#615338
Table of Contents
A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-16 (DEE16) is caused by homozygous or compound heterozygous mutation in the TBC1D24 gene (613577) on chromosome 16p13.
Mutation in the TBC1D24 gene can also cause familial infantile myoclonic epilepsy (FIME; 605021), a less severe disorder.
Developmental and epileptic encephalopathy-16 (DEE16) is a severe autosomal recessive neurologic disorder characterized by the onset of seizures in the first weeks or months of life. Seizures can be of various types, are unresponsive to medication, last for long periods of time, and occur frequently. Affected infants show psychomotor regression or lack of psychomotor development, as well as other neurologic features such as extrapyramidal signs and hypotonia. Most die in childhood (summary by Duru et al., 2010 and Milh et al., 2013).
For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Duru et al. (2010) reported a large consanguineous Turkish kindred in which 5 children had severe early-onset epileptic encephalopathy. The patients presented in the first weeks or months of life with myoclonic seizures, focal seizures, and alternating and migrating jerks of the extremities. The seizures tended to be long-lasting and refractory to medication; status epilepticus also occurred in a few patients. All patients had severely impaired neurologic development and neurologic deterioration with permanent neurologic sequelae, including severe hypotonia, hemiparesis with pyramidal signs, and dystonia. The patients became inattentive to visual and acoustic stimuli as the disease progressed; most ended up in a vegetative state. One patient examined late in the disease course showed optic atrophy and macular degeneration. Brain imaging showed progressive atrophic changes in the brain and cerebellum and/or delayed myelination. All patients died by age 7 years. Duru et al. (2010) referred to the disorder as 'progressive myoclonic epilepsy with dystonia (PMED).'
Milh et al. (2013) reported 2 sisters, born of unrelated parents, with DEE16 manifest clinically as malignant migrating partial seizures of infancy (MMPSI). Both had onset of clonic seizures early in the second month of life that progressed to a 'stormy' phase, with almost continuous clonic migrating seizures and psychomotor regression. Both patients had severe neurologic impairment with axial hypotonia, no voluntary movement, no eye contact, and acquired microcephaly. Brain MRI at birth was normal in both patients, but later showed brain atrophy. One sib died of seizures at age 18 months.
Nakashima et al. (2019) reported a 16-month-old Japanese girl with DEE16. Auditory brainstem response testing in the neonatal period was consistent with profound hearing loss. At 2 months of age, she had attacks of apnea that required ventilator management; the attacks improved with treatment with midazolam. At 3 months of age, she began to show myoclonus and infantile spasms, and an interictal EEG at 4 months of age showed hypsarrhythmia. By 4 months of age, she developed superrefractory status epilepticus accompanied by apnea that presented monthly, which required ventilator management several times, subsequently leading to a tracheotomy at 10 months of age. Seizures were intractable despite use of several antiepileptic drugs. Eventually a combination of high-dose phenobarbital and potassium bromide was effective, with resolution of her apnea attacks and infantile spasms; however, myoclonus continued. Head MRI was normal up to 7 months of age but showed prominent cerebral atrophy at 13 months of age. The patient required tube feeding and lacked head control, ocular pursuit, and purposeful movements.
The transmission pattern of DEE16 in the families reported by Duru et al. (2010) and Milh et al. (2013) was consistent with autosomal recessive inheritance.
By linkage analysis of a large consanguineous Turkish kindred with early-onset epileptic encephalopathy, Duru et al. (2010) identified a locus on chromosome 16pter-p13.3 (maximum multipoint lod score of 7.83 between markers TTTA028 and D16S3-26; maximum 2-point lod score of 4.25 at D16S2618). Haplotype analysis delineated a 6.73-Mb candidate interval. Sequencing of the ATP6V0C gene (108745) did not reveal any pathogenic mutations. The locus overlapped that reported by Zara et al. (2000) for FIME, but Duru et al. (2010) noted that the phenotypes differed significantly in severity.
