrally active alpha 2-adrenoreceptor agonist used to lower blood pressure, has been proposed to differentiate central from peripheral autonomic deficits and multiple system atrophy (MSA) from untreated idiopathic Parkinson's disease (IPD). A lack of growth hormone (GH) increase after clonidine infusion is found in patients with MSA, but not in those with IPD or with pure autonomic failure. We studied 19 IPD and 7 MSA patients to assess whether this test could be used in clinical practice to distinguish MSA from IPD, whatever the stage of the disease. Serum GH levels were measured 15, 30, 45 and 60 min after a 10-min infusion of 2 micrograms/kg clonidine. GH levels remained stable after clonidine infusion in all 7 MSA patients but increased in only 12 of the 19 IPD patients, while remaining stable in the other 7. No correlation was found with the presence of orthostatic hypotension. We conclude that the GH response to clonidine infusion has a very high sensitivity (100% in our series and in previous studies) for the diagnosis of MSA. However, this response cannot be used as a diagnostic test because of its poor specificity.

Aged↗
PubMed2000

Factors associated to hypermanganesemia in patients receiving home parenteral nutrition.

BACKGROUND: Home parenteral nutrition (HPN) patients often present hypermanganesamia. AIM: To examine which factors may be associated to hypermanganesemia in HPN patients. METHODS: Plasma manganese (Mn), liver function tests, C-reactive protein concentrations, erythrocyte sedimentation rate (ESR), tumor necrosis factor-alpha (TNF- alpha), interleukin-6, soluble receptors of interleukin-2, and blood neopterin concentrations were determined in 21 HPN patients and 10 healthy controls. Brain magnetic resonance imaging (MRI) and careful neurologic clinical examination were performed in 11 patients. RESULTS: Mn concentration was higher in HPN patients than controls (1.96+/-1.1 vs 0.81+/- 0.4 microg/L;P<0.001) and positively correlated to the amount of parenteral nutrition (PN) supply, transaminases and alkaline phosphatase (r=0.53, P<0.0001) concentrations, as well as to ESR (r=0.61, P<0.0001), TNF- alpha and blood neopterin. The amount of calories provided by PN was positively correlated to inflammatory markers and liver parameters. All patients investigated by MRI showed hyperintense basal ganglia on T1-weighted images suggesting brain Mn deposition. Only one had slight clinical extrapyramidal symptoms. CONCLUSION: In HPN patients, sustained inflammation may facilitate hypermanganesemia through 1. cholestatic liver disease and thereby decreased Mn biliary excretion, 2. high nutritional requirements (responsible for increased Mn supply), and/or 3. modified Mn metabolism or body distribution. Neurologic complications appeared marginal whereas Mn brain deposition seems frequent.

Adult↗
PubMed2000

[Myotubular myopathy].

The myotubular myopathy is an X-linked centronuclear myopathy characterized by severe neonatal hypotonia and generalized muscle weakness which most frequently results in the premature death of the newborn infants by respiratory failure. The characteristic muscle histopathology consists in centrally positioned nuclei in most muscle fibers. In 1996, the gene responsible for the disease, MTM1, was identificated in Xq28 region. Since then, more than hundred mutations have been isolated. Genotype - phenotype correlation is complex because mutations are found along the entire coding sequence of the MTM1 gene. Most mutations are associated with very severe phenotype with death before the first year of life, however a milder phenotype has been individualized. It is important to be aware of the existence of such milder MTM phenotype because in those patients a very mild expression permit normal life into adulthood.

Cytogenetics↗
PubMed2000

[Genetic tests: how far should we go? A case of late-onset Friedreich's disease].

Two sisters developed isolated cerebellar ataxia with pyramidal signs and preservation of reflexes at 49 and 63 years of age. Presence of two abnormal expansions GAA on both allels of the frataxine gene led to the diagnosis of Friedreich ataxia. These cases demonstrate the place of genetic tests in the diagnosis of late onset autosomal recessive ataxia.

Adult↗
PubMed1999

Protection of immunoreactivity of dry immobilized proteins on microtitration plates in ELISA: application for detection of autoantibodies in myasthenia gravis.

