Alternative titles; symbols
SNOMEDCT: 784342008; ORPHA: 352582, 352587;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p13.3 | Myoclonic epilepsy, infantile, familial | 605021 | Autosomal recessive | 3 | TBC1D24 | 613577 |
A number sign (#) is used with this entry because familial infantile myoclonic epilepsy is caused by homozygous or compound heterozygous mutation in the TBC1D24 gene (613577) on chromosome 16p13.
Mutation in the TBC1D24 gene can also cause developmental and epileptic encephalopathy-16 (DEE16; 615338), a more severe disorder.
Zara et al. (2000) studied a large Italian pedigree segregating a recessive idiopathic myoclonic epilepsy that started in early infancy and manifest as myoclonic seizures, febrile convulsions, and tonic-clonic seizures. There was a favorable response to antiepileptic medication, and intellectual and neurologic development was normal.
Clinical Variability
Corbett et al. (2010) reported a consanguineous Arab family from northern Israel with early-onset seizures and intellectual disability. Affected individuals had focal seizures with prominent eye blinking and facial and limb jerking beginning around 2 months of age. Generalized convulsive seizures also occurred. The disorder persisted throughout life but could be controlled by antiepileptic medication. Some children had mildly delayed early motor and speech development, and as adults, they showed borderline to moderate intellectual disability associated with mild dysarthria and ataxia. Brain MRI suggested abnormal cortical thickening most obvious in the anteromesial frontal areas.
Afawi et al. (2013) reported the clinical and neuroradiologic features of 4 of the Arab sibs with early-onset seizures and intellectual disability reported by Corbett et al. (2010). The patients ranged in age from 23 to 40 years. All had onset of eye blinking or twitching at 2 months of age and had seizures throughout life, with variably good response to medication. The seizures tended to be focal, with a perirolandic or perisylvian origin; convulsive seizures occurred infrequently. All had delayed psychomotor development, and 2 were unable to run. Additional features included cerebellar signs such as dysarthria, clumsiness, and abnormal gait. Interictal EEG showed mild slowing of background rhythms. Brain MRI of 2 patients showed atrophy of the cerebellar ansiform lobule with signal abnormalities in the cortical and subcortical white matter. There was also cerebral cortical thickening and blurring of the gray/white matter interface. One patient had right hippocampal sclerosis. Afawi et al. (2013) noted that the phenotype in this Arab family differed from that reported by Zara et al. (2000).
By linkage analysis, Zara et al. (2000) mapped the disease locus to chromosome 16p13, with a maximum lod score of 4.48 for marker D16S3027 at a recombination fraction of 0.0. Haplotype analysis placed the critical region within a 3.4-cM interval between D16S3024 and D16S423. Zara et al. (2000) stated that this was the first report of an idiopathic epilepsy inherited as an autosomal recessive trait.
The transmission pattern of epilepsy in the families reported by Zara et al. (2000) and Corbett et al. (2010) indicated autosomal recessive inheritance.
In affected members of a large Italian family with infantile myoclonic epilepsy mapping to chromosome 16p13.3 (Zara et al., 2000), Falace et al. (2010) identified compound heterozygosity for 2 mutations in the TBC1D24 gene (613577.0001 and 613577.0002) that were shown to decrease protein function. The identification of these mutations suggested involvement of the ARF6 (600464)-dependent molecular pathway in the generation of brain hyperexcitability and seizures. The findings also suggested a critical role for TBC1D24 in developmentally regulated events essential for the morphologic and functional maturation of neuronal circuitry, disruption of which likely plays a role in the etiology of epileptic disorders.
By genomewide linkage analysis followed by candidate gene sequencing of a large consanguineous Arab family with seizures and intellectual disability, Corbett et al. (2010) found linkage to chromosome 16p13 and identified a homozygous loss-of-function mutation in the TBC1D24 gene (F251L; 613577.0003). The findings suggested that TBC1D24 plays an important role in normal human brain development.
Afawi, Z., Mandelstam, S., Korczyn, A. D., Kivity, S., Walid, S., Shalata, A., Oliver, K. L., Corbett, M., Gecz, J., Berkovic, S. F., Jackson, G. D. TBC1D24 mutation associated with focal epilepsy, cognitive impairment and a distinctive cerebro-cerebellar malformation. Epilepsy Res. 105: 240-244, 2013. [PubMed: 23517570] [Full Text: https://doi.org/10.1016/j.eplepsyres.2013.02.005]
Corbett, M. A., Bahlo, M., Jolly, L., Afawi, Z., Gardner, A. E., Oliver, K. L., Tan, S., Coffey, A., Mulley, J. C., Dibbens, L. M., Simri, W., Shalata, A., Kivity, S., Jackson, G. D., Berkovic, S. F., Gecz, J. A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24. Am. J. Hum. Genet. 87: 371-375, 2010. [PubMed: 20797691] [Full Text: https://doi.org/10.1016/j.ajhg.2010.08.001]
Falace, A., Filipello, F., La Padula, V., Vanni, N., Madia, F., De Pietri Tonelli, D., de Falco, F. A., Striano, P., Dagna Bricarelli, F., Minetti, C., Benfenati, F., Fassio, A., Zara, F. TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy. Am. J. Hum. Genet. 87: 365-370, 2010. [PubMed: 20727515] [Full Text: https://doi.org/10.1016/j.ajhg.2010.07.020]
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]