Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization.

AIMS: To report the clinical, pathological and genetic findings in a group of patients with a previously not described phenotype of congenital myopathy due to recessive mutations in the gene encoding the type 1 muscle ryanodine receptor channel (RYR1). METHODS: Seven unrelated patients shared a predominant axial and proximal weakness of varying severity, with onset during the neonatal period, associated with bilateral ptosis and ophthalmoparesis, and unusual muscle biopsy features at light and electron microscopic levels. RESULTS: Muscle biopsy histochemistry revealed a peculiar morphological pattern characterized by numerous internalized myonuclei in up to 51% of fibres and large areas of myofibrillar disorganization with undefined borders. Ultrastructurally, such areas frequently occupied the whole myofibre cross section and extended to a moderate number of sarcomeres in length. Molecular genetic investigations identified recessive mutations in the ryanodine receptor (RYR1) gene in six compound heterozygous patients and one homozygous patient. Nine mutations are novel and four have already been reported either as pathogenic recessive mutations or as changes affecting a residue associated with dominant malignant hyperthermia susceptibility. Only two mutations were located in the C-terminal transmembrane domain whereas the others were distributed throughout the cytoplasmic region of RyR1. CONCLUSION: Our data enlarge the spectrum of RYR1 mutations and highlight their clinical and morphological heterogeneity. A congenital myopathy featuring ptosis and external ophthalmoplegia, concomitant with the novel histopathological phenotype showing fibres with large, poorly delimited areas of myofibrillar disorganization and internal nuclei, is highly suggestive of an RYR1-related congenital myopathy.

Hemorragia hipertensiva bilateral espontánea de ganglios basales. ¿Algo más que aneurismas de Charcot-Bouchard? / Spontaneous bilateral hypertensive haemorrhage of the basal ganglia. Something more than Charcot-Bouchard aneurysms?

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[Chiari type I malformation in a patient with bulbar onset amyotrophic lateral sclerosis]. / Malformación de Chiari de tipo I en una paciente con esclerosis lateral amiotrófica de inicio bulbar.

INTRODUCTION: Diagnosis of amyotrophic lateral sclerosis (ALS) requires of the exclusion of several pathologies of the cranio cervical junction that mimic ALS. The importance of such exclusion is in fact sustained by the prognostic implications that ALS has. CASE REPORT: We report the case of a 58-year-old woman with bulbar onset sporadic ALS associated with Chiari type I malformation on the MRI of the craniocervical junction. At the time of consultation, ALS was clinically defined but some of the symptoms were contributed by cerebellar amygdala compression of the medulla. CONCLUSION: To our knowledge this is the first time were both diseases are reported symptomatic on the same patient, and despite its rarity, it is important to be aware of this possible association for the diagnostic, therapeutic and prognostic implications it has.

Malformación de Chiari de tipo I en una paciente con esclerosis lateral amiotrófica de inicio bulbar / Chiari type i malformation in a patient with bulbar onset amyotrophic lateral sclerosis

Introducción. El diagnóstico de esclerosis lateral amiotrófica (ELA) requiere la exclusión de varias otras patologías de la charnela craneocervical que simulan la ELA. Las implicaciones que tiene el pronóstico de la ELA hacen todavía más importante esta exclusión. Caso clínico. Presentamos el caso de una paciente de 58 años de edad con ELA esporádica de inicio bulbar asociada a una malformación de Chiari tipo I en las imágenes de la charnela craneocervical obtenidas por resonancia magnética. En el momento de la consulta, ELA se había definida clínicamente pero algunos síntomas se debían a la compresión de la médula por parte de la amígdala cerebelosa. Conclusión. Según nuestras investigaciones ésta es la primera vez que se describe las dos enfermedades sintomáticas en el mismo paciente y, a pesar de su poca frecuencia, es importante saber que existe esta posible asociación, ya que tiene implicaciones significantes en el diagnóstico, la terapéutica y el pronóstico (AU)

