Novel mutations in Myoclonin1/EFHC1 in sporadic and familial juvenile myoclonic epilepsy.

BACKGROUND: Juvenile myoclonic epilepsy (JME) accounts for 3 to 12% of all epilepsies. In 2004, the GENESS Consortium demonstrated four missense mutations in Myoclonin1/EFHC1 of chromosome 6p12.1 segregating in 20% of Hispanic families with JME. OBJECTIVE: To examine what percentage of consecutive JME clinic cases have mutations in Myoclonin1/EFHC1. METHODS: We screened 44 consecutive patients from Mexico and Honduras and 67 patients from Japan using heteroduplex analysis and direct sequencing. RESULTS: We found five novel mutations in transcripts A and B of Myoclonin1/EFHC1. Two novel heterozygous missense mutations (c.755C>A and c.1523C>G) in transcript A occurred in both a singleton from Mexico and another singleton from Japan. A deletion/frameshift (C.789del.AV264fsx280) in transcript B was present in a mother and daughter from Mexico. A nonsense mutation (c.829C>T) in transcript B segregated in four clinically and seven epileptiform-EEG affected members of a large Honduran family. The same nonsense mutation (c.829C>T) occurred as a de novo mutation in a sporadic case. Finally, we found a three-base deletion (-364--362del.GAT) in the promoter region in a family from Japan. CONCLUSION: Nine percent of consecutive juvenile myoclonic epilepsy cases from Mexico and Honduras clinics and 3% of clinic patients from Japan carry mutations in Myoclonin1/EFCH1. These results represent the highest number and percentage of mutations found for a juvenile myoclonic epilepsy causing gene of any population group.

Motor impairments in an oxidative stress model and its correlation with cytological changes on rat striatum and prefrontal cortex.

Exposure to ozone results in an increased production of free radicals which causes oxidative stress. The purpose of this study was to determine the effects of ozone exposure on motor behavior and its correlation with the cytology of the striatum and prefrontal cortex. Twenty-four male Wistar rats were exposed to 1 p.p.m. (parts per million) ozone for 4 hrs in a closed chamber. Control group was exposed to flowing air. Twenty-four hours after ozone exposure, the motor behavior was measured. After that, the animals were perfused and the brains were placed in Golgi stain. The analysis consisted in counting the dendritic spines in 5 secondary and 5 tertiary dendrites of each of the 20 medium size spiny neurons of striatum and 20 pyramidal neurons of prefrontal cortex analyzed. Our results showed alterations in motor behavior and a significant reduction of dendritic spines, and provided evidence that the deterioration in motor behavior is probably due to the reduction in spine density in the neurons of striatum and prefrontal cortex.

Morphologic alteration of the olfactory bulb after acute ozone exposure in rats.

The interaction of ozone with some molecules results in an increased production of free radicals. The objective of this study was to identify whether acute ozone exposure to 1-1.5 ppm for 4 h, produced cytological and ultrastructural modifications in the olfactory bulb cells. The results showed that in rats exposed to ozone there was a significant loss of dendritic spines on primary and secondary dendrites of granule cells, whereas the control rats did not present such changes. Besides these exposed cells showed vacuolation of neuronal cytoplasm, swelling of Golgi apparatus and mitochondrion, dilation cisterns of the rough endoplasmic reticulum. These findings suggest that oxidative stress produced by ozone induces alterations in the granule layer of the olfactory bulb, which may be related to functional modifications.

Degenerative ultrastructural changes observed in the neuropil of caudate nuclei from Parkinson's disease patients.

Degenerative changes of the pars compacta of the substantia nigra are considered the main physiopathological basis of Parkinson's disease, while most authors believe that the neostriatum is well preserved in these cases. This paper deals with the preliminary ultrastructural observations made in the neuropil of the caudate nucleus of Parkinson's disease patients. We have observed (1) astrocytic proliferation, neuronal degeneration, degenerated axons, and hyperdense postsynaptic neurites (dendrites), and (2) that degenerative patterns vary from one case to another. Physiopathological and therapeutical implications are discussed.

