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Biomedical subjects

F Zimprich

Publications and source records attributed to F Zimprich.

At least 19 recordsLinked to original sources

Idiopathic generalized epilepsy phenotypes associated with different EFHC1 mutations.

We sequenced 61 patients with various idiopathic generalized epilepsy (IGE) syndromes for mutations in the EFHC1 gene. We detected three novel heterozygous missense mutations (I174V, C259Y, A394S) and one possibly pathogenic variant in the 3' UTR (2014t>c). The mutation I174V was also detected in 1 of 372 screened patients with temporal lobe epilepsy. We conclude that mutations in the EFHC1 gene may underlie different types of epilepsy syndromes.

3' Untranslated Regions↗

Andreas Rett and benign familial neonatal convulsions revisited.

In 1964 Andreas Rett published the first account of a family with benign familial neonatal convulsions (BFNC). The authors retraced Rett's family and report that the clinical and genetic features of this original family fit the currently accepted definitions of BFNC. They also consider the career of Dr. Rett, a researcher and social reformer as well as an advocate for the rights of children with developmental disabilities.

Aged↗

Mutations in the CLCN2 gene are a rare cause of idiopathic generalized epilepsy syndromes.

Mutations in the chloride channel gene CLCN2 have been reported in families with generalized and focal epilepsy syndromes. To evaluate the contribution of mutations in the CLCN2 gene to the etiology of epilepsies in our population, we screened 96 patients with different epilepsy syndromes and a putative genetic background. No definite mutations were found in our study population. We conclude that mutations in the CLCN2 gene are only a rare cause of idiopathic generalized epilepsy.

CLC-2 Chloride Channels↗

Inclusion body myopathy and Paget disease is linked to a novel mutation in the VCP gene.

Mutations in the valosin-containing protein (VCP) on chromosome 9p13-p12 were recently found to be associated with hereditary inclusion body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD). We identified a novel missense mutation in the VCP gene (R159H; 688G>A) segregating with this disease in an Austrian family of four affected siblings, who exhibited progressive proximal myopathy and Paget disease of the bone but without clinical signs of dementia.

Adenosine Triphosphatases↗

Association of an ABCB1 gene haplotype with pharmacoresistance in temporal lobe epilepsy.

The multidrug transporter P-glycoprotein is suspected of contributing to pharmacoresistance in temporal lobe epilepsy (TLE). To assess the role of functional variations in its coding gene (ABCB1) the authors genotyped 210 patients with TLE who were stratified according to their degree of drug resistance. They identified a common haplotype that when present in the homozygous state significantly increased the risk for pharmacoresistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Vestibular processing in human paramedian precuneus as shown by electrical cortical stimulation.

The authors describe a 16-year-old patient with recurrent episodes of epileptic linear self-motion perception and occasional body tilts. Intracranial seizure monitoring located the seizure onset, caused by a circumscribed ependymoma, in the right paramedian precuneus. Electrical cortical stimulation of this area could reproduce the same vestibular sensations, which ceased after lesionectomy. The findings implicate the paramedian area of the precuneus in the processing of static and dynamic vestibular, probably otolithic, information.

Adolescent↗

Altered expression of voltage-dependent calcium channel alpha(1) subunits in temporal lobe epilepsy with Ammon's horn sclerosis.

Voltage-dependent calcium channels, the initial components in the calcium signalling cascade, are increasingly being recognised as relevant factors in the pathology of epilepsy. To further characterise their role in temporal lobe epilepsy associated with Ammon's horn sclerosis, we investigated the immunohistochemical distribution of five different voltage-dependent calcium channel alpha(1) subunits (alpha(1A), alpha(1B), alpha(1C), alpha(1D), alpha(1E)) in 14 hippocampal specimens of patients with Ammon's horn sclerosis in comparison with eight autopsy control cases. In epilepsy specimens an increased immunoreactivity was observed for alpha(1A), alpha(1B), alpha(1D) and alpha(1E) in the neuropil of the dentate gyrus molecular layer. Dentate gyrus granule cells and residual CA3 pyramidal neurones showed enhanced immunoreactivity for alpha(1A), while labelling of these neurones was decreased for alpha(1C). Astrocytes in Ammon's horn sclerosis specimens were strongly immunoreactive for the alpha(1C) subunit contrasting with an absent astrocytic alpha(1C) labelling in controls. Our results suggest that the expression of calcium channels in neurones and glial cells is dynamically regulated in temporal lobe epilepsy, supporting the relevance of calcium signalling pathways for this disease.

Adolescent↗

Buffering intracellular calcium disrupts motoneuron development in intact zebrafish embryos.

