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Biomedical subjects

W Robberecht

Publications and source records attributed to W Robberecht.

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

Demographic characteristics and prognosis in a Flemish amyotrophic lateral sclerosis population.

We describe the genetic and demographic characteristics of patients with amyotrophic lateral sclerosis (ALS) in Flanders, Belgium. Prognostic factors related to survival are examined. ALS was familial in 8.6% of all MND patients. In 6 of 8 apparently unrelated families, an SOD1 mutation was found. In sporadic ALS, mean age at onset was 57.1 years. There was a male preponderance (1.2:1) and the disease had a bulbar onset in 19%. Median survival was 32 months (95% CI 26-46). The presence of an APOE-epsilon 4 allele was not associated with a bulbar onset of ALS, an earlier age at onset or a shorter median survival. Variables examined in a multivariate analysis included age, sex, site of onset, delay from onset to diagnosis, and % forced vital capacity. Shorter survival was independently associated with higher age, bulbar onset, a short diagnostic delay, and a lower percent-predicted vital capacity at study entry. Simple clinical baseline characteristics can assist the clinician in estimating prognosis in ALS. The demographic characteristics of the Flemish ALS population do not seem to differ from those described in other parts of the world.

Adult↗
PubMed2000

Genetics of amyotrophic lateral sclerosis.

The genetic cause of amyotrophic lateral sclerosis (ALS) is known in a minority of cases. Mutations in SOD1, the gene encoding a superoxide dismutase on chromosome 21, are indeed found in 20% of familial ALS patients, who constitute only 5 or 10% of all ALS patients. In rare cases, a mutation in NFH, the gene encoding the heavy subunit of neurofilament, is present. Familial ALS has been linked to other loci but the genes involved remain to be identified. A genetic component is also thought to at least contribute to the pathogenesis of sporadic ALS. Their identification is now possible thanks to progress in molecular genetics.

Amyotrophic Lateral Sclerosis↗
PubMed2000

Genetic markers of ALS.

As a result of the advances made in the field of molecular and population genetics, it is anticipated that several genes underlying ALS or predisposing to ALS might be identified in the near future. This will enable physicians to establish a diagnosis of ALS based on molecular findings in addition to clinical and electrophysiological findings. At present, mutations in the gene encoding for the free radical scavenging enzyme, superoxide dismutase (SOD1), is the only basis for a molecular diagnosis. Other mutations are under investigation and confirmed results are eagerly awaited.

Amyotrophic Lateral Sclerosis↗
PubMed1999

Diffusion-weighted MRI in sporadic Creutzfeldt-Jakob disease.

Diffusion-weighted MRI (DWI) was used in three patients with autopsy-proven sporadic Creutzfeldt-Jakob disease (CJD) to provide a rapid noninvasive way to make this sometimes confusing diagnosis. DWI prompted the diagnosis of CJD at an early stage and appears to be particularly useful for monitoring the progression of the disease. We suggest that patients with suspected CJD and no abnormalities on T2- and proton density-weighted images may have cortical involvement on DWI.

Aged↗
PubMed1999

Evolution of motor and sensory deficits in amyotrophic lateral sclerosis estimated by neurophysiological techniques.

Although amyotrophic lateral sclerosis is a degenerative disease of the upper and lower motor neurons, there is evidence that the disease can affect other systems, including the sensory system. On the other hand, within the motor neuron pool there is possibly a predilection of the degenerative process for the motor neurons fibers with the fastest conduction velocity (MNFCV). We studied these two aspects of the disease in a group of 50 patients by prospectively assessing several sensory indices and by studying the selectivity of the spinal motor neuron loss. At baseline, nerve conduction studies and somatosensory evoked potentials showed abnormal slowing in the peripheral and central sensory pathways. Thermal thresholds for heating were elevated but were normal for cooling. In more than 60% of the patients at least one of the sensory tests studied was abnormal. However, except for a significant decrease in the amplitude of the sensory nerve action potentials of the sural nerves, these afferent dysfunctions were not progressive over the follow-up period of 6 months, in contrast to the marked deterioration in motor functions. Three different statistical models were applied to evaluate the presence of demyelination, selective loss of MNFCV, or the purely random degeneration of fast- and slow-conducting motor neurons. These data indicate a selective loss of the MNFCV and suggest that subclinical abnormalities of the sensory system in ALS are often present but almost nonprogressive. Furthermore, the amyotrophic lateral sclerosis disease process seems preferentially to affect MNFCV.