Multidisciplinary analysis of the effectiveness of autologous neural transplant (adrenal medulla) as treatment of Parkinson's disease.

The neurobiological aspects of human neural transplants are far from being understood. We have approached their study by means of a multidisciplinary working team. Nine patients with Parkinson's disease were subjected to open brain surgery for grafting of autologous adrenal medulla. Not all patients improved. Those patients that did so showed different patterns of improvement. Rigidity was the sign most relieved in this group of patients. Electroencephalographic changes were attributable to surgical manipulation. High-performance liquid chromatographic quantification of catecholaminergic metabolites did not correlate with post-grafting outcome. Biopterin levels showed a significant increment after surgery. More interdisciplinary studies ought to be done on neural transplants.

Dendritic and axonal spherules in the neocortex of a patient with Creutzfeldt-Jakob disease (CJD): Golgi and electron-microscopical investigation--neurobiological significance.

Vacuolization is a pathognomonic change occurring in Creutzfeldt-Jakob disease (CJD) and in other spongiform encephalopathies. The spongiform status takes place within nerve and glial cells. Its mechanism of formation is unknown. This paper concentrates on a possible sequence of morphological changes that culminate with empty and dilated neurites. A biopsy was taken from the right frontal cortex of a 44-year-old man, who had a brief history of dementia and myoclonus. An EEG showed periodical discharges and the routine histological stains showed changes compatible with CJD, including prominent vacuolization. Some fragments of tissue were impregnated with the rapid-Golgi method, and some others were processed for transmission electron microscopy (TEM). In the Golgi stained material, many of the impregnated neurons showed fewer dendrites and loss of spines, and the dendritic processes appeared smaller in diameter. Frequently the silhouette of nerve-cell bodies was distorted; irregular surfaces and lumpinesses had replaced the otherwise smooth contour of many granule and pyramidal cells. In addition, spherical axonal and dendritic dilations were found. These globular dilations were seen in primary and secondary dendrites, mainly from pyramidal cells. They were not present in all the impregnated cells, showed a stochastic distribution, and appeared to proportionally reach a larger diameter in axons. The light-microscopic changes are correlated with those obtained with the TEM, and a morphological classification of affected neurites is used to postulate a hypothetical centrifugal emptying process, which is proposed as the putative mechanism for the production of these spherules. The possible neurobiological significance of these spherules is discussed.

Abnormal dendritic patterns and aberrant spine development in Bourneville's disease--a Golgi survey.

Few reports have dealt with the structural abnormalities shown by the neuropil in mentally retarded patients. This Golgi study describes the morphologic changes observed in a brain biopsy from the cerebral cortex of a patient with Bourneville's disease (epiloia). At the time this study was made, the patient was 12 years old and had had a long history of mental retardation and uncontrollable seizures. She, her father, and three other siblings had classic cutaneous signs of epiloia. A biopsy from the right frontal cortex was immediately fixed by immersion, was processed by both H & E and the Golgi method respectively, and examined by electron microscopy. The Golgi-stained material showed a marked fibrillary gliosis at the upper and lower cortical layers, as well as in the heterotopias; the presence of giant cells, closely resembling immature pyramidal cells, with short dendrites growing from their somata and bearing few spines; some other large cells having features compatible with astrocytes; spiral-like glial processes converging upon distorted apical dendrites; these and some other neuronoglial formations establishing specialized anatomical contacts; unorderly arrangement of small and large pyramids within an abnormally compact cortex; abnormal dendritic growths at the level of dendrite bifurcations; and several aberrant patterns of spine morphology, including the megaspine. This first application of the Golgi method to the study of neuropathologic features of epiloia suggests that a poorly developed neuronal circuitry led to the abnormal brain function observed in this case. The same anatomical substrate may occur in other cases of mental retardation.