Numerous studies, performed mainly on dissociated cells, have shown that calcium signals have a role during different stages of neuronal development. However, the actions of calcium during neuronal development in vivo remain to be established. The present study has investigated the role of intracellular calcium signals during development of motoneurons in the spinal cord of intact zebrafish embryos. Loading blastomeres of early embryos with either the calcium buffer BAPTA or the calcium reporter dye Calcium Green, was shown to disrupt motoneuron development in the spinal cord of embryos at 24 h postfertilisation. Loading the calcium buffer BAPTA, at an intracellular concentration of 1 mM, into the blastomeres of early embryos did not alter the resting levels of intracellular calcium, but significantly dampened transient rises in intracellular calcium in the cells of later stage embryos. Loading cells with 1 mM BAPTA significantly decreased the number of motoneurons present in the spinal cord at 24 h, indicating that calcium signals are important for normal motoneuron differentiation. Furthermore, in those BAPTA-filled cells that did adopt a motoneuron cell fate, axogenesis was found to be inhibited, suggestive of a role for calcium signalling in neurite initiation. This work provides evidence that calcium signals are necessary at several stages of motoneuron development in vivo.

Animals↗

Distribution of a calcium channel subunit in dystrophic axons in multiple sclerosis and experimental autoimmune encephalomyelitis.

Multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) are immune-mediated diseases of the CNS. They are characterized by widespread inflammation, demyelination and a variable degree of axonal loss. Recent magnetic resonance spectroscopy studies have indicated that axonal damage and loss are a reliable correlate of permanent clinical disability. Accordingly, neuropathological studies have confirmed the presence and timing of axonal injury in multiple sclerosis lesions. The mechanisms of axonal degeneration, however, are unclear. Since calcium influx may mediate axonal damage, we have studied the distribution of the pore-forming subunit of neuronal (N)-type voltage-gated calcium channels in the lesions of multiple sclerosis and EAE. We found that alpha(1B), the pore-forming subunit of N-type calcium channels, was accumulated within axons and axonal spheroids of actively demyelinating lesions. The axonal staining pattern of alpha(1B) was comparable with that of beta-amyloid precursor protein, which is an early and sensitive marker for disturbance of axonal transport. Importantly, within these injured axons, alpha(1B) was not only accumulated, but also integrated in the axoplasmic membrane, as shown by immune electron microscopy on the EAE material. This ectopic distribution of calcium channels in the axonal membrane may result in increased calcium influx, contributing to axonal degeneration, possibly via the activation of neutral proteases. Our data suggest that calcium influx through voltage-dependent calcium channels is one possible candidate mechanism for axonal degeneration in inflammatory demyelinating disorders.

Adult↗

An autosomal dominant early adult-onset distal muscular dystrophy.

In this study we describe an autosomal dominant distal muscular dystrophy in a small Austrian family. The myopathy started in early adulthood with a slowly progressive weakness of the muscles of the anterior tibial compartment, followed by the long finger extensors and sternocleidomastoids in some family members. Other muscles were spared. Histopathology showed fiber size variation and autophagic vacuoles. This disease pattern is similar to Laing distal myopathy, which has been described previously in only one other family.

Adult↗

Real-time measurements of calcium dynamics in neurons developing in situ within zebrafish embryos.

We have developed a non-invasive technique to measure intracellular calcium ([Ca2+]i) in neurons growing within intact embryos of the zebrafish (Danio rerio). A single blastomere was injected with a calcium-sensitive fluorescent dye (Calcium Green dextran) between the 32- and 128-cell stage and the embryo imaged between 16 h and 20 h postfertilisation using laser scanning confocal microscopy. Labelled nerve cells from embryos preinjected with dye and dissociated at 16 h showed a fluorescence increase (66+/-22%; n=11) in response to depolarisation with KCl confirming that the dye remained intracellular and was sensitive to calcium. In addition, fluorescence changes in activated muscle cells of intact embryos showed that the dye was capable of responding to [Ca2+]i changes in vivo. Imaging of dye loaded cells over 30-min periods in embryos between 16 and 20 h revealed that the majority of neurons within the brain and spinal cord did not show spontaneous fluorescence changes distinguishable from noise. However, a subset of neurons within the ventral spinal cord exhibited spontaneous, repetitive [Ca2+]i oscillations which may have a functional significance during neuronal development.

Animals↗

Calcium channels in neuroblastoma cell growth cones.

