#619317
Table of Contents
A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-6B (DEE6B) is caused by heterozygous mutation in the SCN1A gene (182389) on chromosome 2q24.
Heterozygous mutation in the SCN1A gene also causes Dravet syndrome (DEE6A; 607208), which has overlapping but less severe features.
Developmental and epileptic encephalopathy-6B (DEE6B) is a severe neurodevelopmental disorder characterized by early-infantile seizure onset, profoundly impaired intellectual development, and a hyperkinetic movement disorder. Brain imaging usually shows progressive atrophy and other abnormalities (summary by Sadleir et al., 2017).
Ohashi et al. (2014) reported a 6-year-old Japanese girl, born of unrelated parents, who presented with multifocal seizures at 2 to 3 months of age. The seizures evolved to frequent episodes of hyperthermia-induced status epilepticus. Around 6 months of age, she developed a hyperkinetic movement disorder with sudden jerky movements resembling chorea and ballismus, as well as hand stereotypies. She had profound developmental delay with poor overall growth, inability to speak, sit, or walk, spastic quadriplegia, and no purposeful hand movements. Brain imaging showed progressive cortical and white matter atrophy, thin corpus callosum, and impaired myelination. She had mild nonspecific dysmorphic features. The authors noted that the phenotype was severe and atypical for Dravet syndrome.
Sadleir et al. (2017) reported 9 unrelated children, ranging from 3 to 12 years of age, with a severe epileptic encephalopathy. Two of the patients (patients 3 and 4) were previously reported by Dhamija et al. (2014). The 9 patients presented with various types of seizures at a mean age of 9 weeks (range 6 to 12 weeks) after normal early development. Seizure types included infantile spasms, tonic-clonic, hemiclonic, myoclonic, and tonic; 8 patients had episodes of status epilepticus. Several had seizures associated with fever or illness; most seizures were intractable to multiple medications. EEG showed multifocal discharges, generalized spike and slow waves, and diffuse background slowing. Brain imaging showed multiple variable abnormalities, including generalized cerebral atrophy, dysmorphic corpus callosum, small hippocampus, and progressive white matter abnormalities. All had profoundly impaired development, with inability to walk independently, absent speech, and poor eye contact; most were tube-fed. Periods of neurologic regression were also observed. Other prominent features included axial hypotonia, limb hypertonia, dystonia, choreoathetosis, orofacial myoclonus or hyperkinesia, nystagmus, ataxia, and generalized or multifocal myoclonic movements. A few patients had nonspecific dysmorphic features, such as microcephaly, hypertelorism, and scoliosis. One patient died at age 10 years. In their paper, Dhamija et al. (2014) found subtle sleep disturbances in their patients with SCN1A mutations.
Harkin et al. (2007) reported a 5-year-old patient (patient 78) with onset of seizures at 2 months of age. The patient had severely impaired intellectual development and increased muscle tone. Another patient (patient 61) with DEE6B was noted to have severe myoclonic epilepsy of infancy (SMEI)-borderland (SMEB, which refers to patients who lack several of the key features of SMEI such as myoclonic seizures or generalized spike-wave activity), but clinical details were limited.
The heterozygous mutations in the SCN1A gene that were identified in patients with DEE6B by Sadleir et al. (2017) occurred de novo.
In a 6-year-old Japanese girl with DEE6B, Ohashi et al. (2014) identified a de novo heterozygous missense mutation in the SCN1A gene (V422L; 182389.0025). The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project or in 408 in-house Japanese controls. Functional studies of the variant were not performed.
In 8 unrelated patients with DEE6B, Sadleir et al. (2017) identified a de novo recurrent heterozygous missense mutation in the SCN1A gene (T226M; 182389.0026). Another patient (patient 9) carried a de novo heterozygous P1345S mutation (182389.0027). Functional studies of the variants were not performed, but the authors speculated a gain-of-function effect.
