Biomedical subjects

J Schramm

Publications and source records attributed to J Schramm.

At least 19 recordsLinked to original sources

PubMed2003

Down-regulation of mGluR8 in pilocarpine epileptic rats.

Activation of presynaptic metabotropic glutamate receptors (mGluRs) leads to a powerful inhibition of glutamate release from many synaptic terminals throughout the CNS. mGluRs as autoreceptors are believed to provide a negative feedback system that prevents potentially toxic accumulation of glutamate in the extracellular space during synchronous synaptic activity such as epileptic seizures. In this study we analyzed the function of presynaptic mGluR8 on terminals of the lateral perforant pathway in the pilocarpine model of limbic epilepsy. Field excitatory postsynaptic potentials (fEPSPs) recorded in hippocampal slices of rats that developed spontaneous recurrent seizures after pilocarpine-induced status epilepticus (SRS group) showed a significantly reduced sensitivity to Group III mGluR agonists and severe mossy fiber sprouting. The Group III mGluR agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4, 10 microM) depressed fEPSPs in the SRS group only by 26 +/- 21% compared to 50 +/- 18% in untreated rats. Similarly, the mGluR8 preferring agonist (R,S)-4-phosphonophenylglycine (PPG, 5 microM) was significantly less effective in slices from SRS rats (43 +/- 4% vs. 83 +/- 5%). Concentration-response curves for L-AP4 revealed that the EC(50) values were not different between the control and SRS group (13 +/- 7 microM vs. 9 +/- 9 microM), while the maximal depressing effect was significantly reduced. The remaining depressing effect of L-AP4 in the SRS group could be blocked by the Group III specific antagonists (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG) and alpha-methyl-L-AP4 (MAP4). Rats that did not develop SRS following pilocarpine-induced status epilepticus were indistinguishable from control rats: fEPSPs were highly sensitive to L-AP4 and there was no mossy fiber sprouting. The results show that pilocarpine-induced status epilepticus can lead to a downregulation of mGluR8 and suggest that the condition of SRS is associated with a deteriorated autoregulation of glutamate release.

Animals↗

PubMed2003

Outcome of epilepsy surgery in focal cortical dysplasia.

OBJECTIVE: To describe the outcome of surgery in patients with drug resistant epilepsy and a histopathological diagnosis of focal cortical dysplasia. METHODS AND SUBJECTS: Analysis of histories and presurgical and follow up data was carried out in 53 patients with a histological diagnosis of focal cortical dysplasia. Their mean age was 24.0 years (range 5 to 46), and they included 14 children and adolescents. Mean age at seizure onset was 12.4 years (0.4 to 36) and mean seizure duration was 11.6 years (1 to 45). RESULTS: The presurgical detection rate of focal cortical dysplasia with magnetic resonance imaging (MRI) was 96%. There were 24 temporal and 29 extratemporal resections; additional multiple subpial transections were done in 12 cases to prevent spread of seizure discharges. There was a 6% rate of complications with permanent neurological deficit, but no deaths. All resected specimens were classified by neuropathological criteria as focal cortical dysplasia. Balloon cells were seen in most cases of extratemporal focal cortical dysplasia. After a mean follow up of 50 months, 38 patients (72%) were seizure-free, two (4%) had less than two seizures a year, nine (17%) had a reduction of seizure frequency of more than 75%, and four (8%) had no improvement. Seizure outcome was similar after temporal and extratemporal surgery. The patients in need of multilobar surgery had the poorest outcome. CONCLUSIONS: Circumscribed lesionectomy of focal dysplastic lesions provides seizure relief in patients with chronic drug resistant temporal and extratemporal epilepsy. There was a trend for the best seizure outcome to be in patients with early presurgical evaluation and early surgery, and in whom lesions were identified on the preoperative MRI studies.

Adolescent↗

PubMed2002

Diagnosis and staging of Rasmussen's encephalitis by serial MRI and histopathology.

