#612164
Table of Contents
A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-4 (DEE4) is caused by heterozygous mutation in the STXBP1 gene (602926) on chromosome 9q34. One family has been reported with a homozygous mutation in the STXBP1 gene.
Developmental and epileptic encephalopathy-4 (DEE4) is a neurologic disorder characterized by the onset of tonic seizures in early infancy (usually in first months of life). In most cases, seizures increase in frequency and become refractory. Affected individuals have profoundly impaired psychomotor development with poor head control, limited or no ability to walk, spastic quadriplegia, and poor or absent speech. Brain imaging may show cortical atrophy and hypomyelination. EEG studies in the more severe cases show a burst-suppression pattern, consistent with a clinical diagnosis of Ohtahara syndrome, and/or hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. Less severely affected individuals have later onset of seizures (summary by Saitsu et al., 2008; Hamdan et al., 2009).
For a general phenotypic description and a discussion of genetic heterogeneity of developmental and epileptic encephalopathy, see 308350.
Saitsu et al. (2008) reported 4 unrelated Japanese patients who presented with tonic seizures between 10 days and 3 months of age. All patients had a burst-suppression pattern on EEG, consistent with a clinical diagnosis of Ohtahara syndrome; several patients showed hypsarrhythmia on EEG, consistent with West syndrome. Three patients continued to have refractory seizures, whereas the patient with onset at 10 days had remission of seizures at 3 months. All 4 patients had severe to profoundly impaired psychomotor development with intellectual disability, poor motor and language skills, and spastic di- or quadriplegia. Brain imaging showed cerebral atrophy and delayed myelination.
Deprez et al. (2010) identified heterozygous truncating mutations in the STXBP1 gene in 6 (5.7%) of 106 patients with various types of early-onset epileptic encephalopathies. Variable seizures first occurred between 3 days and 4.5 months of life, and all patients subsequently had severe to profound mental retardation. Three patients developed hypsarrhythmia by 5 months of age, consistent with a clinical diagnosis of West syndrome. Four patients showed an initial favorable response to vigabatrin and became seizure-free later in childhood even without medication, but 2 had continued seizures despite treatment with antiepileptic medications. None of the patients had a burst-suppression pattern on EEG, as had been observed in the patients reported by Saitsu et al. (2008). Three patients were wheelchair-bound due to hypotonia or dyskinesias. Five patients had proven de novo mutations; parental DNA from the sixth patient was not available. Deprez et al. (2010) emphasized the phenotypic variability in the severity of the epilepsy, but noted that all patients had mental retardation, which suggested that neurodegeneration is an intrinsic property of the disorder.
Clinical Variability
Hamdan et al. (2009) reported 2 unrelated French Canadian patients with developmental delay associated with early-onset seizures. Patient 1 was a 27-year-old woman who developed partial complex seizures at age 6 weeks. Patient 2 was a 15-year-old girl who developed partial complex seizures at 2 years, 9 months of age. Both patients had severely impaired intellectual development, hypotonia, and tremor. Brain imaging in both patients was normal; burst-suppression and hypsarrhythmia were not observed. Hamdan et al. (2009) noted that the phenotypes of these patients were slightly different from that reported by Saitsu et al. (2008), with later onset of seizures and some response to antiepileptic medication.
Carvill et al. (2014) reported 3 unrelated patients with DEE4, who were clinically diagnosed with Dravet syndrome. The patients had onset of seizures between 6 and 12 months of age, which the authors noted was later than other patients with this disorder. Seizure types included tonic-clonic, absence, atonic, myoclonic, focal dyscognitive, and status epilepticus. The seizures were fever-sensitive. Two patients showed developmental regression and had severely impaired intellectual development, whereas the third patient had learning difficulties. EEG in the patients with more severe outcomes showed multifocal discharges, whereas EEG in the patient with mild features was normal. One severely affected patient showed cerebral atrophy on brain MRI, and the other severely affected patient died at age 11 years.
Lammertse et al. (2020) reported 2 female sibs, aged 23 and 26 years, with DEE4. The 23-year-old patient presented from birth with refractory epilepsy, developmental delay, impaired intellectual development, and behavioral abnormalities. The 26-year-old patient was similarly affected but had more moderately impaired intellectual development. The seizure phenotype for both patients was clinically Lennox-Gastaut syndrome.
The heterozygous mutations in the STXBP1 gene that were identified in patients with DEE4 by Saitsu et al. (2008) occurred de novo.
Saitsu et al. (2011) reported a girl with DEE4 who inherited a heterozygous truncating mutation in the STXBP1 gene from her unaffected father, who was somatic mosaic for the mutation. Cloning of PCR products amplified with the paternal DNA samples extracted from his blood, saliva, buccal cells, and nails suggested that 5.3%, 8.7%, 11.9%, and 16.9% of alleles harbored the mutation, respectively. Although sperm was not tested, the father likely carried the mutation in the mosaic state in his germ cells. Saitsu et al. (2011) emphasized the importance of the finding for genetic counseling, as recurrence of the disorder in this family is possible.
Lammertse et al. (2020) reported a family with DEE4 with a homozygous mutation in the STXBP1 gene.
