Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two unrelated patients with macrocephaly, seizures, and mild cerebellar signs had a dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). Both also had autosomal dominant Cowden disease as evidenced by facial, oral, and acral papules. In the two families, 9 sibs demonstrated the mucocutaneous lesions, thyroid disease, breast tumors, and ovarian tumors compatible with the diagnosis of Cowden disease. Some of the sibs also showed various degrees of neurological signs such as macrocephaly, mental retardation, seizures, tremor, and dysdiadochokinesia. Magnetic resonance imaging scans of sibs of one family demonstrated megalencephaly and other mild abnormalities. The occurrence of these two rare disorders in single patients is more than a coincidence, and the clinical findings in the combined condition establishes it as a new phakomatosis.
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PMID:Lhermitte-Duclos disease and Cowden disease: a single phakomatosis. 164 66

Glial neoplasms that are peripherally located and involve the cortical gray matter are noteworthy because of their predilection to serve as a seizure locus, their amenability to surgical resection, their generally favorable prognosis, and their characteristic imaging features, which facilitate diagnosis before surgery. The smaller lesions include ganglioglioma and dysembryoplastic neuroepithelial tumor. Gangliogliomas contain both neuronal and glial components and occur most commonly in the temporal lobe. Variant forms of gangliogliomas may occur and are related to the different compositions of the underlying cellular population. Gangliocytomas lack glial cells and are located both in the cerebral hemispheres and the cerebellum. Lhermitte-Duclos disease represents a specific type of cerebellar gangliocytoma with dysplastic features and is characterized by a laminar pattern at imaging. Dysembryoplastic neuroepithelial tumors occur predominantly in children and young adults with partial seizures and most commonly arise in the temporal lobe, frequently in combination with cortical dysplasia. Surrounding vasogenic edema is conspicuously absent in both gangliogliomas and dysembryoplastic neuroepithelial tumors. The larger masses in this group include desmoplastic infantile ganglioglioma and pleomorphic xanthoastrocytoma and tend to involve the leptomeninges and cortical territory. Both invoke an intense desmoplastic reaction, which appears as an enhancing soft-tissue component at imaging.
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PMID:From the archives of the AFIP: superficial gliomas: radiologic-pathologic correlation. Armed Forces Institute of Pathology. 1170 24

Initially identified in high-grade gliomas, mutations in the PTEN tumor-suppressor are also found in many sporadic cancers and a few related autosomal dominant hamartoma syndromes. PTEN is a 3'-specific phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) phosphatase and functions as a negative regulator of PI3K signaling. We generated a tissue-specific deletion of the mouse homolog Pten to address its role in brain function. Mice homozygous for this deletion (PtenloxP/loxP;Gfap-cre), developed seizures and ataxia by 9 wk and died by 29 wk. Histological analysis showed brain enlargement in PtenloxP/loxP;Gfap-cre mice as a consequence of primary granule-cell dysplasia in the cerebellum and dentate gyrus. Pten mutant cells showed a cell-autonomous increase in soma size and elevated phosphorylation of Akt. These data represent the first evidence for the role of Pten and Akt in cell size regulation in mammals and provide an animal model for a human phakomatosis condition, Lhermitte-Duclos disease (LDD).
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PMID:Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. 1172 26

Somatic inactivation of PTEN occurs in different human tumors including glioblastoma, endometrial carcinoma and prostate carcinoma. Germline mutations in PTEN result in a range of phenotypic abnormalities that occur with variable penetrance, including neurological features such as macrocephaly, seizures, ataxia and Lhermitte-Duclos disease (also described as dysplastic gangliocytoma of the cerebellum). Homozygous deletion of Pten causes embryonic lethality in mice. To investigate function in the brain, we used Cre-loxP technology to selectively inactivate Pten in specific mouse neuronal populations. Loss of Pten resulted in progressive macrocephaly and seizures. Neurons lacking Pten expressed high levels of phosphorylated Akt and showed a progressive increase in soma size without evidence of abnormal proliferation. Cerebellar abnormalities closely resembled the histopathology of human Lhermitte-Duclos disease. These results indicate that Pten regulates neuronal size in vivo in a cell-autonomous manner and provide new insights into the etiology of Lhermitte-Duclos disease.
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PMID:Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease. 1172 27