OBJECTIVE: To correlate MRI and histopathologic findings in patients with Rasmussen's encephalitis (RE). PATIENTS AND METHODS: MRI features of 10 patients with RE were studied on serial scans. In surgical specimens from these patients, densities of T lymphocytes, microglial cells and nodules, and reactive astrocytes were evaluated. RESULTS: Densities of T cells, microglial nodules, and astrocytes were inversely correlated to disease duration. MRI abnormalities had a focal onset and spread across one hemisphere. The following course of MRI abnormalities in a given brain region was observed: on very early scans, the cortex was swollen and showed a hyperintense T2/fluid-attenuated inversion recovery signal. Consecutively, progressive atrophy of the affected hemisphere occurred. Correlation of MRI features with quantitative histopathology revealed that there was a higher number of T cells and reactive astrocytes in the earlier MRI stages compared with the late (merely atrophic) stage. CONCLUSION: These data suggest a disease course in RE with the highest inflammatory intensity in the early stages and a subsequent decrease in inflammation. The MRI abnormalities and their characteristic sequence may help to identify patients with RE and to obtain informative biopsies.

Adolescent↗

PubMed2002

Endocrinological outcome following first time transsphenoidal surgery for GH-, ACTH-, and PRL-secreting pituitary adenomas.

BACKGROUND: To study remission rates and pituitary functions following transsphenoidal surgery of newly diagnosed GH-, ACTH-, and PRL-secreting pituitary adenomas. METHODS: Out of a series of 329 newly diagnosed pituitary adenomas, 131 (39.8%) were hormone (67 GH-, 27 ACTH-, 37 PRL-) secreting. PRL-secreting adenomas were subjected to surgery because they failed to respond to previous medical treatment therapy. The data on secreting adenomas, regarding the results of standardised endocrinological testing, MRI findings and water metabolism disturbances, were extracted retrospectively from the pituitary data-base of the hospital. The mean follow-up was 3.7 years. RESULTS: The overall remission rate for PRL-secreting adenomas (27%) was significantly lower than for GH- (71.6%) and ACTH-secreting (81.5%) ones. Remission rates correlated negatively with the magnitude of preoperative hormone excess (not in Cushing's disease), tumour size (not in prolactinoma) and invasiveness. Generally, the improvement of the adenopituitary functions was statistically significant during the first three postoperative months, and thereafter remained unchanged. Diabetes insipidus persisting for more than three months occurred with similar frequency in the three patient groups (in 9.4% of GH-, in 6.7% of ACTH-, and in 10% of PRL-secreting adenomas). Tumour regrowth occurred more often in PRL-(20%) than in ACTH- (9.1%) and GH- (0%) secreting tumours. CONCLUSIONS: In GH- and ACTH-secreting pituitary adenomas, remission rates were significantly higher and recurrence rates lower than in PRL-secreting adenomas, which had failed to respond to previous medical therapy. The overall postoperative adenopituitary function was improved in all patient groups. Diabetes insipidus occurred with similar frequency in all patient groups. When reporting on results of surgery for secreting pituitary adenomas, not only remission and recurrence rates, but also the results of the pituitary function should be included.

Adrenocorticotropic Hormone↗

PubMed2002

Presynaptic group II metabotropic glutamate receptors reduce stimulated and spontaneous transmitter release in human dentate gyrus.