The concentration of free calcium ions in the cytosol has been shown to influence many components of growth cone behaviour, including the extension of filopodia and veils, the addition of new membrane to the plasmalemma, the retraction and disappearance of filopodia, and gross collapse and retraction of the growth cone. A spatially localized modulation of these processes by very local calcium changes has been proposed to underlie the steering of growth cones by gradients of neurotransmitters, voltage and cell adhesion molecules. Such local control can be studied in mouse neuroblastoma cells, where depolarization causes calcium to rise in a limited number of spatially restricted hotspots, triggering a localized advance. We have studied the simple, club-shaped growth cones that are characteristically found on advancing neurites. Depolarization caused calcium to increase most at the distal, leading tip. Agents that disrupt calcium-induced calcium release do not affect growth cone calcium dynamics, ruling out a local release of calcium at the tip as a cause of the gradient. Using cell-attached patch recording, we find that L-type calcium channels are present at a higher density at the distal tip than in the proximal growth cone. Our results show that the calcium gradients seen in depolarized growth cones are a direct consequence of a gradient of calcium channel density.

Animals↗

Nuclear calmodulin responds rapidly to calcium influx at the plasmalemma.

We have studied the rate and extent of calcium binding to calmodulin in neuronal cytosol and nucleus during brief calcium influx across the plasmalemma. Rat sensory neurones were whole-cell patch clamped using a pipette containing a fluorescent analogue of calmodulin that reports when it has bound calcium. Cytosolic and nuclear signals were separated using a confocal microscope. Plasmalemmal calcium influx during a one second depolarization that activated L type calcium channels caused large fractions of calmodulin in both the cytosol and nucleus to bind calcium. Thus, contrary to previous predictions, nuclear processes that require the calcium:calmodulin complex will be activated readily by even brief cell stimulation.

Action Potentials↗

Biphasic effect of calcium on neurite outgrowth in neuroblastoma and cerebellar granule cells.

We have examined the effect of cytosolic calcium concentration ([Ca2+]i) on neurite outgrowth in two neuronal cells, cerebellar granule cells and N1E-115 neuroblastoma cells. The set point [Ca2+]i in unstimulated cells bathed in normal extracellular medium was 37 nM and 108 nM, respectively. When we altered extracellular calcium concentration to cause small excursions of [Ca2+]i either above or below the set point, neurite outgrowth from granule cells declined. Thus granule cells show the bell-shaped dependence of neurite outgrowth on [Ca2+]i characteristic of sensory and other neurones [Dev. Brain Res., 70 (1992) 287-290; The Axon, Oxford University Press, New York, 1994]. In contrast, neurite outgrowth from N1E-115 cells increased monotonically as [Ca2+]i was reduced. This result, which is consistent with results obtained by studying individual growth cones [J. Neurosci., 9 (1989) 4007-4020], implies that these transformed cells are aberrant in having no bell-shaped dependence of neurite outgrowth on [Ca2+]i. In both cell types an increase of [Ca2+]i above the set point reduced neurite outgrowth. However, this decline did not persist as [Ca2+]i was set to increasingly high levels by increasing extracellular calcium. Rather, in both cell types, an increase of extracellular calcium above 6.9 mM produced a second, increasing phase of neurite outgrowth.

Animals↗

The demyelinating potential of antibodies to myelin oligodendrocyte glycoprotein is related to their ability to fix complement.

A panel of 13 monoclonal antibodies (mAbs) has been raised to the central nervous system-specific glycoprotein, myelin oligodendrocyte glycoprotein; five of these mAbs recognize a carbohydrate epitope on the molecule. Although all of the mAbs recognized surface epitopes on cultured oligodendrocytes and stained central nervous system tissue sections in a similar manner, marked differences were seen in their ability to induce demyelination in experimental allergic encephalomyelitis in the Lewis rat. This variation in pathogenic potential was not related to the specificity of a given mAb for carbohydrate or peptide epitopes of myelin oligodendrocyte glycoprotein, but correlated with its ability to fix complement.

Animals↗

Nucleocapsid or spike protein-specific CD4+ T lymphocytes protect against coronavirus-induced encephalomyelitis in the absence of CD8+ T cells.

To investigate the antiviral CD4+ T cell response in coronavirus MHV-JHM-induced encephalomyelitis, spleen and thymic lymphocytes from diseased rats were stimulated in culture with virus Ag, expanded and tested for their specificity to viral proteins and nucleocapsid (N) and spike (S) proteins that had been expressed in bacteria. A strong T cell response specific for N was measurable during acute disease, whereas S-specific T cells were only detectable in rats with a later onset of disease. CD4+ T cell lines with specificity for virus and either N or S protein were established and their influence on the course of a mouse hepatitis virus-JHM infection was investigated. All lines were of the CD4+ phenotype. Both N and S protein-specific CD4+ T cells conferred protection to infected Lewis rats and reduced the amount of infectious virus in the central nervous system. After transfer of CD4+ T cells and challenge with virus, an increase in the antiviral IgM response occurred, but neutralizing antibodies were not detectable during the period of virus clearance. Previous CD8+ cell depletion did not abrogate protection mediated by CD4+ T cell line transfer.

Animals↗