#615473
Table of Contents
A number sign (#) is used with this entry because developmental and epileptic encephalopathy-17 (DEE17) is caused by heterozygous mutation in the GNAO1 gene (139311) on chromosome 16q13.
Heterozygous mutation in the GNAO1 gene can also cause neurodevelopmental disorder with involuntary movements (NEDIM; 617493).
Developmental and epileptic encephalopathy-17 (DEE17) is a severe neurologic disorder characterized by onset of intractable seizures in the first weeks or months of life. EEG often shows a burst-suppression pattern consistent with a clinical diagnosis of Ohtahara syndrome. Affected infants have very poor psychomotor development and may have brain abnormalities, such as cerebral atrophy or thin corpus callosum. Some patients may show involuntary movements (summary by Nakamura et al., 2013).
For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Nakamura et al. (2013) reported 4 unrelated girls with early-onset epileptic encephalopathy. Three patients had onset of intractable tonic seizures in the first weeks of life associated with suppression-burst pattern on EEG, consistent with a clinical diagnosis of Ohtahara syndrome. The fourth patient presented with opisthotonic posturing and developmental delay at age 7 months. All had severely delayed psychomotor development, with lack of sitting and no speech; only 1 patient had head control. One child died at age 11 months. EEG studies were consistently abnormal, including hypsarrhythmia and multifocal sharp waves. One patient showed dystonia and another had severe chorea and athetosis. Brain MRI was abnormal in 3 patients, showing cerebral atrophy, delayed myelination, and/or thin corpus callosum.
Saitsu et al. (2016) reported 2 unrelated girls who presented in early infancy with epileptic encephalopathy. They had intractable complex-partial seizures and EEG abnormalities, including multiform discharges, slow-wave bursts, and hypsarrhythmia. They had severe intellectual disability and motor developmental delay. One patient had severe chorea and the other had hand stereotypies. Brain imaging showed progressive cerebral atrophy in both patients, and 1 patient had microcephaly and hypotonia. The patients were severely disabled with little or no eye contact or head control, and inability to sit, walk, or talk.
The heterozygous mutations in the GNAO1 gene that were identified in patients with DEE17 by Nakamura et al. (2013) and Saitsu et al. (2016) occurred de novo.
In 4 unrelated girls with DEE17, Nakamura et al. (2013) identified 4 different de novo heterozygous mutations in the GNAO1 gene (139311.0001-139311.0004). One of the patients was somatic mosaic for the mutation. The mutations in the first 2 patients were found by whole-exome sequencing, and the mutations in the second 2 patients were found by direct sequencing of the GNAO1 gene in 367 individuals with epileptic encephalopathy. In vitro functional expression studies showed that 3 of the mutations caused impaired protein localization to the plasma membrane, and electrophysiologic analysis showed that 3 of the mutations caused decreased GNAO1-mediated inhibition of calcium currents by norepinephrine compared to wildtype. The findings suggested that aberrant GNAO1 signaling can cause multiple neurodevelopmental phenotypes, including epileptic encephalopathy and involuntary movements.
In 2 unrelated patients with DEE17, Saitsu et al. (2016) identified de novo heterozygous missense mutations in the GNAO1 gene (see, e.g., 139311.0004).
Kehrl et al. (2014) found that mutant mice heterozygous for a G184S mutation in the Gnao1 gene died in the perinatal period or early in life due to sudden death associated with severe seizures and/or increased frequency of interictal epileptiform discharges. Homozygous mutant mice were essentially nonviable. Heterozygous mice showed enhanced sensitivity to seizure kindling with a GABA antagonist compared to controls. Heterozygous knockout mice, representing a loss of function, did not show such a phenotype, suggesting that the G184S mutation results in a gain of function. Kehrl et al. (2014) noted that several studies have shown that the G184S allele results in a gain-of-function effect and suggested that DEE17 may also result from a gain-of-function mechanism.
Kehrl, J. M., Sahaya, K., Dalton, H. M., Charbeneau, R. A., Kohut, K. T., Gilbert, K., Pelz, M. C., Parent, J., Neubig, R. R. Gain-of-function mutation in Gnao1: a murine model of epileptiform encephalopathy (EIEE17)? Mammalian Genome 25: 202-210, 2014. [PubMed: 24700286, images, related citations] [Full Text]
Nakamura, K., Kodera, H., Akita, T., Shiina, M., Kato, M., Hoshino, H., Terashima, H., Osaka, H., Nakamura, S., Tohyama, J., Kumada, T., Furukawa, T., and 14 others. De novo mutations in GNAO1, encoding a G-alpha-o subunit of heterotrimeric G proteins, cause epileptic encephalopathy. Am. J. Hum. Genet. 93: 496-505, 2013. [PubMed: 23993195, images, related citations] [Full Text]
Saitsu, H., Fukai, R., Ben-Zeev, B., Sakai, Y., Mimaki, M., Okamoto, N., Suzuki, Y., Monden, Y., Saito, H., Tziperman, B., Torio, M., Akamine, S., and 10 others. Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay. Europ. J. Hum. Genet. 24: 129-134, 2016. [PubMed: 25966631, images, related citations] [Full Text]
Alternative titles; symbols
DO: 0080450;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16q13 | Developmental and epileptic encephalopathy 17 | 615473 | Autosomal dominant | 3 | GNAO1 | 139311 |
A number sign (#) is used with this entry because developmental and epileptic encephalopathy-17 (DEE17) is caused by heterozygous mutation in the GNAO1 gene (139311) on chromosome 16q13.