Metabotropic glutamate receptors (mGluRs) control excitatory neurotransmission as inhibitory autoreceptors at many synapses throughout the CNS. Since pharmacological activation of mGluRs potently depresses excitatory transmission, anticonvulsive effects were found in a number of experimental epilepsies. However, although native rodent mGluRs and heterologously expressed human mGluRs have so far been investigated in great detail, our knowledge about native human mGluRs in situ is limited. Here we used acute human hippocampal slices prepared from hippocampi surgically removed for the treatment of temporal lobe epilepsy in order to investigate the modulation of glutamatergic transmission by human mGluRs at the perforant path-granule cell synapse. The broad spectrum mGluR agonist (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) profoundly and reversibly reduced field EPSPs (fEPSPs) with an EC(50) of 30+/-7.4 microM. Paired-pulse depression of fEPSPs was converted into strong facilitation. The inhibition of fEPSPs by ACPD was mimicked by the specific group II mGluR agonist (2S, 2'R, 3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV), while the specific group I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) was ineffective. The effect of ACPD was blocked by group II antagonist (2S,3S,4S)-2methyl-2-(carboxycyclopropyl)glycine (MCCG) but was not changed by coapplication of the specific group III antagonist (S)2 amino2methyl4phosphonobutanoic acid (MAP4). ACPD reduced pharmacologically isolated intracellular EPSPs in granule cells to the same extent as fEPSPs, whereas a specific group III agonist had no effect on EPSPs. Whole-cell recordings from morphologically identified granule cells revealed that DCG-IV significantly reduced the frequency of miniature EPSCs (mEPSCs) in granule cells while the mean amplitude of mEPSCs was not affected. We conclude that in human dentate gyrus mGluR2/3 can almost completely depress glutamate release by a presynaptic mechanism which acts downstream of presynaptic voltage gated calcium-entry and most likely involves a direct modulation of the release machinery.

Action Potentials↗

PubMed2002

Editorial.

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Editorial↗

PubMed2002

Results for microsurgical removal of tentorial meningiomas.

OBJECTIVE: Growth patterns of tentorial meningiomas are related to the deep cerebral venous system and to cranial nerves IV-XI. Localization and surgical aggressiveness are decisive for the outcome to be expected. PATIENTS AND METHODS: n = 25 patients (22 f, 3 m), aged from 26-77 (mean: 56.4) years underwent microsurgical removal of their tentorial meningioma. Tumor size was as follows: n = 11 < 3 cm, n = 6 3-5 cm, n = 8 > 5 cm. The median of the preoperative Karnofsky scores was 90. The operative approaches chosen were suboccipital in n = 14, subtemporal in n = 6, occasionally a combined supra- and infratentorial approach was chosen. Data regarding surgery, histology and postoperative course were available through the patient's charts and through outpatient clinic. RESULTS: n = 20 (80%) of the tumors were rated WHO grade I, n = 5 (20%) WHO grade II. Tumor removal according to Simpson was degrees I in n = 9 (36%), degrees II in n = 14 (56%), degrees III in n = 2 (8%). Mortality was 0%. In n = 6 patients (24%) neurological worsening, mainly due to transient cranial nerve deficits was noted. Surgical complications (CSF fistula, wound healing problems) occurred in n = 5 patients (20%). The median of the postoperative Karnofsky scores on last follow up was 90 after a median of 41.9 months. Two patients (8%), one of whom underwent reoperation developed tumor recurrency during follow up. CONCLUSIONS: Neurological deficits following microsurgical removal of tentorial meningiomas are transient in the majority of patients. The apparently high rate of incomplete tumor resection (app. 60% Simpson grades II and III) is due to the close topographical relationship of these tumors with important neurovascular structures. Thus, the operative strategy should not be excessively aggressive, but rather take into account the option to observe residual tumor or to apply additional stereotactic convergent beam radiation in selected cases.

Adult↗

PubMed2002

Preoperative evaluation for epilepsy surgery (Bonn Algorithm).

SUMMARY: Epilepsy surgery has been established as a successful treatment in patients with drug-resistant focal epilepsies. Different standardized surgical approaches were developed for resective or functional treatment. Successful surgical treatment, however, necessitates a careful presurgical evaluation. Although there are international standards for non invasive and invasive presurgical procedures most centers differ in their diagnostic strategy. This article gives a survey of the Bonn Epilepsy surgery program within which more than 1300 patients have been treated. After the method of patient selection different we describe tools of non invasive and invasive evaluation. This article serves only as a description of current practice in one center with a relatively large volume of cases. It presents just one opinion of a specific group within a wide spectrum of possible algorithms for presurgical evaluation that have briefly been outlined for 33 centers in Engels book [4].

