Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 1003429001, 1003430006, 1003461002; ORPHA: 268994, 269001, 269008, 65683;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.22 | Focal cortical dysplasia, type II, somatic | 607341 | 3 | MTOR | 601231 | |
| 9q34.13 | Focal cortical dysplasia, type II, somatic | 607341 | 3 | TSC1 | 605284 | |
| 16p13.3 | ?Focal cortical dysplasia, type II, somatic | 607341 | 3 | TSC2 | 191092 |
A number sign (#) is used with this entry because of evidence that focal cortical dysplasia type II (FCORD2) is caused by somatic mutation in the MTOR (601231), TSC1 (605284), or TSC2 (191092) genes.
Focal cortical dysplasia type II (FCORD2), or focal cortical dysplasia of Taylor (FCDT), is a cerebral developmental malformation that results in a clinical phenotype of intractable epilepsy, usually requiring surgery. FCORD2 has been classified histologically into 2 subtypes: a type without balloon cells, known as type IIA, and a type with balloon cells, known as type IIB (Palmini et al., 2004). Affected individuals have refractory seizures, usually with onset in early childhood, and may have persistent intellectual disability. Most patients require neurosurgical resection of affected brain tissue to ameliorate seizure frequency and severity (summary by Moller et al., 2016).
Taylor et al. (1971) reported distinctive neuropathologic findings in 10 patients undergoing surgery for refractory epilepsy described as 'masses of large aberrant neurons littered apparently in chaos through all but the first molecular layer.' In 7 of the 10 cases, 'balloon' cells were also present.
Wolf et al. (1995) reported 8 cases of chronic drug-resistant epilepsy that were characterized neuropathologically by large, disfigured neurons, oversized and atypical astrocytes, and ballooned multinucleated giant cells similar to those seen in tuberous sclerosis. Despite the strong histomorphologic similarity to tuberous sclerosis, the patients lacked additional features of neurocutaneous phacomatosis. High-resolution magnetic resonance imaging (MRI) showed a hyperintense funnel-shaped subcortical lesion tapering toward the lateral ventricle on fluid-attenuated inversion recovery. Wolf et al. (1995) postulated a defect in neuronal cell migration. Surgical lesionectomy usually resulted in seizure relief.
Lawson et al. (2005) ascertained 34 cases of cortical dysplasia of Taylor from a surgical database; 15 were classified as CDT with balloon cells (CDT-BC) and 19 as CDT with dysplasia only (CDT-D). The common fundamental neuropathologic characteristic of the 2 subtypes was the presence of large, bizarre neurons (neuronal cytomegaly), which is also seen in tuberous sclerosis and hemimegalencephaly. The CDT-BC cases were characterized by a diffuse increase in cortical thickness (at least 2 times normal); no clear cortical-white matter junction due to excess 'spillover' of neurons; panlaminar diffuse replacement of cortical neurons by giant, dysmorphic, maloriented neurons; many GFAP (137780)-immunoreactive balloon cells; GFAP-immunoreactive fibrillar astrocytosis; and focal, severe white matter abnormalities. The features of CDT-D cases included multifocal laminar replacement of cortical neurons by giant, dysmorphic, maloriented neurons with no clearly defined borders; absence of GFAP-immunoreactive balloon cells; moderate astrocytosis; and generally well-preserved white matter. Lawson et al. (2005) noted that the neuropathologic findings of CDT-BC were similar to those seen in tuberous sclerosis, whereas the findings in CDT-D were similar to hemimegalencephaly, suggesting separate pathophysiologies for the 2 subtypes of CDT. MRI findings showed that nearly one-third of CDT-BC cases had normal or very subtle changes, whereas some cases showed focal cortical thickening, blurring of the gray-white margins, and white matter abnormalities. Clinically, patients with CDT presented with severe, intractable epilepsy of very early onset, multiple daily seizures, cognitive disability, and focal neurologic deficits. On the whole, patients with CDT-D had a more severe phenotype, with earlier onset, lower rate of seizure-free time after surgery, higher prevalence of hemiparesis, and lower IQ.