Adult↗
PubMed1999

Calcium handling proteins in isolated spinal motoneurons.

Amyotrophic lateral sclerosis is characterized by motoneuron degeneration, in which glutamate-induced cell death is thought to play a pathogenic role. This excitotoxic process is mediated by cytosolic Ca2+ overload. The glutamatergic ionotropic channel molecules, which constitute a major route of Ca2+ entry, were present on cultured spinal motoneurons. Using ratio RT-PCR, the relative presence in isolated motoneurons of the GluR subunits of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor was evaluated. GluR1 and GluR2 mRNAs were present abundantly, while GluR3 and GluR4 mRNAs were much less abundant. The relative amount of mRNAs encoding the different protein isoforms responsible for Ca2+ uptake into the internal stores and for controlled release of Ca2+ from these stores was also determined. For the sarco/endoplasmic reticulum Ca2+ ATPases (SERCAs), only the SERCA2b class 4 splice variant was found. The inositol 1,4,5-trisphosphate receptor (IP3R) mRNAs were mainly transcribed from the IP3RI and IP3RII genes. Heterogeneity was also observed for the ryanodine receptors (RyR) as the RyR1, RyR2 and RyR3 mRNAs were present.

Animals↗
PubMed1999

Intravascular lymphomatosis of the brain: a diagnostic problem.

Intravascular lymphomatosis (of B- or T-cell origin) is a rare lymphoproliferative disorder characterised by neoplastic proliferation of lymphoid cells within the lumen of capillaries, small veins and arteries with no or minimal involvement of the parenchyma. Its predilection sites are the skin and the brain. We studied a 44-year-old man who presented with a 2 year history of unexplained LDH elevation followed by a neurological syndrome without systemic involvement. Brain biopsy showed an intravascular lymphoma of the B-cell lineage. This report illustrates the diagnostic challenge of this rare disorder with a grim prognosis.

Adult↗
PubMed1999

A retrospective study of Creutzfeldt-Jakob disease in Belgium.

Using data from Belgian neuropathological archives, completed with the results of a comprehensive study of available medical records, we found 100 patients who fulfilled diagnostic criteria for probable or definite Creutzfeldt-Jakob d1551isease (CJD). Mean age at death was 63 years. The median disease duration was 9 months. Progressive mental deterioration was present in all cases, whereas signs of cerebellar dysfunction and myoclonus were found in approximately 80% of the patients. In 50% of the population, the EEG revealed characteristic abnormalities. Ninety-six patients suffered from the sporadic type of CJD, while 4 suffered from a hereditary form. In our series, we could find no evidence for the new variant, neither for an iatrogenic cause.

Adult↗
PubMed1999

Mutational analysis of the Cu/Zn superoxide dismutase gene in 23 familial and 69 sporadic cases of amyotrophic lateral sclerosis in Belgium.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder caused by degeneration of motor neurons of the spinal cord and brain. The majority of ALS cases are sporadic (SALS). However, in 10-15% of ALS cases the disease is inherited as an autosomal dominant trait (familial ALS or FALS). We used a non-radioactive SSCP method, in combination with solid phase sequencing, to screen the entire SOD1 (Cu/Zn superoxide dismutase) coding region and flanking intronic sequences for mutations. Twenty-three patients from 11 ALS families and 69 SALS patients of Belgian origin were studied. Three different mutations were identified (L38V, D90A and G93C) in seven families. Importantly, the D90A was only found in the heterozygous state. In addition two single base pair variants (IVS1 + 19G > A and AAC139 AAT) were identified in two SALS patients. These results suggest that the SOD1 analysis is useful in FALS but less so in SALS cases. The SSCP analysis has proved fast and reliable for this purpose.