Electroencephalography↗

PubMed2002

Vertebral artery injury after cervical spine trauma: a prospective study.

OBJECTIVES: Vertebral artery (VA) -injury is rarely symptomatic and can therefore easily be overlooked. However, thromboembolic complications may result in permanent morbidity or mortality due to brainstem ischemia and infarction. In this prospective study a standardized protocol for the diagnosis and management of VA-injury following blunt cervical spine trauma with subluxation or fractures affecting the transverse foramen was evaluated. METHODS: During a 48 months period 31 (12 female, 19 male; mean age 44.2 years) of 119 patients with blunt cervical spine trauma were suspicious for VA-injury and subjected to a predefined radiological work-up. Selective digital subtraction angiography (DSA) was performed at admission in 31 patients. For comparison magnetic resonance angiography (MRA) was added within 2 days in 7 patients. RESULTS: The incidence of VA injury detected by DSA (n = 5) was 4% in all types of blunt cervical spinal injury, 16% in cases suspicious for VA injury, i.e. cases with mono- or bifacet dislocation and/or cases with fractures extending into the transverse foramen. Unilateral VA-stenosis was found in 4 and VA-occlusion in one patients. In one case a VA-stenosis by an intimal flap after transverse foramen fracture was detected by DSA but not by MRA. In 2 patients with VA injury headache occurred without signs of vertebro-basilar insufficiency. All 5 patients with VA-injury were treated with anticoagulation without complications or side effects. 14 of 31 patients which had DSA/MRA had unstable spine conditions and were treated surgically within 4 days after admission. CONCLUSION: The subgroup of patients with dislocation or fracture related stenosis of the transverse foramen should undergo early angiography for establishment of anticoagulation to prevent thromboembolic complications. It appears that the radiological diagnosis of VA-insufficiency is more sensitive than clinical findings, which rarely indicate VA-insufficiency. In this series one VA injury was overlooked with MRA.

Adolescent↗

PubMed2001

Comparative analysis of the NF2, TP53, PTEN, KRAS, NRAS and HRAS genes in sporadic and radiation-induced human meningiomas.

Irradiation to the head is associated with a significantly increased incidence of meningiomas. Radiation-induced meningiomas morphologically resemble their sporadically arising counterparts; however, they frequently exhibit a more malignant phenotype. Several genes have been shown to carry mutations in meningiomas, with the NF2 gene being most frequently affected. To examine whether the NF2 gene also plays a role in the development of radiation-induced meningiomas, we compiled a series of meningiomas from 25 patients with a history of previous cranial radiation. This series was compared with 21 atypical WHO grade II meningiomas and 15 anaplastic WHO grade III meningiomas, all from patients without a history of prior irradiation. NF2 mutations occurred significantly more often in sporadic atypical and anaplastic than in radiation-induced meningiomas (p < 0.02). In addition, all meningiomas were examined for mutations in the PTEN, TP53, HRAS, KRAS and NRAS genes. Two mutations in the TP53 gene in a sporadic and a radiation-induced tumor were detected. PTEN mutations were observed in 1 anaplastic and 1 radiation-induced meningioma. No structural alterations were seen in the RAS genes. Our data suggest that, while there is a certain overlap in the mutational spectrum, NF2 mutations may not play such a prominent role in the pathogenesis of radiation-induced compared to sporadic meningiomas.

Adult↗

PubMed2001

Increase of nestin-immunoreactive neural precursor cells in the dentate gyrus of pediatric patients with early-onset temporal lobe epilepsy.