In a 5-year-old patient (patient 78) with DEE6B, Harkin et al. (2007) identified a de novo heterozygous T226M mutation in the SCN1A gene. Another patient (patient 61) also carried this mutation. Functional studies of the variant were not performed. The patients were part of a cohort of 188 patients with DEE who were examined for mutations in the SCN1A gene.
Dhamija, R., Erickson, M. K., St. Louis, E. K., Wirrell, E., Kotagal, S. Sleep abnormalities in children with Dravet syndrome. Pediat. Neurol. 50: 474-478, 2014. [PubMed: 24656210, related citations] [Full Text]
Harkin, L. A., McMahon, J. M., Iona, X., Dibbens, L., Pelekanos, J. T., Zuberi, S. M., Sadleir, L. G., Andermann, E., Gill, D., Farrell, K., Connolly, M., Stanley, T., and 12 others. The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain 130: 843-852, 2007. [PubMed: 17347258, related citations] [Full Text]
Ohashi, T., Akasaka, N., Kobayashi, Y., Magara, S., Kawashima, H., Matsumoto, N., Saitsu, H., Tohyama, J. Infantile epileptic encephalopathy with a hyperkinetic movement disorder and hand stereotypies associated with a novel SCN1A mutation. Epileptic Disord. 16: 208-212, 2014. [PubMed: 24776920, related citations] [Full Text]
Sadleir, L. G., Mountier, E. I., Gill, D., Davis, S., Joshi, C., DeVile, C., Kurian, M. A., Mandelstam, S., Wirrell, E., Nickels, K. C., Murali, H. R., Carvill, G., Myers, C. T., Mefford, H. C., Scheffer, I. E. Not all SCN1A epileptic encephalopathies are Dravet syndrome: early profound thr226met phenotype. Neurology 89: 1035-1042, 2017. [PubMed: 28794249, related citations] [Full Text]
ORPHA: 442835; DO: 0070379;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
2q24.3 | Developmental and epileptic encephalopathy 6B, non-Dravet | 619317 | Autosomal dominant | 3 | SCN1A | 182389 |
A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-6B (DEE6B) is caused by heterozygous mutation in the SCN1A gene (182389) on chromosome 2q24.
Heterozygous mutation in the SCN1A gene also causes Dravet syndrome (DEE6A; 607208), which has overlapping but less severe features.
Developmental and epileptic encephalopathy-6B (DEE6B) is a severe neurodevelopmental disorder characterized by early-infantile seizure onset, profoundly impaired intellectual development, and a hyperkinetic movement disorder. Brain imaging usually shows progressive atrophy and other abnormalities (summary by Sadleir et al., 2017).
Ohashi et al. (2014) reported a 6-year-old Japanese girl, born of unrelated parents, who presented with multifocal seizures at 2 to 3 months of age. The seizures evolved to frequent episodes of hyperthermia-induced status epilepticus. Around 6 months of age, she developed a hyperkinetic movement disorder with sudden jerky movements resembling chorea and ballismus, as well as hand stereotypies. She had profound developmental delay with poor overall growth, inability to speak, sit, or walk, spastic quadriplegia, and no purposeful hand movements. Brain imaging showed progressive cortical and white matter atrophy, thin corpus callosum, and impaired myelination. She had mild nonspecific dysmorphic features. The authors noted that the phenotype was severe and atypical for Dravet syndrome.