Amyotrophic Lateral Sclerosis↗
PubMed1999

A novel 7.4 kb mitochondrial deletion in a patient with congenital progressive external ophthalmoplegia, muscle weakness and mental retardation.

We present a patient with external ophthalmoplegia, bilateral ptosis, progressive muscle weakness with "ragged-red fibres" and mental retardation. Mitochondrial DNA analysis by Southern blot revealed heteroplasmy in muscle for a 7.4 kb deletion. In white blood cells, the deletion was only detectable by PCR. There was no evidence for duplications, nor for multiple deletions in the proband or siblings. PCR analysis did not reveal the presence of a mitochondrial DNA defect in the parents and siblings. Thus, there is no experimental support for a maternally inherited mitochondrial DNA deletion. We consider this a sporadic case with a de novo deletion. Diabetes and complaints of fatigue, also seen in this family, are probably coincidental. Mental retardation has been reported occasionally in patients with mitochondrial deletions, but is not common.

Adult↗
PubMed1998

Glial cells potentiate kainate-induced neuronal death in a motoneuron-enriched spinal coculture system.

AMPA/kainate receptor-mediated excitotoxicity is believed to play a pathogenic role in amyotrophic lateral sclerosis. To further characterize the mechanisms involved in AMPA/kainate receptor-mediated motoneuron injury, we investigated the influence of spinal glial cells on kainate-induced motoneuron death in vitro. A motoneuron-enriched neuronal population was obtained from embryonic mouse spinal cord by metrizamide density centrifugation. This population was cultured either on a pre-established glial feeder layer of ventral spinal origin (coculture) or in glia-free conditions (monoculture). Glial feeder layers significantly enhanced basal survival of neurons, and supported neuronal differentiation as judged by neuronal morphology and expression of the motoneuron markers peripherin and SMI-32. Neuronal vulnerability to kainate was two- to three-fold higher in coculture than in monoculture, and increased significantly with time in coculture. The effects of glial feeder layers on neuronal basal survival, differentiation and kainate vulnerability were not mimicked by conditioned medium from glial cells. The increase in neuronal kainate vulnerability with time in coculture was associated with a marked rise in the proportion of cocultured neurons possessing Ca2+-permeable AMPA/kainate receptors, as determined by kainate-activated Co2+-uptake. Neurons in monoculture were unstained by kainate-activated Co2+-uptake. Neurons were immunoreactive to specific antibodies against the AMPA receptor subunits GluR1 and GluR2 both in monoculture and coculture. This study indicates that motoneuron differentiation in coculture is associated with increased vulnerability to kainate and increased expression of Ca2+-permeable AMPA/kainate receptors. In this paradigm glial cells support basal survival and differentiation of neurons, but potentiate kainate-induced neuronal death.

Animals↗
PubMed1998

Tissue-type plasminogen activator is not required for kainate-induced motoneuron death in vitro.

Spinal motoneurons are highly vulnerable to kainate both in vivo and in vitro. Tissue-type plasminogen activator (tPA) and plasmin have recently been shown to mediate kainate-induced neuronal death in the mouse hippocampus in vivo. The aim of the present study was to determine whether tPA also mediates the kainate-induced death of motoneurons in vitro. A motoneuron-enriched neuronal population was isolated from the ventral spinal cord of wild-type (WT) and tPA-deficient (tPA-/-) mouse embryos. WT and tPA-/- neurons were cultured on WT and tPA-/- spinal glial feeder layers, respectively. WT and tPA-/- co-cultures were morphologically indistinguishable. Expression of tPA in WT co-cultures was demonstrated using RT-PCR. WT and tPA-/- co-cultures were exposed to kainate for 24 h. The neurotoxic effect of kainate did not differ significantly between WT and tPA-/- cultures. The plasmin inhibitor alpha2-antiplasmin did not protect WT neurons against kainate-induced injury. These results indicate that the plasmin system is not a universal mediator of kainate-induced excitotoxicity.