Pure neuronal and mixed neuronal-glial tumors of the central nervous system are uncommon but fascinating because they are less aggressive than the more common glial tumors and their prognosis is excellent. Neurologic manifestations are varied and include seizures, symptoms of increased intracranial pressure, and neurologic deficits according to tumor location. Many neuronal tumors of the central nervous system demonstrate characteristic radiologic findings. At magnetic resonance (MR) imaging, gangliocytomas demonstrate low signal intensity on T1-weighted images, high signal intensity on T2-weighted images, and frequent enhancement on gadolinium-enhanced T1-weighted images. Characteristic MR imaging findings of Lhermitte-Duclos disease are a nonenhancing mass in a cerebellar hemisphere with a striated pattern. Central neurocytomas are typically located in the lateral ventricles near the foramen of Monro with a characteristic attachment to the septum pellucidum. Ganglioneurocytoma is a rare variant of central neurocytoma that is characterized by differentiation toward ganglion cells. In ganglioglioma, a well-defined cystic mass with a solid mural nodule is typically seen. Extension of enhancement to the leptomeninges is characteristic of desmoplastic infantile ganglioglioma and correlates with the firm dural attachment of the solid component. Dysembryoplastic neuroepithelial tumor has a well-demarcated, multilobulated or gyriform appearance.
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PMID:Neuronal tumors of the central nervous system: radiologic findings and pathologic correlation. 1223 46

The mechanisms that regulate mammalian cell size during development and homeostatic maintenance are poorly understood. The tumor suppressor Pten is required for correct maintenance of mammalian neuronal soma size. Selective inactivation of Pten in postnatal granule neurons of the cerebellum and dentate gyrus in mouse causes cell-autonomous hypertrophy as well as more complex phenotypes, including progressive macrocephaly, seizures, and premature death. To determine the contribution of mTor signaling to Pten-mediated growth regulation in the mammalian nervous system, we treated Pten conditional knockout mice with CCI-779, a specific mTor inhibitor. mTor inhibition decreased the seizure frequency and death rate in Pten mutant mice, prevented the increase in Pten-deficient neuronal soma size in young mice, and reversed neuronal soma enlargement in adult mice. mTor inhibition did not decrease the size of wild-type adult neurons. Thus, mTor is required for neuronal hypertrophy downstream of Pten deficiency, but is not required for maintenance of normal neuronal soma size. mTOR inhibitors may be useful therapeutic agents for diseases in brain resulting from PTEN deficiency such as Lhermitte-Duclos disease or glioblastoma multiforme.
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PMID:mTor is required for hypertrophy of Pten-deficient neuronal soma in vivo. 1453 28

The tumor suppressor PTEN (phosphatase and tensin homolog) plays a critical role in the development and maintenance of the mammalian nervous system. Effects of inherited mutation of PTEN are highly variable and include macrocephaly, Lhermitte-Duclos disease (LDD) caused by a hamartomatous enlargement of the cerebellum, ataxia, seizures and autism, in addition to cancer predisposition. In the mouse, selective inactivation of Pten in post-mitotic granule neurons of the cerebellum and dentate gyrus showed that Pten was required for proper regulation of neuronal nuclear and soma size. Hypertrophy of Pten-deficient neurons required the activity of the serine-threonine kinase mTor. mTor is a master regulator of cell and organ growth which can trigger a cascade of downstream signaling pathways involving, in part, components of the translational machinery, including S6k1 and its substrate the ribosomal protein S6. Deletion of S6k1 in mice results in decreased size. Therefore, to determine the relative contribution of S6k1 to Pten-deficient neuronal hypertrophy in vivo, we crossed Pten brain-conditional knockouts with S6k1 null mice. Double mutant mice show no reversion or improvement in their Pten-related size and neurological defects including enlarged cerebella and dentate gyri with increased size of neuronal nuclei and somata, ataxia, and premature death. The hypertrophic Pten/S6k1-deficient neurons contained high levels of phosphorylated S6, similar to Pten-deficient neurons, suggesting that the mTor/S6k/S6 branch of the pathway was still active. Thus, we conclude that S6k1 is not required to cause hypertrophy of Pten-deficient neurons. This study reveals a cell type-dependent role for S6k1 in PI3K-dependent hypertrophy.
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PMID:S6k1 is not required for Pten-deficient neuronal hypertrophy. 1677 79