Introduction. Diagnosis of amyotrophic lateral sclerosis (ALS) requires of the exclusion of several pathologies of the cranio-cervical junction that mimic ALS. The importance of such exclusion is in fact sustained by the prognostic implications that ALS has. Case report. We report the case of a 58 year old woman with bulbar onset sporadic ALS associated with Chiari type I malformation on the MRI of the craniocervical junction. At the time of consultation, ALS was clinically defined but some of the symptoms were contributed by cerebellar amygdala compression of the medulla. Conclusion. To our knowledge this is the first time were both diseases are reported symptomatic on the same patient, and despite its rarity, it is important to be aware of this possible association for the diagnostic, therapeutic and prognostic implications it has (AU)

Muscarinic M1 receptors activate phosphoinositide turnover and Ca2+ mobilisation in rat sympathetic neurones, but this signalling pathway does not mediate M-current inhibition.

1. The relationship between muscarinic receptor activation, phosphoinositide turnover, calcium mobilisation and M-current inhibition has been studied in rat superior cervical ganglion (SCG) neurones in primary culture. 2. Phosphoinositide-specific phospholipase C (PLC) stimulation was measured by the accumulation of [3H]-cytidine monophosphate phosphatidate (CMP-PA) after incubation with [3H]-cytidine in the presence of Li+. The muscarinic agonist oxotremorine methiodide (oxo-M) stimulated PLC in a dose-dependent manner with an EC50 of approximately 3.5 microM. 3. The concentration-response curve for oxo-M was shifted to the right by a factor of about 10 by pirenzepine (100 nM), suggesting a pKB (-log of the apparent dissociation constant) of 7.9 +/- 0.4, while himbacine (1 microM) shifted the curve by a factor of about 13 (pKB approximately 7.1 +/- 0.6). This indicates involvement of the M1 muscarinic receptor in this response. 4. The accumulation of CMP-PA was localised by in situ autoradiography to SCG principal neurones, with no detectable signal in glial cells present in the primary cultures. 5. The ability of oxo-M to release Ca2+ from inositol(1,4, 5)trisphosphate (InsP3)-sensitive stores was determined by fura-2 microfluorimetry of SCG neurones voltage clamped in perforated patch mode. Oxo-M failed to evoke intracellular Ca2+ (Ca2+i) mobilisation in SCG neurones voltage clamped at -60 mV, but produced a significant Ca2+i rise (67 +/- 15 nM, n = 9) in cells voltage clamped at -25 mV. 6. Thapsigargin (0.5-1 microM) caused a 70 % inhibition of the oxo-M-induced Ca2+i increase, indicating its intracellular origin, while oxo-M-induced inhibition of M-current in the same cells was unaffected by thapsigargin. 7. Our results do not support the involvement of InsP3-sensitive calcium mobilisation in M-current inhibition.

Transiently selective activation of phosphoinositide turnover in layer V pyramidal neurons after specific mGluRs stimulation in rat somatosensory cortex during early postnatal development.

Biochemical analysis of muscarinic- and metabotropic-glutamate receptor stimulated phosphoinositide (PI) turnover in rat cortical preparations during the first three weeks of postnatal development indicates the existence of a transiently increased accumulation of labeled inositol polyphosphates during the first postnatal week (Gonzales and Crews, 1985; Dudek et al., 1989). We now report for first time the visualization of those neurons responding with increased PI turnover to glutamatergic or cholinergic-receptor stimulation in rat somatosensory cortex during early postnatal development utilizing a recently described method (Bevilacqua et al, 1994). Three, 7, 10, 14, and 21 d old rats were studied. Carbachol in the presence of lithium stimulates 3H-CMP-PA accumulation throughout the cortex at all ages studied. In comparison labeled neurons responding to t-ACPD in the presence of lithium were located exclusively in layer V at P3 and P7, but were found labeled throughout the cortex at P10. Given that glutamate and cholinergic agonist stimulation are both necessary but not sufficient for cortical plasticity to occur, and that muscarinic and mGluRs stimulation both induce a peak in PI turnover response during the same period of experience-dependent neocortical plasticity, PI derived second messengers signals might be involved in the regulation of the molecular mechanisms of neuronal plasticity. Furthermore, our results show the anatomical correlate of receptor-specific PI turnover activation, and indicate that specific agonist induced PI responses are age, and layer specific.