Animals↗
PubMed1998

Increased sensitivity of fibroblasts from amyotrophic lateral sclerosis patients to oxidative stress.

Although the cause of amyotrophic lateral sclerosis (ALS) is unkNown, free radical toxicity is thought to play a pathogenic role. We investigated whether cells from ALS patients are more vulnerable to exogenously induced oxidative stress than cells from controls. We therefore studied the sensitivity of fibroblasts from patients with sporadic ALS (SALS), and from patients with familial ALS (FALS) associated with copper/zinc superoxide dismutase (Cu/ZnSOD) mutations (SOD1-FALS), to the free radical-generating agents 3-morpholinosydnonimine (SIN-1) and hydrogen peroxide (H2O2), and to serum withdrawal. SOD1-FALS and SALS fibroblasts were significantly more sensitive than controls to SIN-1 but not to serum withdrawal. In addition, SOD1-FALS fibroblasts were more sensitive to H2O2 than SALS fibroblasts and than fibroblasts of controls. These results suggest that the mechanism underlying both SOD1-FALS and SALS jeopardizes the cell's defense against free radical stress, and that SOD1-FALS cells are particularly sensitive to H2O2. The latter finding is compatible with biochemical data on the increased affinity of the mutated Cu/ZnSOD for H2O2.

Amyotrophic Lateral Sclerosis↗
PubMed1998

Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegeneration resulting in paralysis and death from respiratory failure within 3-5 years. About 20% of familial cases are associated with mutations in the gene for copper/zinc superoxide dismutase ( SOD1 ), which catalyses the dismutation of the superoxide radical to hydrogen peroxide and oxygen. Experimental evidence suggests mutations act by a toxic gain of function but the mechanism is unknown. There are >60 known SOD1 mutations associated with ALS and all are dominant except for one in exon 4, a D90A substitution which is recessive. D90A pedigrees with dominant inheritance have now been reported and this apparent contradiction needs to be explained. We performed a worldwide haplotype study on 28 D90A pedigrees using six highly polymorphic microsatellite markers. We now show that all 20 recessive families share the same founder (alpha = 0.999), regardless of geographical location, whereas several founders exist for the eight dominant families (alpha = 0.385). This finding confirms that D90A can act in a dominant fashion in keeping with all other SOD1 mutations, but that on one occasion, a new instance of this mutation has been recessive. We propose a tightly linked protective factor which modifies the toxic effect of mutant SOD1 in recessive families.

Amino Acid Substitution↗
PubMed1998

A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF-I Study Group.

To test the safety and efficacy of recombinant human insulin-like growth factor-I (rhIGF-I) in ALS, 183 patients from eight European centers were randomized to receive double-blind placebo (n = 59) or rhIGF-I 0.1 mg/kg/day (n = 124) subcutaneously for 9 months. At study completion, the primary efficacy outcome measure (change in disease progression as assessed by the Appel ALS rating scale) showed no significant difference between treatment groups. RhIGF-I appeared to be safe and well-tolerated.

Adult↗
PubMed1997

Familial juvenile focal amyotrophy of the upper extremity (Hirayama disease). Superoxide dismutase 1 genotype and activity.

BACKGROUND: Juvenile focal amyotrophy of the arm is an unusual focal motor neuron disease that is rarely familial. Its pathogenesis is unknown. We recently described a family with amyotrophic lateral sclerosis associated with a mutation in the superoxide dismutase 1 (SOD1) gene substituting an aspartate for an alanine (D9OA). One of the carriers of this mutation had focal and nonprogressive amyotrophy of the arm, suggesting that focal amyotrophy might be associated with SOD1 mutations. OBJECTIVES: To describe the phenotype of 2 brothers with juvenile focal amyotrophy of the upper extremity and to characterize their SOD1 genotype and SOD activity. METHODS: Polymerase chain reaction and sequencing of the SOD1 gene and colorimetric measurement of the enzyme activity. RESULTS: We compared the phenotype of our patients to that of 375 patients described in the Western literature. The 5 exons of the SOD1 gene were normal, as was the SOD activity in red blood cells.

Adult↗