Table 1.
Genes involved in neurodevelopmental epileptic syndromes and their corresponding mouse models.
| Syndrome (phenotype) | Affected genes | Animal models (phenotype) | Reference |
|---|---|---|---|
| TUBEROUS SCLEROSIS COMPLEX | |||
| Benign tumors (hamartomas) in multiple organs (brain, skin, heart, kidneys, lung), renal and skin lesions, epilepsy, behavioral and learning disabilities, autism. | TSC1 (hamartin) | Tsc1+/− mice. Renal and hepatic tumors. Increased number of astrocytes but no cerebral lesions. No spontaneous seizures, but impaired social behavior and impaired learning in hippocampal-dependent tasks. Tsc1−/− mice are lethal. | Kobayashi et al. (2001), Uhlmann et al. (2002), Goorden et al. (2007) |
| Conditional mutant mice lacking Tsc1 in glia. Glial proliferation, enlarged brain size, progressive epilepsy, and premature death. | Zeng et al. (2008), Feliciano et al. (2011) | ||
| TSC2 (tuberin) | Tsc2+/− mice. Renal and hepatic defects. Cognitive deficits in the absence of neuropathology or seizures. Tsc2−/− mice are lethal. | Uhlmann et al. (2002), Ehninger et al. (2008), Bonnet et al. (2009) | |
| Conditional mutant mice lacking Tsc2 in glia. Cortical and hippocampal lamination defects, hippocampal heterotopias, enlarged dysplastic neurons and glia, abnormal myelination, astrocytosis, megalencephaly, epilepsy, and premature death. | Way et al. (2009), Zeng et al. (2011) | ||
| LISSENCEPHALY | |||
| Different forms of the disease, due to different genetic mutations. Absent or decreased cerebral convolutions, resulting in cortical thickening and smooth cerebral surface. Developmental delay, myoclonic jerks, seizures. | LIS1 | Lis1 knockout mice. Lethal Lis1−/− mice. Neuronal migration defects in Lis1+/− mice (aberrant morphology of cortical neurons and radial glia, slower neuronal migration, cortical plate splitting, and abnormal thalamocortical innervation). Behavioral defects not reported. | Cahana et al. (2001) |
| TUBA1A | N-ethyl-N-nitrosourea-induced mouse with S140G mutation in the TUBA1A gene. Abnormal neuronal migration in layers II/III and IV of the visual, auditory, and somatosensory cortices. Fractured pyramidal cell layer in the hippocampus. Impaired spatial working memory, reduced anxiety, abnormal nesting. | Keays et al. (2007) | |
| SUBCORTICAL BAND HETEROTOPIA (SBH) | |||
| Bands of gray matter interposed between the cortex and lateral ventricles (“double cortex”). Developmental delay, myoclonic jerks, seizures. DCX mutations are also associated to lissencephaly. | DCX (doublecortin) | Hemizygous Dcx−/y male mice. Hippocampal lamination defects, reduced number of hippocampal interneurons, no gross anatomical defects of the cerebral cortex. Learning deficits in hippocampus-dependent tasks. Spontaneous seizures with hippocampal onset, hyperexcitability. | Corbo et al. (2002), Nosten-Bertrand et al. (2008) |
| Dcx−/yDclk1−/− mice. Perinatal lethality, disorganized neocortical, and hippocampal layering. | Deuel et al. (2006), Koizumi et al. (2006), Kerjan and Gleeson (2007) | ||
| Dcxin utero electroporation in rats. SBH-like migration defects of cortical neurons, seizures. Rescued by postnatal re-expression of Dcx. | Bai et al. (2003), Ackman et al. (2009), Lapray et al. (2010), Manent et al. (2009), Kerjan and Gleeson (2009) | ||
| X-LINKED LISSENCEPHALY WITH ABNORMAL GENITALIA | |||
| Intellectual disability, autism, and epilepsy without cortical malformations. | ARX | Arx−/− mice. Perinatal lethality. Absent interneuron migration from the lateral and medial ganglionic eminences. Reduced number of CR, NPY, CB but not PV interneurons. Conditional deletion of Arx in Dlx5/6 expressing interneurons results in early-onset seizures in hemizygous (Arx−/y) male mice. | Kitamura et al. (2002), Colombo et al. (2007), Friocourt et al. (2008), Marsh et al. (2009), Friocourt and Parnavelas (2010) |
| Arx knock-in mice for human ARX mutations. P355R mutants die at P0, with anatomical defects similar to Arx−/− mice. 330ins(GCG)7 and P355L mutants die after birth, with cortical malformations and altered development of GABAergic and cholinergic neurons. More severe seizures and learning deficits in 330ins(GCG)7 than P355L mutants. | Kitamura et al. (2009) | ||
| TUBEROUS SCLEROSIS COMPLEX | |||