A considerable potential for neurogenesis has been identified in the epileptic rat hippocampus. Here, we explore this feature in human patients suffering from chronic mesial temporal lobe epilepsy. Immunohistochemical detection of the neurodevelopmental antigen nestin was used to detect neural precursor cells, and cell-type specific markers were employed to study their histogenetic origin and potential for neuronal or glial differentiation. The ontogenetic regulation of nestin-positive precursors was established in human control brains (week 19 of gestation-15 years of age). A striking increase of nestin-immunoreactive cells within the hilus and dentate gyrus could be observed in a group of young patients with temporal lobe epilepsy (TLE) and surgical treatment before age 2 years compared to adult TLE patients and controls. The cellular morphology and regional distribution closely resembled nestin-immunoreactive granule-cell progenitors transiently expressed during prenatal human hippocampus development. An increased Ki-67 proliferation index and clusters of supragranular nestin-immunoreactive cells within the molecular layer of the dentate gyrus were also noted in the group of young TLE patients. Confocal studies revealed colocalization of nestin and the betaIII isoform of tubulin, indicating a neuronal fate for some of these cells. Vimentin was consistently expressed in nestin-immunoreactive cells, whereas cell lineage-specific markers, i.e., glial fibrillary acidic protein, MAP2, neurofilament protein, NeuN, or calbindin D-28k failed to colocalize. These findings provide evidence for increased neurogenesis in pediatric patients with early onset of temporal lobe epilepsy and/or point towards a delay in hippocampal maturation in a subgroup of patients with TLE.

Adolescent↗

PubMed2001

Posterior cerebral artery Wada test: sodium amytal distribution and functional deficits.

Inadequate sodium amytal delivery to the posterior hippocampus during the intracarotid Wada test has led to development of selective tests. Our purpose was to show the sodium amytal distribution in the posterior cerebral artery (PCA) Wada test and to relate it to functional deficits during the test. We simultaneously injected 80 mg sodium amytal and 14.8 MBq 99mTc-hexamethylpropyleneamine oxime (HMPAO) into the P2-segment of the PCA in 14 patients with temporal lobe epilepsy. To show the skull, we injected 116 MBq 99mTc-HDP intravenously. Sodium amytal distribution was determined by high-resolution single-photon emission computed tomography (SPECT). In all patients, HMPAO was distributed throughout the parahippocampal gyrus and hippocampus; it was also seen in the occipital lobe in all cases and in the thalamus in 11. Eleven patients were awake and cooperative; one was slightly uncooperative due to speech comprehension difficulties and perseveration. All patients showed contralateral hemianopia during the test. Four patients had nominal dysphasia for 1-3 min. None developed motor deficits or had permanent neurological deficits. Neurological deficits due to inactivation of extrahippocampal areas thus do not grossly interfere with neuropsychological testing during the test.

Adult↗

PubMed2001

Postsurgical outcome of children and adolescents with medically refractory frontal lobe epilepsies.

OBJECTS: In the adult population surgical treatment is generally less favorable for refractory frontal lobe epilepsy (FLE) than for temporal lobe epilepsy (TLE). Predictive factors and outcome of FLE surgery had not previously been described for the pediatric and adolescent population. Therefore, 32 children and adolescents who underwent FLE surgery were analyzed in this study. METHODS: Medical records were reviewed for demographic data, presurgical evaluation procedures, surgical procedures, pathological findings and follow-up. RESULTS: Mean age at operation was 10.8 years, with seizure onset at 4.6 years. Excellent outcomes were observed in 21 of the 32 patients following evaluation a mean of 34.5 months after surgery. Nineteen of 22 patients became seizure free after tailored resections, versus 2 out of 10 after lobectomy. Transient neurological and surgical complications occurred in 4 patients. Focal neoplastic lesions detectable by MRI were associated with a favorable outcome. CONCLUSIONS: As seen in adult FLE series, the detection of a resectable ictal neoplastic lesion on preoperative MRI is associated with an excellent outcome comparable to that of TLE surgery.