In affected members of a family with DEE16, previously reported by Duru et al. (2010), Guven and Tolun (2013) identified a homozygous truncating mutation in the TBC1D24 gene (613577.0004). The severity of the mutation paralleled the severity of the phenotype.
In 2 sisters with DEE16, Milh et al. (2013) identified compound heterozygous mutations in the TBC1D24 gene (F229S, 613577.0005 and C156X, 613577.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not present in several large exome databases and segregated with the disorder in the family.
By exome sequencing in a 16-month-old Japanese girl with DEE, Nakashima et al. (2019) identified a homozygous missense mutation in the TBC1D24 gene (E148K; 613577.0019). Sanger sequencing showed that her mother was heterozygous for the variant, but her father had only wildtype alleles. An analysis of loss-of-heterozygosity (LOH) showed an approximately 11-Mb LOH region encompassing TBC1D24. Analysis of variants in the region was consistent with maternal segmental uniparental disomy of chromosome 16.
Tona et al. (2019) found that mice homozygous for a frameshift mutation at ser324 of Tbc1d24, which was identical to the human mutation (613577.0004) associated with DEE16, exhibited spontaneous seizures and died by 3 weeks of age, resembling the human phenotype. Mutant mice also showed high-velocity wild running that was associated with seizures rather than auditory or vestibular defects. Wildtype mice express 2 Tbc1d24 splice variants that encode a short and a long isoform in neural tissues. Analysis of expression of the variants in wildtype mouse brain at various developmental stages revealed a postnatal switch from the short isoform to the long isoform, with predominant expression of the short isoform during embryonic and early postnatal development and predominant expression of the long isoform at and after postnatal day 7. Since the frameshift mutation affects only the long variant, the wildtype short isoform was still expressed in mutant mice, whereas the long isoform was not. In mutant mice, expression of the short isoform increased dramatically in brain during early postnatal development a few days before abrupt onset of seizures, implying that lack of the long isoform may have been related to onset of seizures. Further analysis identified Srrm3 as a regulator of Tbc1d24 alternative splicing in mouse brain, with Srrm3 supporting generation of the variant encoding the long isoform. Tbc1d24 was not spliced in mouse inner ear to generate the long isoform, providing a possible explanation as to why mice with the frameshift mutation had normal hearing.
Tona et al. (2020) generated mice compound heterozygous for the Ser324ThrfsTer3 (613577.0004) and His336GlnfsTer12 (613577.0010) Tbc1d24 mutations, found in patients with DEE16 and DOORS (220500), respectively, as a model for human syndromic deafness and found that these mutant mice recapitulated the human seizure phenotype but had normal hearing. Modeling of mouse and human TBC1D24 suggested that deafness arising from the TBC1D24 D70Y (613577.0012) mutation in human, but not in mouse, is related to evolutionary divergence in functional necessity and cell type-specific regulation of expression of human TBC1D24 compared with mouse Tbc1d24. In contrast, the S178L (613577.0014) mutation, which results in nonsyndromic deafness in humans but not in mice, had a stabilizing effect on the Tbc1d24 protein in mouse but not in human, providing a possible explanation for the interspecies phenotypic differences.