We show the ability of the BSA-trehalose film to convert normally fragile proteins such as mouse monoclonal antibody to the Alzheimer precursor protein A4 (APP695) and cell line TE671 acetylcholine receptor (AChRTE671) into a stable reagent, after its immobilization on microtitration plates. The remarkable property of the dry immobilized proteins are their stability under prolonged exposure to temperatures as high as 50 degrees C. Using the AChRTE671, the proposed method was applied for the measurement of anti-AChR autoantibodies in Myasthenia gravis by means of an enzyme-linked immunosorbent assay (ELISA). The test was shown to be specific and able to detect anti-AChR autoantibodies at concentrations as low as 3 nM. Using the same AchRTE671 as antigen, the results of examination of 34 serum samples for detection of anti-AChR autoantibodies by ELISA were compared with those of the conventional radioimmunoprecipitation assay (RIA). It was concluded that ELISA is another useful method for the diagnosis of M. gravis. The ELISA method offers a rapid, simple, safe and inexpensive means for mass screening of M. gravis.

Autoantibodies↗
PubMed1999

High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2.

OBJECTIVE: To characterize the nature of CACNA1A mutations in episodic ataxia type 2 (EA2), to search for mutations in sporadic cases, and to delineate better the clinical spectrum. BACKGROUND: EA2 is an autosomal dominant disorder characterized by recurrent acetazolamide-responsive attacks of cerebellar ataxia. The mutated gene, CACNA1A, located on chromosome 19, encodes the alpha1A subunit of a voltage-dependent calcium channel. So far, only three CACNA1A mutations have been identified-in two EA2 families and in one sporadic case. These three mutations disrupted the reading frame and led to truncated proteins. Interestingly, distinct types of CACNA1A mutations have been identified in familial hemiplegic migraine (missense mutations) and spinocerebellar ataxia type 6 (SCA-6) progressive cerebellar ataxia (expanded CAG repeats). However, except for SCA-6, these genotype-phenotype correlations relied on the analysis of very few families. METHODS: To characterize CACNA1A mutations, eight familial and seven sporadic EA2 patients were selected. All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis. In addition, the length of the CAG repeat has been determined in all patients. RESULTS: Seven new mutations were detected in four multiple case families and three sporadic cases. Six of them lead most likely to truncated or aberrant proteins. CAG repeat sizes were in the normal range. CONCLUSION: These data clearly establish the specificity of EA2 mutations compared with SCA-6 and familial hemiplegic migraine. Detailed clinical analysis of the mutation carriers showed the highly variable penetrance and expression of this disorder: Several of the carriers did not show any clinical symptom; others displayed atypical or permanent neurologic symptoms (such as recurrent, transient diplopia or severe, permanent, and isolated cerebellar ataxia).

Adolescent↗
PubMed1999

Basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease.

OBJECTIVE: To determine the correlation of clinical and pathologic features with prion protein (PrP) gene polymorphism at codon 129 and with biochemical characteristics of the protease-resistant PrP (PrPres) in sporadic Creutzfeldt-Jakob disease (CJD). METHODS: Clinical data acquisition, determination of the codon 129 genotype of the PrP gene, brain pathologic study, and immunoblot analysis of crude brain extracts were carried out in 14 patients. RESULTS: The first group of 10 subjects showed the classic clinical triad, with dementia, myoclonus, and periodic sharp waves on EEG. None of the subjects had amyloid plaques, but PrP immunoreactivity was of diffuse synaptic type in the cerebellar cortex. All subjects were methionine-methionine at codon 129 and the PrPres had a biochemical profile of type 1 (unglycosylated band of 21.5 kD). A second group of three patients showed cerebellar ataxia and later dementia. Periodic sharp waves on EEG were absent. PrP amyloid plaques predominated in the cerebellar cortex, along with diffuse PrP immunoreactivity. These subjects were valine-valine at codon 129 and had a type 2 PrPres (unglycosylated band of 19.4 kD). In the last patient cerebellar ataxia and dementia appeared simultaneously. Many Kuru-type plaques were present in the cerebellar cortex; many PrP amyloid plaques were present in the basal ganglia. This patient was methionine-valine at codon 129 and the PrPres was of type 1. CONCLUSIONS: The codon 129 genotype is only one of the factors determining CJD phenotype, and the biochemical pattern of PrP has no direct correlation with this phenotype.