Siegel et al. (2005) identified 21 adult patients with FCDT who underwent surgery for medically refractory epilepsy. Most patients had seizure onset in their twenties (range, 18 to 55 years), and the most common seizure type was complex partial, often with secondary generalization. Three patients had simple partial seizures and 1 had generalized tonic-clonic seizures. Sixteen (76%) of the 21 patients were rendered seizure-free after surgery, which the authors noted was favorable compared to results of surgical intervention for patients with early-onset seizures. Seizure outcome was the same for both types IIA and IIB.
Lim et al. (2015) reported 12 unrelated patients with FCD type II associated with somatic mutations in the MTOR gene. All patients had epilepsy and underwent brain surgery between 11 months and 10 years of age. Histologic examination of resected brain tissue showed cortical dyslamination and dystrophic neurons, either with or without balloon cells, consistent with FCD type IIa or IIb. Brain imaging in some patients showed focal cortical dysplasia, whereas imaging was normal in some patients.
Nakashima et al. (2015) reported 6 unrelated patients with FCD type IIb associated with somatic mutations in the MTOR gene. The patients had onset of refractory daily seizures in the first months or years of life. Seizures were associated with EEG abnormalities and focal cortical dysplasia on brain imaging. Seizure types included complex partial seizures and secondary generalized tonic-clonic seizures. IQ before surgery was decreased in most patients, although it increased somewhat after surgery in some patients. Two patients had hemiparesis. Brain tissue from all patients was consistent with FCD type IIb with balloon cells.
Moller et al. (2016) reported 6 unrelated patients with FCD type II associated with somatic mutations in the MTOR gene. Onset of seizures occurred within the first 2 years of life in most patients, although 1 patient had onset at age 6 years. Seizure types were mainly focal and asymmetric, and EEG showed focal and multifocal abnormalities. All patients had MRI evidence of focal cortical dysplasia. All patients underwent surgical resection: affected brain tissue showed FCD type IIa in 1 patient and FCD type IIb with balloon cells in the other patients. One patient had normal cognition, 1 had memory impairment, and 4 had mild intellectual disability.
Lim et al. (2017) reported 5 unrelated patients with FCD type II associated with somatic mutations in the TSC1 (4 patients) or TSC2 (1 patient) genes. None of the patients had clinical findings related to tuberous sclerosis (see TSC1, 191100 and TSC2, 613254). All had intractable seizures and underwent brain resection. Histology in 4 patients showed cortical dyslamination and dysmorphic neurons consistent with FCD type IIa; histology in the fifth patient showed these features as well as balloon cells, consistent with FCD type IIb. Brain imaging showed no abnormal signal intensity in 2 patients, focal cortical dysplasia in 2, and subependymal heterotopia in 1; the last-mentioned patient was the only patient with a TSC2 mutation.
In brain tissue resected from 12 children with seizures due to FCD type II, Lim et al. (2015) identified 9 different de novo somatic missense mutations in the MTOR gene (see, e.g., 601231.0003 and 601231.0004). The mutations in the first 4 patients were found by whole-exome sequencing and verified by several methods; subsequent mutations were found in an additional 73 patients with FCD type II who underwent sequencing of the MTOR gene. The mutations were not found in the patients' blood samples. The allelic frequencies of the mutations ranged from about 1 to 12%. Overall, MTOR mutations were found in 15.6% of 77 patients with FCD type II who were studied. Transfection of 3 of the mutations into HEK293 cells showed that they resulted in constitutively increased kinase activity compared to controls.
