Cerebral cavernous malformations (CCM) are hamartomatous vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. They cause seizures and focal neurological deficits due to cerebral hemorrhages. CCM loci have already been assigned to chromosomes 7q (CCM1), 7p (CCM2), and 3q (CCM3) and have been identified in 40%, 20%, and 40%, respectively, of families with CCM. Loss-of-function mutations have been identified in CCM1/KRIT1, the sole CCM gene identified to date. We report here the identification of MGC4607 as the CCM2 gene. We first reduced the size of the CCM2 interval from 22 cM to 7.5 cM by genetic linkage analysis. We then hypothesized that large deletions might be involved in the disorder, as already reported in other hamartomatous conditions, such as tuberous sclerosis or neurofibromatosis. We performed a high-density microsatellite genotyping of this 7.5-cM interval to search for putative null alleles in 30 unrelated families, and we identified, in 2 unrelated families, null alleles that were the result of deletions within a 350-kb interval flanked by markers D7S478 and D7S621. Additional microsatellite and single-nucleotide polymorphism genotyping showed that these two distinct deletions overlapped and that both of the two deleted the first exon of MGC4607, a known gene of unknown function. In both families, one of the two MGC4607 transcripts was not detected. We then identified eight additional point mutations within MGC4607 in eight of the remaining families. One of them led to the alteration of the initiation codon and five of them to a premature termination codon, including one nonsense, one frameshift, and three splice-site mutations. All these mutations cosegregated with the disease in the families and were not observed in 192 control chromosomes. MGC4607 is so far unrelated to any known gene family. Its implication in CCMs strongly suggests that it is a new player in vascular morphogenesis.

No abstract

This method, in which both sulcal and functional mapping are used for surgery planning and neuronavigation, provides helpful information. It is a promising procedure for the treatment of patients who harbor lesions in areas around the eloquent cortex.

In this study, the authors present the results of 50 dissections of the anterior choroidal a. in man. Fifty cerebral hemispheres were prepared with the classic techniques of preservation and vascular injection. An ectopic origin was observed in 4% of cases. The intracisternal segment of the anterior choroidal a. forms a neurovascular bundle with the optic tract and basal v. Most of its intraparenchymatous branches arise from the cisternal segment, while branches supplying the optic tract, lateral geniculate body and thalamus arise from the intraplexual segment. Constant anastomoses exist with the vertebrobasilar system, specially the postero-lateral choroidal and posterior cerebral aa. We discuss the importance of an adequate knowledge of the anatomy of the anterior choroidal a. and its relations in the surgical approach to arterial aneurysms and arteriovenous malformations of the region.

A reduction in GABAergic neurotransmission has been put forward as a pathophysiological mechanism for human epilepsy. However, in slices of human epileptogenic neocortex, GABAergic inhibition can be clearly demonstrated. In this article we present data showing an increase in the functional lability of GABAergic inhibition in epileptogenic tissue compared with nonepileptogenic human tissue. We have previously shown that the glycolytic enzyme GAPDH is the kinase involved in the glycolysis-dependent endogenous phosphorylation of the ␣1-subunit of GABAA receptor, a mechanism necessary for maintaining GABA A function. In human epileptogenic cortex obtained during curative surgery of patients with partial seizures, we demonstrate an intrinsic deficiency of GABA A receptor endogenous phosphorylation resulting in an increased lability of GABAergic currents in neurons isolated from this tissue when compared with neurons from nonepileptogenic human tissue. This feature was not related to a reduction in the number of GABA A receptor ␣1-subunits in the epileptogenic tissue as measured by [ 3 H]flunitrazepam photoaffinity labeling. Maintaining the receptor in a phosphorylated state either by favoring the endogenous phosphorylation or by inhibiting a membrane-associated phosphatase is needed to sustain GABA A receptor responses in epileptogenic cortex. The increased functional lability induced by the deficiency in phosphorylation can account for transient GABAergic disinhibition favoring seizure initiation and propagation. These findings imply new therapeutic approaches and suggest a functional link to the regional cerebral glucose hypometabolism observed in patients with partial epilepsy, because the dysfunctional GABAergic mechanism depends on the locally produced glycolytic ATP.GABAA receptor phosphorylation ͉ GAPDH ͉ human epilepsy ͉ neuronal inhibition P rotein phosphorylation is an important mechanism for the rapid modulation of ion channel properties. Receptorassociated endogenous phosphorylation is required for maintaining the GABA A currents, the principal inhibitory system in the mammalian brain (1, 2). We have identified the kinase of the endogenous phosphorylation as being GAPDH (3), a key glycolytic enzyme. GAPDH is closely associated with the GABA A receptor (GABA A R) macrocomplex at the plasma membrane. GAPDH has a dual role, first as a dehydrogenase in the glycolysis cascade contributing to ATP production and second as a kinase phosphorylating the GABA A R ␣1-subunit (3). All factors promoting the GAPDH-dependent ␣1-phosphorylation also favor the maintenance of the receptor in a functional state, thus directly linking GABAergic inhibition with glucose metabolism. The ␣1-phosphorylation state of the receptor also depends on a membrane-bound phosphatase that is yet to be characterized (4).A wealth of studies have shown that a decrease, even transient, in the efficacy of the GABA A inhibition induces pathological neuronal synchronization resulting in epileptic seizures (5, 6). A deficiency of endogenous GABA A R...