Aged↗
PubMed1999

Compensatory mechanism of motor defect in SOD1 transgenic mice by overactivation of striatal cholinergic neurons.

Expression of a mutant superoxide dismutase 1 (SOD1) gene in transgenic mice induces a gradual degeneration of cholinergic motor neurons in the spinal cord, causing progressive muscle weakness and hindlimb paralysis. Transgenic mice over-expressing the human SOD1 gene containing a Gly-->Ala substitution at position 93 (G93A) were employed to explore the effects of the SOD1 mutation on choline acetyltransferase (ChAT) expression in the striatum, and in the lumbar and cervical spinal cord. These mice showed a progressive loss of their spinal cord motor neurons, and at 130 days of age showed an up-regulation of ChAT mRNA expression in the striatum. On the other hand, ChAT mRNA decreased in cervical and lumbar motor neurons. These findings suggest that cholinergic interneurons in striatum in SOD1 transgenic mice are over-activated in an attempt to compensate for the death of spinal motor neurons.

Adaptation, Physiological↗
PubMed1999

Unusual phenotypic alteration of beta amyloid precursor protein (betaAPP) maturation by a new Val-715 --> Met betaAPP-770 mutation responsible for probable early-onset Alzheimer's disease.

We have identified a novel beta amyloid precursor protein (betaAPP) mutation (V715M-betaAPP770) that cosegregates with early-onset Alzheimer's disease (AD) in a pedigree. Unlike other familial AD-linked betaAPP mutations reported to date, overexpression of V715M-betaAPP in human HEK293 cells and murine neurons reduces total Abeta production and increases the recovery of the physiologically secreted product, APPalpha. V715M-betaAPP significantly reduces Abeta40 secretion without affecting Abeta42 production in HEK293 cells. However, a marked increase in N-terminally truncated Abeta ending at position 42 (x-42Abeta) is observed, whereas its counterpart x-40Abeta is not affected. These results suggest that, in some cases, familial AD may be associated with a reduction in the overall production of Abeta but may be caused by increased production of truncated forms of Abeta ending at the 42 position.

Age of Onset↗
PubMed1999

[Spinocerebellar ataxia and polyneuropathy secondary to vitamin E deficiency].

BACKGROUND: Cerebellar ataxia or peripheral neuropathy can be signs of vitamin E deficiency. We report two cases. CASE REPORTS: Two patients developed vitamin E deficiency subsequent to intestinal malabsorption. The first patient had a duodenogastric communication and dilatation of the first jejunal loop. The second patient had deficient pancreas secretion and dilatation of the biliary tree. DISCUSSION: Vitamin E deficiency is generally secondary to acquired or hereditary malabsorption syndrome. It can also occur in the absence of malabsorption by hereditary deficiency in alpha-tocopherol transporter. Vitamin E supplements are required for malabsorption. The etiology work-up of neuropathy or cerebellar ataxia should include vitamin E assay.

Adolescent↗
PubMed1999

Effect of the nonpeptide neurotrophic compound SR 57746A on the phenotypic survival of purified mouse motoneurons.

1. Neurotrophic factors have been used for the treatment of several neurodegenerative diseases. However, their use is limited by their inability to cross the blood-brain barrier, their short half life and their side effects. SR 57746A is a new orally active compound that exhibits in vivo and in vitro neurotrophic effects in several experimental models. 2. We show here that SR 57746A (1 microM) increases the phenotypic survival of embryonic purified mouse motoneurons in vitro to the same extent as brain-derived neurotrophic factor (100 ng ml-1), and increases the outgrowth and number of their neurites. It acts in a dose-dependent manner up to 1 microM which is the optimal concentration. Above this concentration, its neurotrophic effect decreases. 3. Genistein (10 microM), a protein tyrosine kinase inhibitor, also increases the phenotypic survival and differentiation of mouse motoneurons. It does not act in a synergistic or additive manner with SR 57746A. However, at concentrations equal or superior to 25 microM, it decreases the survival of motoneurons. This suggests that the neurotrophic effect of genistein is due to a favourable alteration of equilibrium between phosphorylated and dephosphorylated states of proteins involved in survival and differentiation of motoneurons. 4. Like genistein, SR 57746A should be used at a critical concentration (1 microM) to exert its optimal effects. Since SR 57746A does not act synergistically with genistein, it is likely that its mechanism of action involves a pathway similar to that affected by this tyrosine kinase inhibitor. 5. At the present time, SR 57746A is the only orally active compound and the only synthetic compound shown to be active on motoneurons in vitro. It should thus be considered as a good candidate for the treatment of motoneuron diseases.