Duru, N., Iseri, S. A. U., Selcuk, N., Tolun, A. Early-onset progressive myoclonic epilepsy with dystonia mapping to 16pter-p13.3. J. Neurogenet. 24: 207-215, 2010. [PubMed: 21087195, related citations] [Full Text]
Guven, A., Tolun, A. TBC1D24 truncating mutation resulting in severe neurodegeneration. J. Med. Genet. 50: 199-202, 2013. [PubMed: 23343562, related citations] [Full Text]
Milh, M., Falace, A., Villeneuve, N., Vanni, N., Cacciagli, P., Assereto, S., Nabbout, R., Benfenati, F., Zara, F., Chabrol, B., Villard, L., Fassio, A. Novel compound heterozygous mutations in TBC1D24 cause familial malignant migrating partial seizures of infancy. Hum. Mutat. 34: 869-872, 2013. [PubMed: 23526554, related citations] [Full Text]
Nakashima, M., Negishi, Y., Hori, I., Hattori, A., Saitoh, S., Saitsu, H. A case of early-onset epileptic encephalopathy with a homozygous TBC1D24 variant caused by uniparental isodisomy. Am. J. Med. Genet. 179A: 645-649, 2019. [PubMed: 30680869, related citations] [Full Text]
Tona, R., Chen, W., Nakano, Y., Reyes, L. D., Petralia, R. S., Wang, Y. X., Starost, M. F., Wafa, T. T., Morell, R. J., Cravedi, K. D., du Hoffmann, J., Miyoshi, T., and 9 others. The phenotypic landscape of a Tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy. Hum. Molec. Genet. 28: 1530-1547, 2019. [PubMed: 30602030, images, related citations] [Full Text]
Tona, R., Lopez, I. A., Fenollar-Ferrer, C., Faridi, R., Anselmi, C., Khan, A. A., Shahzad, M., Morell, R. J., Gu, S., Hoa, M., Dong, L., Ishiyama, A., Belyantseva, I. A., Riazuddin, S., Friedman, T. B. Mouse models of human pathogenic variants of TBC1D24 associated with non-syndromic deafness DFNB86 and DFNA65 and syndromes involving deafness. Genes 11: 1122, 2020. [PubMed: 32987832, images, related citations] [Full Text]
Zara, F., Gennaro, E., Stabile, M., Carbone, I., Malacarne, M., Majello, L., Santangelo, R., Antonio de Falco, F., Bricarelli, F. D. Mapping of a locus for a familial autosomal recessive idiopathic myoclonic epilepsy of infancy to chromosome 16p13. Am. J. Hum. Genet. 66: 1552-1557, 2000. Note: Erratum: Am. J. Hum. Genet. 66: 1728 only, 2000. [PubMed: 10741954, related citations] [Full Text]
Alternative titles; symbols
ORPHA: 293181, 352596; DO: 0080449;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p13.3 | Developmental and epileptic encephalopathy 16 | 615338 | Autosomal recessive | 3 | TBC1D24 | 613577 |
A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-16 (DEE16) is caused by homozygous or compound heterozygous mutation in the TBC1D24 gene (613577) on chromosome 16p13.
Mutation in the TBC1D24 gene can also cause familial infantile myoclonic epilepsy (FIME; 605021), a less severe disorder.
Developmental and epileptic encephalopathy-16 (DEE16) is a severe autosomal recessive neurologic disorder characterized by the onset of seizures in the first weeks or months of life. Seizures can be of various types, are unresponsive to medication, last for long periods of time, and occur frequently. Affected infants show psychomotor regression or lack of psychomotor development, as well as other neurologic features such as extrapyramidal signs and hypotonia. Most die in childhood (summary by Duru et al., 2010 and Milh et al., 2013).
For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Duru et al. (2010) reported a large consanguineous Turkish kindred in which 5 children had severe early-onset epileptic encephalopathy. The patients presented in the first weeks or months of life with myoclonic seizures, focal seizures, and alternating and migrating jerks of the extremities. The seizures tended to be long-lasting and refractory to medication; status epilepticus also occurred in a few patients. All patients had severely impaired neurologic development and neurologic deterioration with permanent neurologic sequelae, including severe hypotonia, hemiparesis with pyramidal signs, and dystonia. The patients became inattentive to visual and acoustic stimuli as the disease progressed; most ended up in a vegetative state. One patient examined late in the disease course showed optic atrophy and macular degeneration. Brain imaging showed progressive atrophic changes in the brain and cerebellum and/or delayed myelination. All patients died by age 7 years. Duru et al. (2010) referred to the disorder as 'progressive myoclonic epilepsy with dystonia (PMED).'
Milh et al. (2013) reported 2 sisters, born of unrelated parents, with DEE16 manifest clinically as malignant migrating partial seizures of infancy (MMPSI). Both had onset of clonic seizures early in the second month of life that progressed to a 'stormy' phase, with almost continuous clonic migrating seizures and psychomotor regression. Both patients had severe neurologic impairment with axial hypotonia, no voluntary movement, no eye contact, and acquired microcephaly. Brain MRI at birth was normal in both patients, but later showed brain atrophy. One sib died of seizures at age 18 months.