The phosphatidylinositol 3-kinase (PI3K) signaling pathway modulates growth, proliferation and cell survival in diverse tissue types and plays specialized roles in the nervous system including influences on neuronal polarity, dendritic branching and synaptic plasticity. The tumor-suppressor phosphatase with tensin homology (PTEN) is the central negative regulator of the PI3K pathway. Germline PTEN mutations result in cancer predisposition, macrocephaly and benign hamartomas in many tissues, including Lhermitte-Duclos disease, a cerebellar growth disorder. Neurological abnormalities including autism, seizures and ataxia have been observed in association with inherited PTEN mutation with variable penetrance. It remains unclear how loss of PTEN activity contributes to neurological dysfunction. To explore the effects of Pten deficiency on neuronal structure and function, we analyzed several ultra-structural features of Pten-deficient neurons in Pten conditional knockout mice. Using Golgi stain to visualize full neuronal morphology, we observed that increased size of nuclei and somata in Pten-deficient neurons was accompanied by enlarged caliber of neuronal projections and increased dendritic spine density. Electron microscopic evaluation revealed enlarged abnormal synaptic structures in the cerebral cortex and cerebellum. Severe myelination defects included thickening and unraveling of the myelin sheath surrounding hypertrophic axons in the corpus callosum. Defects in myelination of axons of normal caliber were observed in the cerebellum, suggesting intrinsic abnormalities in Pten-deficient oligodendrocytes. We did not observe these abnormalities in wild-type or conditional Pten heterozygous mice. Moreover, conditional deletion of Pten drastically weakened synaptic transmission and synaptic plasticity at excitatory synapses between CA3 and CA1 pyramidal neurons in the hippocampus. These data suggest that Pten is involved in mechanisms that control development of neuronal and synaptic structures and subsequently synaptic function.
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PMID:Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities. 1808 64

PTEN (phosphatase and tensin homolog deleted on chromosome ten) is a lipid phosphatase that counteracts the function of phosphatidylinositol-3 kinase (PI3K). Loss of function of PTEN results in constitutive activation of AKT and downstream effectors and correlates with many human cancers, as well as various brain disorders, including macrocephaly, seizures, Lhermitte-Duclos disease, and autism. We previously generated a conditional Pten knock-out mouse line with Pten loss in limited postmitotic neurons in the cortex and hippocampus. Pten-null neurons developed neuronal hypertrophy and loss of neuronal polarity. The mutant mice exhibited macrocephaly and behavioral abnormalities reminiscent of certain features of human autism. Here, we report that rapamycin, a specific inhibitor of mammalian target of rapamycin complex 1 (mTORC1), can prevent and reverse neuronal hypertrophy, resulting in the amelioration of a subset of PTEN-associated abnormal behaviors, providing evidence that the mTORC1 pathway downstream of PTEN is critical for this complex phenotype.
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PMID:Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. 1921 84

Cerebellar gangliocytoma can correspond to Lhermitte-Duclos disease, a benign hamartomatous malformation encountered in young adults. It can also be a part of gangliogliomas/gangliocytomas family, which usually encompasses temporal pediatric neoplasms associated with longstanding seizures. We report a case of a young 11-year-old patient who presented with a gangliocytoma of the cerebellum revealed by neurologic manifestations (headache, dyspraxia, equilibrium and gait disturbances). Diagnosis was made on surgical material. Tumour was characterized by dysplastic mature ganglion cells, perivascular lymphocytic infiltrates and no glial neoplastic component. By immunohistochemistry, ganglion cells expressed neurofilaments, MAP2 protein, synaptophysin, chromogranin A and S100 protein. BRAF V600E mutation was absent. Clinical characteristics, radiology, histopathology of the two main diagnoses are discussed.
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PMID:[Cerebellar gangliocytoma in an 11-year-old child]. 2549 64


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