In brain tissue of 6 unrelated patients with FCD type IIb, Nakashima et al. (2015) identified 4 different de novo somatic missense mutations in the MTOR gene (see, e.g., 601231.0005 and 601231.0006). The mutations in the first 2 patients were found by whole-exome sequencing; subsequent mutations were found by direct sequencing of the MTOR gene in additional patients. Overall, mutations were found in 6 (46%) of 13 individuals with FCD type IIb. Mutant allele frequencies in brain tissue were very low (range 1.11 to 9.31%). Transfection of the mutations into HEK293 cells showed that all resulted in constitutive activation of mTOR, with increased phosphorylation of 4EBP, the direct target of mTOR kinase. Lesion-specific brain tissue from affected individuals showed increased phosphorylation of S6K (RPS6KB1; 608938) compared to controls, consistent with a gain of function of the mTOR pathway. Nakashima et al. (2015) concluded that somatic MTOR mutation caused hyperactivation of the mTOR-signaling pathway, which is involved in growth, migration, and maturation of neurons and glial cells. Aberrant activation of this pathway can result in the formation of dysmorphic neurons and balloon cells, particularly during brain development.
In resected brain tissue from 6 (37%) of 16 patients with FCD type II, Moller et al. (2016) identified somatic missense mutations in the MTOR gene (see, e.g., 601231.0005 and 601231.0008). The mutations were found by targeted sequencing of the MTOR gene and other genes in the MTOR pathway. The mutant allele frequency was low, less than 7% in patient brain tissue. Hyperactivation of the mTOR pathway as shown by S6 intense phosphorylation was observed in dysmorphic neurons of patients with FCD types IIa and IIb, in contrast to apparently normal adjacent neurons. The findings were consistent with hyperactivation of the mTOR pathway.
In brain tissue resected from 5 unrelated patients with seizures due to FCD type II, Lim et al. (2017) identified de novo somatic missense mutations in the TSC2 gene (V1547I, 191092.0018, 1 patient) and the TSC1 gene (R22W, 605284.0010 and R204C, 605284.0011, 4 patients). The mutant allele frequency in patient brain tissue was very low, less than 3%. Three patients with TSC1 mutations had FCD type IIa and 1 had FCD type IIb; the patient with the TSC2 mutation had FCD type IIa. The patients were part of a cohort of 40 individuals with FCD type II whose brain tissue was negative for somatic mTOR mutations, accounting for 12.5% of patients. Patient dystrophic brain cells and cells transfected with the mutations showed increased S6K phosphorylation compared to wildtype, consistent with hyperactivation of the mTOR pathway. Abnormal S6K phosphorylation in transfected cells was inhibited by treatment with rapamycin.
Lim et al. (2015) found that transfection of the L2427P MTOR mutation (601231.0003) into the embryonic developing mouse cortex resulted in neuronal migration defects, cytomegalic neurons, and seizures associated with aberrantly increased mTOR kinase activity. Treatment with rapamycin rescued the cytomegalic neurons and seizure activity.
Lim et al. (2017) demonstrated that knockdown of the Tsc1 or Tsc2 genes in developing mouse neurons, using the CRISPR/CASP9 somatic genome editing method in utero, resulted in abnormal neuronal phenotypes resembling focal cortical dysplasia type II in humans, hyperactivation of the mTOR pathway, and epileptic seizures in mice. There was also evidence of abnormal radial migration of cortical neurons in CRISPR-treated neurons. Seizures in Tsc2-mutant mice were almost completely rescued by rapamycin treatment.