Nakashima et al. (2019) reported a 16-month-old Japanese girl with DEE16. Auditory brainstem response testing in the neonatal period was consistent with profound hearing loss. At 2 months of age, she had attacks of apnea that required ventilator management; the attacks improved with treatment with midazolam. At 3 months of age, she began to show myoclonus and infantile spasms, and an interictal EEG at 4 months of age showed hypsarrhythmia. By 4 months of age, she developed superrefractory status epilepticus accompanied by apnea that presented monthly, which required ventilator management several times, subsequently leading to a tracheotomy at 10 months of age. Seizures were intractable despite use of several antiepileptic drugs. Eventually a combination of high-dose phenobarbital and potassium bromide was effective, with resolution of her apnea attacks and infantile spasms; however, myoclonus continued. Head MRI was normal up to 7 months of age but showed prominent cerebral atrophy at 13 months of age. The patient required tube feeding and lacked head control, ocular pursuit, and purposeful movements.
The transmission pattern of DEE16 in the families reported by Duru et al. (2010) and Milh et al. (2013) was consistent with autosomal recessive inheritance.
By linkage analysis of a large consanguineous Turkish kindred with early-onset epileptic encephalopathy, Duru et al. (2010) identified a locus on chromosome 16pter-p13.3 (maximum multipoint lod score of 7.83 between markers TTTA028 and D16S3-26; maximum 2-point lod score of 4.25 at D16S2618). Haplotype analysis delineated a 6.73-Mb candidate interval. Sequencing of the ATP6V0C gene (108745) did not reveal any pathogenic mutations. The locus overlapped that reported by Zara et al. (2000) for FIME, but Duru et al. (2010) noted that the phenotypes differed significantly in severity.
In affected members of a family with DEE16, previously reported by Duru et al. (2010), Guven and Tolun (2013) identified a homozygous truncating mutation in the TBC1D24 gene (613577.0004). The severity of the mutation paralleled the severity of the phenotype.
In 2 sisters with DEE16, Milh et al. (2013) identified compound heterozygous mutations in the TBC1D24 gene (F229S, 613577.0005 and C156X, 613577.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not present in several large exome databases and segregated with the disorder in the family.
By exome sequencing in a 16-month-old Japanese girl with DEE, Nakashima et al. (2019) identified a homozygous missense mutation in the TBC1D24 gene (E148K; 613577.0019). Sanger sequencing showed that her mother was heterozygous for the variant, but her father had only wildtype alleles. An analysis of loss-of-heterozygosity (LOH) showed an approximately 11-Mb LOH region encompassing TBC1D24. Analysis of variants in the region was consistent with maternal segmental uniparental disomy of chromosome 16.
Tona et al. (2019) found that mice homozygous for a frameshift mutation at ser324 of Tbc1d24, which was identical to the human mutation (613577.0004) associated with DEE16, exhibited spontaneous seizures and died by 3 weeks of age, resembling the human phenotype. Mutant mice also showed high-velocity wild running that was associated with seizures rather than auditory or vestibular defects. Wildtype mice express 2 Tbc1d24 splice variants that encode a short and a long isoform in neural tissues. Analysis of expression of the variants in wildtype mouse brain at various developmental stages revealed a postnatal switch from the short isoform to the long isoform, with predominant expression of the short isoform during embryonic and early postnatal development and predominant expression of the long isoform at and after postnatal day 7. Since the frameshift mutation affects only the long variant, the wildtype short isoform was still expressed in mutant mice, whereas the long isoform was not. In mutant mice, expression of the short isoform increased dramatically in brain during early postnatal development a few days before abrupt onset of seizures, implying that lack of the long isoform may have been related to onset of seizures. Further analysis identified Srrm3 as a regulator of Tbc1d24 alternative splicing in mouse brain, with Srrm3 supporting generation of the variant encoding the long isoform. Tbc1d24 was not spliced in mouse inner ear to generate the long isoform, providing a possible explanation as to why mice with the frameshift mutation had normal hearing.