Sadleir et al. (2017) reported 9 unrelated children, ranging from 3 to 12 years of age, with a severe epileptic encephalopathy. Two of the patients (patients 3 and 4) were previously reported by Dhamija et al. (2014). The 9 patients presented with various types of seizures at a mean age of 9 weeks (range 6 to 12 weeks) after normal early development. Seizure types included infantile spasms, tonic-clonic, hemiclonic, myoclonic, and tonic; 8 patients had episodes of status epilepticus. Several had seizures associated with fever or illness; most seizures were intractable to multiple medications. EEG showed multifocal discharges, generalized spike and slow waves, and diffuse background slowing. Brain imaging showed multiple variable abnormalities, including generalized cerebral atrophy, dysmorphic corpus callosum, small hippocampus, and progressive white matter abnormalities. All had profoundly impaired development, with inability to walk independently, absent speech, and poor eye contact; most were tube-fed. Periods of neurologic regression were also observed. Other prominent features included axial hypotonia, limb hypertonia, dystonia, choreoathetosis, orofacial myoclonus or hyperkinesia, nystagmus, ataxia, and generalized or multifocal myoclonic movements. A few patients had nonspecific dysmorphic features, such as microcephaly, hypertelorism, and scoliosis. One patient died at age 10 years. In their paper, Dhamija et al. (2014) found subtle sleep disturbances in their patients with SCN1A mutations.
Harkin et al. (2007) reported a 5-year-old patient (patient 78) with onset of seizures at 2 months of age. The patient had severely impaired intellectual development and increased muscle tone. Another patient (patient 61) with DEE6B was noted to have severe myoclonic epilepsy of infancy (SMEI)-borderland (SMEB, which refers to patients who lack several of the key features of SMEI such as myoclonic seizures or generalized spike-wave activity), but clinical details were limited.
The heterozygous mutations in the SCN1A gene that were identified in patients with DEE6B by Sadleir et al. (2017) occurred de novo.
In a 6-year-old Japanese girl with DEE6B, Ohashi et al. (2014) identified a de novo heterozygous missense mutation in the SCN1A gene (V422L; 182389.0025). The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project or in 408 in-house Japanese controls. Functional studies of the variant were not performed.
In 8 unrelated patients with DEE6B, Sadleir et al. (2017) identified a de novo recurrent heterozygous missense mutation in the SCN1A gene (T226M; 182389.0026). Another patient (patient 9) carried a de novo heterozygous P1345S mutation (182389.0027). Functional studies of the variants were not performed, but the authors speculated a gain-of-function effect.
In a 5-year-old patient (patient 78) with DEE6B, Harkin et al. (2007) identified a de novo heterozygous T226M mutation in the SCN1A gene. Another patient (patient 61) also carried this mutation. Functional studies of the variant were not performed. The patients were part of a cohort of 188 patients with DEE who were examined for mutations in the SCN1A gene.
Dhamija, R., Erickson, M. K., St. Louis, E. K., Wirrell, E., Kotagal, S. Sleep abnormalities in children with Dravet syndrome. Pediat. Neurol. 50: 474-478, 2014. [PubMed: 24656210] [Full Text: https://doi.org/10.1016/j.pediatrneurol.2014.01.017]
Harkin, L. A., McMahon, J. M., Iona, X., Dibbens, L., Pelekanos, J. T., Zuberi, S. M., Sadleir, L. G., Andermann, E., Gill, D., Farrell, K., Connolly, M., Stanley, T., and 12 others. The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain 130: 843-852, 2007. [PubMed: 17347258] [Full Text: https://doi.org/10.1093/brain/awm002]
Ohashi, T., Akasaka, N., Kobayashi, Y., Magara, S., Kawashima, H., Matsumoto, N., Saitsu, H., Tohyama, J. Infantile epileptic encephalopathy with a hyperkinetic movement disorder and hand stereotypies associated with a novel SCN1A mutation. Epileptic Disord. 16: 208-212, 2014. [PubMed: 24776920] [Full Text: https://doi.org/10.1684/epd.2014.0649]
Sadleir, L. G., Mountier, E. I., Gill, D., Davis, S., Joshi, C., DeVile, C., Kurian, M. A., Mandelstam, S., Wirrell, E., Nickels, K. C., Murali, H. R., Carvill, G., Myers, C. T., Mefford, H. C., Scheffer, I. E. Not all SCN1A epileptic encephalopathies are Dravet syndrome: early profound thr226met phenotype. Neurology 89: 1035-1042, 2017. [PubMed: 28794249] [Full Text: https://doi.org/10.1212/WNL.0000000000004331]
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