Visualization of agonist-stimulated inositol phospholipid turnover in individual neurons of the rat cerebral cortex and hippocampus.

A novel autoradiographic method to identify individual neurons responding to neurotransmitter stimulation with increased phosphoinositide turnover is described. When phosphoinositide-coupled receptors are activated, phosphatidylinositol 4,5-bisphosphate is hydrolysed by phospholipase C generating the two second messengers, inositol 1,4,5-trisphosphate and diacylglycerol. During prolonged receptor stimulation, both second messengers are actively recycled to maintain the effective intracellular levels of agonist-sensitive phosphoinositides. Lithium ions inhibit this recycling pathway by blocking the recovery of free inositol from inositol 1,4,5-trisphosphate thus leading to the accumulation of phosphatidyl cytidine monophosphate, a membrane bound molecule which is the activated precursor of the synthesis of phosphoinositides. Therefore, addition of excess myo-inositol reverts the effects of lithium inhibition. Thus, taking advantage of this fact and using [3H]cytidine as precursor, phosphatidyl [3H]cytidine monophosphate accumulation was induced in rat neocortical and hippocampal slices after muscarinic or metabotropic glutamate receptor stimulation. The labelled slices were then fixed, dehydrated and embedded in Durcupan resin. Semithin sections (1 micron thick) were cut and exposed to autoradiographic emulsion for several weeks. Biochemical analysis of the incorporation of [3H]cytidine into the chloroform extracted (containing lipids) and the alkali-solubilized (containing nucleic acids and proteins) fractions were carried out in parallel with morphological studies. The stimulation of both receptor types induced labelling of neurons in neocortex and hippocampus. In labelled cells silver grains were characteristically observed over the cytoplasm surrounding the nucleus and main dendritic processes. The anatomical location and distribution of labelled cells as well as the levels of response obtained in both brain regions studied, was found to be receptor specific. Inclusion of 30 mM myo-inositol in the incubation media reversed completely both the accumulation of phosphatidyl [3H]cytidine monophosphate and the labelling of cells, thus demonstrating that the label detected autoradiographically corresponds to phosphatidyl [3H]cytidine monophosphate. It is concluded that the method is sensitive and specific, allowing identification of individual neurons in both neocortical and hippocampal slices and after stimulation of both muscarinic and metabotropic glutamate receptor subtypes. The method may open a new means to study the phosphoinositide second messenger signalling pathway and the cells in which it takes place.

Effects of growth hormone and thyroxine on thymulin secretion in aging rats.

It is well-established that the activity of the endocrine thymus is under neuroendocrine control. In particular, growth hormone (GH) and thyroxine (T4) have been shown to be capable of reconstituting thymus function in hormone-deficient animals. It was therefore of interest to assess the effect of combined administration of ovine GH (0.1 mg/100 g BW/day) and T4 (10 micrograms/100 g BW/day) on serum thymulin levels in young (5 months), old (21 months) and senescent (29-30 months) male Sprague-Dawley rats. Age-matched controls received 0.1 mg bovine serum albumin/100 g BW daily during the same period (14 days). Prolactin (Prl), GH, T4 and triiodothyronine (T3) were measured in serum by radioimmunoassay, whereas serum thymulin was determined by rosette bioassay. As expected, GH and T4 were lower in the old and senescent controls whereas serum Prl displayed a slight age-related increase. No age changes were detected in serum T3. Hormone-treated animals showed supraphysiologic levels of both T4 and T3, but serum levels were comparable among the three treated age groups for each thyroid hormone. Endogenous GH levels were moderately elevated in the treated rats. In the control rats serum thymulin showed a marked reduction from 5 to 21 months of age but no further reduction was observed between 21 and 29-30 months. Hormone treatment induced a mean relative increase (% increase relative to age-matched controls) in serum thymulin of 44, 38 and 48% in young, old and senescent rats, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)