Tona et al. (2020) generated mice compound heterozygous for the Ser324ThrfsTer3 (613577.0004) and His336GlnfsTer12 (613577.0010) Tbc1d24 mutations, found in patients with DEE16 and DOORS (220500), respectively, as a model for human syndromic deafness and found that these mutant mice recapitulated the human seizure phenotype but had normal hearing. Modeling of mouse and human TBC1D24 suggested that deafness arising from the TBC1D24 D70Y (613577.0012) mutation in human, but not in mouse, is related to evolutionary divergence in functional necessity and cell type-specific regulation of expression of human TBC1D24 compared with mouse Tbc1d24. In contrast, the S178L (613577.0014) mutation, which results in nonsyndromic deafness in humans but not in mice, had a stabilizing effect on the Tbc1d24 protein in mouse but not in human, providing a possible explanation for the interspecies phenotypic differences.
Duru, N., Iseri, S. A. U., Selcuk, N., Tolun, A. Early-onset progressive myoclonic epilepsy with dystonia mapping to 16pter-p13.3. J. Neurogenet. 24: 207-215, 2010. [PubMed: 21087195] [Full Text: https://doi.org/10.3109/01677063.2010.514368]
Guven, A., Tolun, A. TBC1D24 truncating mutation resulting in severe neurodegeneration. J. Med. Genet. 50: 199-202, 2013. [PubMed: 23343562] [Full Text: https://doi.org/10.1136/jmedgenet-2012-101313]
Milh, M., Falace, A., Villeneuve, N., Vanni, N., Cacciagli, P., Assereto, S., Nabbout, R., Benfenati, F., Zara, F., Chabrol, B., Villard, L., Fassio, A. Novel compound heterozygous mutations in TBC1D24 cause familial malignant migrating partial seizures of infancy. Hum. Mutat. 34: 869-872, 2013. [PubMed: 23526554] [Full Text: https://doi.org/10.1002/humu.22318]
Nakashima, M., Negishi, Y., Hori, I., Hattori, A., Saitoh, S., Saitsu, H. A case of early-onset epileptic encephalopathy with a homozygous TBC1D24 variant caused by uniparental isodisomy. Am. J. Med. Genet. 179A: 645-649, 2019. [PubMed: 30680869] [Full Text: https://doi.org/10.1002/ajmg.a.61056]
Tona, R., Chen, W., Nakano, Y., Reyes, L. D., Petralia, R. S., Wang, Y. X., Starost, M. F., Wafa, T. T., Morell, R. J., Cravedi, K. D., du Hoffmann, J., Miyoshi, T., and 9 others. The phenotypic landscape of a Tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy. Hum. Molec. Genet. 28: 1530-1547, 2019. [PubMed: 30602030] [Full Text: https://doi.org/10.1093/hmg/ddy445]
Tona, R., Lopez, I. A., Fenollar-Ferrer, C., Faridi, R., Anselmi, C., Khan, A. A., Shahzad, M., Morell, R. J., Gu, S., Hoa, M., Dong, L., Ishiyama, A., Belyantseva, I. A., Riazuddin, S., Friedman, T. B. Mouse models of human pathogenic variants of TBC1D24 associated with non-syndromic deafness DFNB86 and DFNA65 and syndromes involving deafness. Genes 11: 1122, 2020. [PubMed: 32987832] [Full Text: https://doi.org/10.3390/genes11101122]
Zara, F., Gennaro, E., Stabile, M., Carbone, I., Malacarne, M., Majello, L., Santangelo, R., Antonio de Falco, F., Bricarelli, F. D. Mapping of a locus for a familial autosomal recessive idiopathic myoclonic epilepsy of infancy to chromosome 16p13. Am. J. Hum. Genet. 66: 1552-1557, 2000. Note: Erratum: Am. J. Hum. Genet. 66: 1728 only, 2000. [PubMed: 10741954] [Full Text: https://doi.org/10.1086/302876]
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