Adolescent↗

PubMed2001

Alternative splicing of the p15 cdk inhibitor in glioblastoma multiforme.

Thirty-four to fifty-six percent of malignant gliomas harbor homozygous co-deletions of the INK4a(p16-p14ARF) and INK4b(p15) tumor suppressor genes. Recently, an alternatively spliced form of p15 has been cloned and termed p10 based on the presumed molecular weight of the protein. In this study, we have investigated the role of p10 expression in human glioblastomas. Both, wild-type p15 and p10 were detected in three of nine glioblastoma cell lines. Sixteen of twenty-nine (55%) glioblastoma tumor samples contained INK4b transcripts, but only nine (31%) tumors expressed p15 protein. Three p15 protein-negative tumors expressed only p10 mRNA. Preferential expression of p10 was not due to splice site mutations. Strong suppression of tumorigenicity was seen in four glioblastoma cell lines after transfection with p15 but not with p10. Loss of p15 protein expression was almost always accompanied by loss of p16 expression. p1 6/p15-negative tumors commonly lacked p14ARF expression. These results suggest that differential splicing of the INK4b gene may result in the expression of p10 at the expense of p15, which would lead to loss of p15-mediated growth suppression. This novel mechanism of loss of p15 might complement alterations of the INK4a tumor suppressor gene in some glioblastomas, resulting in combined loss of p16, p15 and p14ARF.

Alternative Splicing↗

PubMed2001

Surgery for upper cervical spine instabilities in children.

BACKGROUND: Due to the paucity of existing data with regard to surgical fusion of upper cervical spine instabilities in the paediatric population, we feel encouraged to report the results of our own series to provide additional information to the available body of literature. METHODS: Since 1991 N = 11 children underwent a total of N = 13 surgical procedures for N = 8 posttraumatic, N = 2 congenital and N = 1 postinfectious instabilities at a mean age of 10 years (range: 3-16 years). Transoral odontectomies, ventral odontoid screw-fixations, dorsal wiring or -clamping and transarticular screw-fixations were performed for stabilization and iliac crest bone graft used for fusion. Pain scores, neurological status and radiological results were documented at regular intervals (mean follow-up: 25.4 months). RESULTS: Stable fusion was achieved in all patients as documented on flexion/extension films and tomographies. At the latest follow-up N = 2 patients had improved and N = 9 were equal to their preoperative neurological status. Pain scores were improved in N = 9 patients. N = 2 children developed "bystander-fusion" after C0/2 wiring. N = 3 peri-operative complications occurred as transient neurological deteriorations. In one case this resulted from the resection of a lower brainstem tumour prior to the stabilization procedure. One was attributed to sublaminar wiring in the case of an os odontoideum and one occurred due to slippage of the halo orthosis after transoral odontectomy before definitive dorsal stabilization was carried out. INTERPRETATION: In accordance with the recent literature, we argue for the application of modern screw fixations and treatment algorithms as established for adults in upper cervical spine instabilities of older children. Techniques and indications remain problematic for those younger than 6 years and may have to be individualized in congenital instabilities.

Adolescent↗

PubMed2001

Tumour surgery of the upper cervical spine--a retrospective study of 13 cases.

A series of tumour cases of the upper cervical spine who we had treated was analysed retrospectively with respect to surgical complications, quality of life and survival, 13 patients (mean age 56 years, metastases 6, plasmocytomas 3, chordomas 2, histiocytosis 1, aneurysmal bone cyst 1) with tumours of the upper cervical spine (C2 n = 7, C2 and C3 n = 4, C3 n = 2) were treated during an 8-year period. A total of 16 operations were carried out with ten one-step procedures and three two step-procedures. Eight extra-oral, one transoral, three dorsal and, in one case, a combined dorsal and extra-oral tumour removal were performed. Four dorsal stabilisation's, four ventral platings and two combined ventral platings plus dorsal fixations and eight vertebral body replacements were carried out. The neurological status and the quality of life were analysed preoperatively and during the follow-up examinations. Flexionextension radiographs were taken during follow-up. There was no operative mortality. The transient morbidity was 8%. The operative intervention significantly improved the quality of life in all patients during the follow-up visits (mean: 20 months). No instability was seen. The average survival time of all patients was 23 months. Six patients died following the operation after a mean time of 28 (4-64) months. Tumour removal in the upper cervical spine using individually modified surgical strategies based on an approach combining tumour location, stabilisation and vertebral body replacement significantly increases the time of survival and quality of life with an acceptable surgical risk for complications.