Lawson, J. A., Birchansky, S., Pacheco, E., Jayakar, P., Resnick, T. J., Dean, P., Duchowny, M. S. Distinct clinicopathologic subtypes of cortical dysplasia of Taylor. Neurology 64: 55-61, 2005. [PubMed: 15642904] [Full Text: https://doi.org/10.1212/01.WNL.0000148647.55705.A3]
Lim, J. S., Gopalappa, R., Kim, S. H., Ramakrishna, S., Lee, M., Kim, W., Kim, J., Park, S. M., Lee, J., Oh, J.-H., Kim, H. D., Park, C.-H., Lee, J. S., Kim, S., Kim, D. S., Han, J. M., Kang, H.-C., Kim, H., Lee, J. H. Somatic mutations in TSC1 and TSC2 cause focal cortical dysplasia. Am. J. Hum. Genet. 100: 454-472, 2017. [PubMed: 28215400] [Full Text: https://doi.org/10.1016/j.ajhg.2017.01.030]
Lim, J. S., Kim, W., Kang, H.-C., Kim, S. H., Park, A. H., Park, E. K., Cho, Y.-W., Kim, S., Kim, H. M., Kim, J. A., Kim, J., Rhee, H., Kang, S.-G., Kim, H. D., Kim, D., Kim, D.-S., Lee, J. H. Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nature Med. 21: 395-400, 2015. [PubMed: 25799227] [Full Text: https://doi.org/10.1038/nm.3824]
Moller, R. S., Weckhuysen, S., Chipaux, M., Marsan, E., Taly, V., Bebin, E. M., Hiatt, S. M., Prokop, J. W., Bowling, K. M., Mei, D., Conti, V., de la Grange, P., and 9 others. Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy. Neurol. Genet. 2: e118, 2016. Note: Electronic Article. [PubMed: 27830187] [Full Text: https://doi.org/10.1212/NXG.0000000000000118]
Nakashima, M., Saitsu, H., Takei, N., Tohyama, J., Kato, M., Kitaura, H., Shiina, M., Shirozu, H., Masuda, H., Watanabe, K., Ohba, C., Tsurusaki, Y., Miyake, N., Zheng, Y., Sato, T., Takebayashi, H., Ogata, K., Kameyama, S., Kakita, A., Matsumoto, N. Somatic mutations in the MTOR gene cause focal cortical dysplasia type IIb. Ann. Neurol. 78: 375-386, 2015. [PubMed: 26018084] [Full Text: https://doi.org/10.1002/ana.24444]
Palmini, A., Najm, I., Avanzini, G., Babb, T., Guerrini, R., Foldvary-Schaefer, N., Jackson, G., Luders, H. O., Prayson, R., Spreafico, R., Vinters, H. V. Terminology and classification of the cortical dysplasias. Neurology 62: S2-S8, 2004. [PubMed: 15037671] [Full Text: https://doi.org/10.1212/01.wnl.0000114507.30388.7e]
Siegel, A. M., Cascino, G. D., Elger, C. E., Devinsky, O., Laff, R., Najjar, S., Sperling, M. R., LoRusso, G., Cossu, M., Urbach, H., Aronica, E., Meyer, F. B., Scheithauer, B. W., Dubeau, F., Andermann, F. Adult-onset epilepsy in focal cortical dysplasia of Taylor type. Neurology 64: 1771-1774, 2005. [PubMed: 15911808] [Full Text: https://doi.org/10.1212/01.WNL.0000162032.20243.00]
Taylor, D. C., Falconer, M. A., Bruton, C. J., Corsellis, J. A. Focal dysplasia of the cerebral cortex in epilepsy. J. Neurol. Neurosurg. Psychiat. 34: 369-387, 1971. [PubMed: 5096551] [Full Text: https://doi.org/10.1136/jnnp.34.4.369]
Taylor, D. C., Ounsted, C. Biological mechanisms influencing the outcome of seizures in response to fever. Epilepsia 12: 33-45, 1971. [PubMed: 5282881] [Full Text: https://doi.org/10.1111/j.1528-1157.1971.tb03913.x]
Wolf, H. K., Wellmer, J., Muller, M. B., Wiestler, O. D., Hufnagel, A., Pietsch, T. Glioneuronal malformative lesions and dysembryoplastic neuroepithelial tumors in patients with chronic pharmacoresistant epilepsies. J. Neuropath. Exp. Neurol. 54: 245-254, 1995. [PubMed: 7876892] [Full Text: https://doi.org/10.1097/00005072-199503000-00011]