| Benign tumors (hamartomas) in multiple organs (brain, skin, heart, kidneys, lung), renal and skin lesions, epilepsy, behavioral and learning disabilities, autism. | TSC1 (hamartin) | Tsc1+/− mice. Renal and hepatic tumors. Increased number of astrocytes but no cerebral lesions. No spontaneous seizures, but impaired social behavior and impaired learning in hippocampal-dependent tasks. Tsc1−/− mice are lethal. | Kobayashi et al. (2001), Uhlmann et al. (2002), Goorden et al. (2007) |
| Conditional mutant mice lacking Tsc1 in glia. Glial proliferation, enlarged brain size, progressive epilepsy, and premature death. | Zeng et al. (2008), Feliciano et al. (2011) | ||
| TSC2 (tuberin) | Tsc2+/− mice. Renal and hepatic defects. Cognitive deficits in the absence of neuropathology or seizures. Tsc2−/− mice are lethal. | Uhlmann et al. (2002), Ehninger et al. (2008), Bonnet et al. (2009) | |
| Conditional mutant mice lacking Tsc2 in glia. Cortical and hippocampal lamination defects, hippocampal heterotopias, enlarged dysplastic neurons and glia, abnormal myelination, astrocytosis, megalencephaly, epilepsy, and premature death. | Way et al. (2009), Zeng et al. (2011) | ||
| LISSENCEPHALY | |||
| Different forms of the disease, due to different genetic mutations. Absent or decreased cerebral convolutions, resulting in cortical thickening and smooth cerebral surface. Developmental delay, myoclonic jerks, seizures. | LIS1 | Lis1 knockout mice. Lethal Lis1−/− mice. Neuronal migration defects in Lis1+/− mice (aberrant morphology of cortical neurons and radial glia, slower neuronal migration, cortical plate splitting, and abnormal thalamocortical innervation). Behavioral defects not reported. | Cahana et al. (2001) |
| TUBA1A | N-ethyl-N-nitrosourea-induced mouse with S140G mutation in the TUBA1A gene. Abnormal neuronal migration in layers II/III and IV of the visual, auditory, and somatosensory cortices. Fractured pyramidal cell layer in the hippocampus. Impaired spatial working memory, reduced anxiety, abnormal nesting. | Keays et al. (2007) | |
| SUBCORTICAL BAND HETEROTOPIA (SBH) | |||
| Bands of gray matter interposed between the cortex and lateral ventricles (“double cortex”). Developmental delay, myoclonic jerks, seizures. DCX mutations are also associated to lissencephaly. | DCX (doublecortin) | Hemizygous Dcx−/y male mice. Hippocampal lamination defects, reduced number of hippocampal interneurons, no gross anatomical defects of the cerebral cortex. Learning deficits in hippocampus-dependent tasks. Spontaneous seizures with hippocampal onset, hyperexcitability. | Corbo et al. (2002), Nosten-Bertrand et al. (2008) |
| Dcx−/yDclk1−/− mice. Perinatal lethality, disorganized neocortical, and hippocampal layering. | Deuel et al. (2006), Koizumi et al. (2006), Kerjan and Gleeson (2007) | ||
| Dcxin utero electroporation in rats. SBH-like migration defects of cortical neurons, seizures. Rescued by postnatal re-expression of Dcx. | Bai et al. (2003), Ackman et al. (2009), Lapray et al. (2010), Manent et al. (2009), Kerjan and Gleeson (2009) | ||
| X-LINKED LISSENCEPHALY WITH ABNORMAL GENITALIA | |||
| Intellectual disability, autism, and epilepsy without cortical malformations. | ARX | Arx−/− mice. Perinatal lethality. Absent interneuron migration from the lateral and medial ganglionic eminences. Reduced number of CR, NPY, CB but not PV interneurons. Conditional deletion of Arx in Dlx5/6 expressing interneurons results in early-onset seizures in hemizygous (Arx−/y) male mice. | Kitamura et al. (2002), Colombo et al. (2007), Friocourt et al. (2008), Marsh et al. (2009), Friocourt and Parnavelas (2010) |
| Arx knock-in mice for human ARX mutations. P355R mutants die at P0, with anatomical defects similar to Arx−/− mice. 330ins(GCG)7 and P355L mutants die after birth, with cortical malformations and altered development of GABAergic and cholinergic neurons. More severe seizures and learning deficits in 330ins(GCG)7 than P355L mutants. | Kitamura et al. (2009) | ||
The cited literature essentially refers to animal model studies; for the clinical features of the listed syndromes, the reader is referred to the “Online Mendelian Inheritance in Man” database (OMIM; www.omim.org). Abbreviations, if not otherwise specified, are as in the text.