Adult↗

PubMed2001

Alterations of INK4a(p16-p14ARF)/INK4b(p15) expression and telomerase activation in meningioma progression.

Dysregulation of cell cycle progression and telomerase activation have been implicated in malignant tumor progression as well as in the evasion of senescence and immortalization. We have investigated expression of the cell cycle control and tumor suppressor genes INK4a(p16-p14ARF), INK4b(p15-p10) and RB, and their relation to telomerase activation during malignant meningioma progression. 7/26 (27%) benign, 3/12 (25%) atypical but 4/7 (57%) anaplastic tumors lacked both, p16 and p15 protein expression. 14/39 (36%) benign and atypical but 5/7 (71%) anaplastic meningiomas contained no p14ARF mRNA. 2/46 (4%) tumors failed to express pRB. We observed frequent differential loss of expression of the alternatively spliced INK4a tumor suppressors p16 and p14ARF. Exclusive expression of the alternative INK4b transcript p10 possibly at the expense of p15 and therefore resulting in loss of p15 tumor suppressor activity was noted in two meningiomas. We have previously described telomerase activity or expression of the telomerase catalytic subunit hTERT in this meningioma series. Telomerase activation was detected in 10/27 (37%) benign, but 18/19 (95%) non-benign meningiomas. We observed no significant overall correlation between loss of INK4a/INK4b expression and telomerase activation. In conclusion, our results suggest a greater role for losses of INK4a/INK4b gene products in meningioma formation and malignant progression than previously thought. Inactivation of p16/p15- and pl4ARF-dependent pathways possibly in conjunction with telomerase activation might be critical steps for a meningioma cell towards escape from senescence, that is, immortalization.

Adult↗

PubMed2001

Mutational analysis of TSC1 and TSC2 genes in gangliogliomas.

Gangliogliomas constitute the most frequent tumour entity in patients with temporal lobe epilepsy. The characteristic histopathological admixture of glial and neuronal elements, the focal nature and their differentiated phenotype and benign biological behaviour suggest an origin from a developmentally compromised or dysplastic precursor lesion. The present study analysed TSC1 and TSC2 genes as potential candidates involved in the pathogenesis of this intriguing neoplasm. Recent data suggest that both genes play a role in cortical differentiation and growth control. DNA sequence analysis of TSC1 and TSC2 was studied in 20 patients with gangliogliomas. Fifteen of these tumours (75%) carried polymorphisms in the TSC2 gene. The frequency of these polymorphisms was significantly increased in intron 4 (12.5%) and exon 41 (15%) compared to control individuals (8.1 and 6.5%, respectively, n = 100). A somatic mutation in intron 32 of the TSC2 gene was encountered in one patient. In the TSC1 gene, seven polymorphisms occurred as a combination of base exchanges in exon 14 and intron 13. No mutations were observed in this gene. Laser microdissection and harvesting of individual neuronal and glial elements identified the intron 32 mutation within the glial portion but not in dysplastic neurones of the tumour. The data demonstrate numerous polymorphisms as well as a novel TSC2 mutation in gangliogliomas from patients with chronic epilepsies. The selective detection of the TSC2 mutation within the glial component of a ganglioglioma suggests that the glioma portion has undergone clonal evolution in this case.

Brain Neoplasms↗