Heterozygous mutation in the GNAO1 gene can also cause neurodevelopmental disorder with involuntary movements (NEDIM; 617493).
Developmental and epileptic encephalopathy-17 (DEE17) is a severe neurologic disorder characterized by onset of intractable seizures in the first weeks or months of life. EEG often shows a burst-suppression pattern consistent with a clinical diagnosis of Ohtahara syndrome. Affected infants have very poor psychomotor development and may have brain abnormalities, such as cerebral atrophy or thin corpus callosum. Some patients may show involuntary movements (summary by Nakamura et al., 2013).
For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Nakamura et al. (2013) reported 4 unrelated girls with early-onset epileptic encephalopathy. Three patients had onset of intractable tonic seizures in the first weeks of life associated with suppression-burst pattern on EEG, consistent with a clinical diagnosis of Ohtahara syndrome. The fourth patient presented with opisthotonic posturing and developmental delay at age 7 months. All had severely delayed psychomotor development, with lack of sitting and no speech; only 1 patient had head control. One child died at age 11 months. EEG studies were consistently abnormal, including hypsarrhythmia and multifocal sharp waves. One patient showed dystonia and another had severe chorea and athetosis. Brain MRI was abnormal in 3 patients, showing cerebral atrophy, delayed myelination, and/or thin corpus callosum.
Saitsu et al. (2016) reported 2 unrelated girls who presented in early infancy with epileptic encephalopathy. They had intractable complex-partial seizures and EEG abnormalities, including multiform discharges, slow-wave bursts, and hypsarrhythmia. They had severe intellectual disability and motor developmental delay. One patient had severe chorea and the other had hand stereotypies. Brain imaging showed progressive cerebral atrophy in both patients, and 1 patient had microcephaly and hypotonia. The patients were severely disabled with little or no eye contact or head control, and inability to sit, walk, or talk.
The heterozygous mutations in the GNAO1 gene that were identified in patients with DEE17 by Nakamura et al. (2013) and Saitsu et al. (2016) occurred de novo.
In 4 unrelated girls with DEE17, Nakamura et al. (2013) identified 4 different de novo heterozygous mutations in the GNAO1 gene (139311.0001-139311.0004). One of the patients was somatic mosaic for the mutation. The mutations in the first 2 patients were found by whole-exome sequencing, and the mutations in the second 2 patients were found by direct sequencing of the GNAO1 gene in 367 individuals with epileptic encephalopathy. In vitro functional expression studies showed that 3 of the mutations caused impaired protein localization to the plasma membrane, and electrophysiologic analysis showed that 3 of the mutations caused decreased GNAO1-mediated inhibition of calcium currents by norepinephrine compared to wildtype. The findings suggested that aberrant GNAO1 signaling can cause multiple neurodevelopmental phenotypes, including epileptic encephalopathy and involuntary movements.
In 2 unrelated patients with DEE17, Saitsu et al. (2016) identified de novo heterozygous missense mutations in the GNAO1 gene (see, e.g., 139311.0004).
Kehrl et al. (2014) found that mutant mice heterozygous for a G184S mutation in the Gnao1 gene died in the perinatal period or early in life due to sudden death associated with severe seizures and/or increased frequency of interictal epileptiform discharges. Homozygous mutant mice were essentially nonviable. Heterozygous mice showed enhanced sensitivity to seizure kindling with a GABA antagonist compared to controls. Heterozygous knockout mice, representing a loss of function, did not show such a phenotype, suggesting that the G184S mutation results in a gain of function. Kehrl et al. (2014) noted that several studies have shown that the G184S allele results in a gain-of-function effect and suggested that DEE17 may also result from a gain-of-function mechanism.
Kehrl, J. M., Sahaya, K., Dalton, H. M., Charbeneau, R. A., Kohut, K. T., Gilbert, K., Pelz, M. C., Parent, J., Neubig, R. R. Gain-of-function mutation in Gnao1: a murine model of epileptiform encephalopathy (EIEE17)? Mammalian Genome 25: 202-210, 2014. [PubMed: 24700286] [Full Text: https://doi.org/10.1007/s00335-014-9509-z]
Nakamura, K., Kodera, H., Akita, T., Shiina, M., Kato, M., Hoshino, H., Terashima, H., Osaka, H., Nakamura, S., Tohyama, J., Kumada, T., Furukawa, T., and 14 others. De novo mutations in GNAO1, encoding a G-alpha-o subunit of heterotrimeric G proteins, cause epileptic encephalopathy. Am. J. Hum. Genet. 93: 496-505, 2013. [PubMed: 23993195] [Full Text: https://doi.org/10.1016/j.ajhg.2013.07.014]
Saitsu, H., Fukai, R., Ben-Zeev, B., Sakai, Y., Mimaki, M., Okamoto, N., Suzuki, Y., Monden, Y., Saito, H., Tziperman, B., Torio, M., Akamine, S., and 10 others. Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay. Europ. J. Hum. Genet. 24: 129-134, 2016. [PubMed: 25966631] [Full Text: https://doi.org/10.1038/ejhg.2015.92]
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