Animals↗
PubMed1999

[Paradoxal lowering of parasympathetic indices in myasthenic patients].

Myasthenia gravis is an autoimmune disease presenting antibodies developed against the nicotinic receptors of acetylcholine. The aim of this study was to evaluate heart rate variability in these patients. Heart rate variability was studied with 24 hour Holter recordings. Eighteen myasthenic patients, 7 men and 11 women, under pyridostigmine treatment, with an average age of 40 years (25 to 63 years) were aged and gender matched to a control group of 18 healthy subjects. All patients exhibited normal cardiac status and Doppler echocardiography. The following parameters were collected over 24 hours and the data further differentiated between night and day: for the temporal domain: heart rate, SDNN, pNN50, rMSSD; and for the spectral domain: total power, high frequency (HF) and low frequency (LF) power. The mean heart rate was slightly higher in the myasthenic group (non significant), due to a less marked nocturnal bradycardia. There was a decrease in the observed absolute values of SDNN as well as temporal and spectral parasympathetic indices (pNN50, rMSSD, HF) (p < 0.01) over the 24 hour period. The results were more significant during the night. Cardiac parasympathetic modulation is significantly modified in myasthenic patients. Considering that lack of bradycardia argues against an over active vagal tone, three hypothesis are discussed that favor of a low vagal tone: antibodies effects on the nicotinic receptors of the autonomic nervous system, respiratory impairment and a desensitization of the acetylcholine receptors.

Adult↗
PubMed1999

Gerstmann-Sträussler-Scheinker disease and the French-Alsatian A117V variant.

Gerstmann-Sträussler-Scheinker disease is a rare familial form of prion disease. This autosomal dominant disorder is constantly associated with a point mutation on the PrP gene. Eight mutations affecting respectively codons 102, 105, 117, 145, 202, 212 and 218, have been so far described. Symptoms are variable and include ataxia and dementia. They generally appear between the fourth and sixth decade. Mean duration of the disease (5 years) is on the whole longer than that of other familial forms of prion diseases. Gerstmann-Sträussler-Scheinker disease is neuropathologically characterized by the presence of numerous multicentric or unicentric PrP amyloid deposits widespread throughout the encephalon. Spongiform change is inconstant. Neurofibrillary tangles have been described in some families. Clinicopathological features show considerable variability. Pathogenesis of amyloidosis and associated lesions as well as factors underlying the phenotypic polymorphism of the disease remain only partially known.

Adult↗
PubMed1998

Muscle could be the therapeutic target in SMA treatment.

A nerve-muscle coculture model (human muscle cells innervated by embryonic rat spinal cord) was used to explore the pathogenesis of spinal muscular atrophy (SMA). Previous studies showed that myofibers from donors with SMA type I or SMA type II (but not SMA type III) undergo a characteristic degeneration 1-3 weeks after innervation (Braun et al. [1995] Lancet 345:694-695). To determine which cells are involved in degeneration, we cloned satellite cells and fibroblasts derived from muscle biopsies of normal (healthy) donors and donors with SMA. We show that fibroblasts are required for successful innervation, that fibroblasts from normal and SMA donors contribute equally well to the establishment of cocultures, and that only SMA satellite cells are responsible for the degeneration of innervated cocultures. We succeeded in preventing the degeneration of cloned satellite cells from SMA donors by adding 50% cloned satellite cells from normal donors to the culture to make heteromyotubes. In mixed cocultures, after innervation, we did not observe degeneration. This result suggests that survival of the cocultures depends on a message derived from the muscle cells. Consequently, we propose that therapeutic approaches for SMA that could repair (or compensate for) the genetic defect in muscle cells (which are otherwise much more accessible for gene therapy than neurons) might prevent motoneuron degeneration. The role of muscle cells in the establishment and the degeneration of neuromuscular junctions deserves further attention and investigation.

Animals↗