In a 29-month-old Japanese girl with early-onset epileptic encephalopathy and cerebral hypomyelination (Tohyama et al., 2008), Saitsu et al. (2008) identified a de novo heterozygous 2.0-Mb microdeletion at chromosome 9q33.3-q34.11 including the STXBP1 gene. Forty other genes mapped within the deletion. Saitsu et al. (2010) later reported that the microdeletion in this patient was 2.25 Mb long and encompassed both the STXBP1 and SPTAN1 (182810) genes. Saitsu et al. (2010) hypothesized that this patient's phenotype was due more to haploinsufficiency of STXBP1, but that haploinsufficiency of SPTAN1 may have had some effect on myelination, because dominant-negative SPTAN1 mutations cause a similar phenotype with hypomyelination and widespread brain atrophy (DEE5; 613477). The patient was originally reported by Tohyama et al. (2008) as presenting with tonic seizures, tremulous arm movements, and oral automatisms at 45 days of age. The pregnancy resulted from in vivo fertilization; her dizygotic twin was unaffected. She continued to have seizures with increased frequency; EEG showed a suppression-burst pattern and hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. She had severely delayed psychomotor development with no language acquisition, inability to sit, spastic quadriplegia, poor visual attention, and poor overall growth with microcephaly (-3.9 SD). Brain MRI showed diffuse hypomyelination, cortical atrophy, and a thin corpus callosum.
Using array CGH, Saitsu et al. (2012) identified 2 different de novo heterozygous deletions involving the STXBP1 gene in 2 (7.1%) of 28 patients with cryptogenic early-onset epileptic encephalopathy. One was a 4.6-kb deletion involving only exon 4 of the STXBP1 gene, and the other was a 2.85-Mb deletion involving 70 genes, including both STXBP1 and SPTAN1. The patient with the smaller deletion developed tonic and myoclonic seizures on day 32 of life. EEG showed a suppression-burst pattern, and brain MRI was normal. Seizure frequency was reduced with high-dose phenobarbital. The patient with the larger deletion had multiple anomalies, including low birth weight, cleft lip and palate, ventricular septal defect, small penis, thin corpus callosum, and small cerebellum. Seizures with suppression-burst pattern on EEG developed around age 1 month. At 19 months, the child showed spastic quadriplegia and profound intellectual disability. Analysis of the breakpoints in both patients suggested that nonhomologous recombination led to the rearrangements.
In 4 unrelated Japanese patients with DEE4, Saitsu et al. (2008) identified heterozygous missense mutations in the STXBP1 gene (602926.0001-602926.0004). The mutations were proven to occur de novo in 3 patients. All mutations occurred in the hydrophobic core of the protein and were predicted to result in destabilization and disruption of protein structure. In vitro studies of the mutant proteins suggested a tendency for aggregation. Saitsu et al. (2008) postulated that the mutations resulted in STXBP1 haploinsufficiency, causing impaired synaptic vesicle release and the DEE phenotype.
In 2 unrelated French Canadian patients with severe mental retardation and epilepsy, Hamdan et al. (2009) identified respective de novo heterozygous truncating mutations in the STXBP1 gene (602926.0005 and 602926.0006). The patients were ascertained from a larger group of 95 patients with idiopathic mental retardation.
In an 11-year-old boy with DEE4, who had a clinical diagnosis of Dravet syndrome but was negative for mutations in the SCN1A gene (182389), Carvill et al. (2014) identified a de novo heterozygous missense mutation in the STXBP1 gene (E283K; 602926.0008). The mutation was found by whole-exome sequencing. Targeted resequencing of 67 patients with a similar disorder identified 2 additional probands with de novo heterozygous missense mutations in the STXBP1 gene. Functional studies of the variants were not performed.
In 2 sibs with DEE4, Lammertse et al. (2020) identified a homozygous missense mutation in the STXBP1 gene (L446F; 602926.0009). The mother and an asymptomatic sib were heterozygous for the mutation; the father was not available for study. Expression of STXBP1 with the L446F mutation in STXBP1-null mouse neurons resulted in shorter dendrites and fewer synapses per dendrite compared to cells expressing wildtype STXBP1. Patch-clamp studies in the mutant cells demonstrated an increased evoked synaptic transmission and impaired recovery after high-frequency stimulation. This appeared to be due to an increased synaptic vesicle response after stimulation with a single action potential. Lammertse et al. (2020) concluded that the L446F mutation leads to a gain-of-function pathogenic mechanism.
In a review of clinical and molecular data from 271 patients with DEE4, Xian et al. (2022) identified 54 recurrent mutations in the STXBP1 gene. Sixteen of the mutations were identified in 5 or more patients, with the most common mutations being R406H (in 20 patients), R406C (in 20 patients), and R292H (in 18 patients). Compared to the entire cohort of patients, those with recurrent mutations did not show an overall phenotypic similarity. However, patients with R406H and R406C mutations were more likely to have a burst suppression pattern on EEG and spastic tetraplegia, and less likely to have ataxia, compared to the rest of the cohort. Additionally, patients with premature termination mutations or deletions in the STXBP1 gene were more likely to have infantile spasms, hypsarrhythmia on EEG, ataxia, hypotonia, and neonatal seizure onset compared to patients with missense mutations.
Carvill, G. L., Weckhuysen, S., McMahon, J. M., Hartmann, C., Moller, R. S., Hjalgrim, H., Cook, J., Geraghty, E., O'Roak, B. J., Petrou, S., Clarke, A., Gill, D., and 14 others. GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology 82: 1245-1253, 2014. [PubMed: 24623842, related citations] [Full Text]
Deprez, L., Weckhuysen, S., Holmgren, P., Suls, A., Van Dyck, T., Goossens, D., Del-Favero, J., Jansen, A., Verhaert, K., Lagae, L., Jordanova, A., Van Coster, R., Yendle, S., Berkovic, S. F., Scheffer, I., Ceulemans, B., De Jonghe, P. Clinical spectrum of early-onset epileptic encephalopathies associated with STXBP1 mutations. Neurology 75: 1159-1165, 2010. [PubMed: 20876469, related citations] [Full Text]
Hamdan, F. F., Piton, A., Gauthier, J., Lortie, A., Dubeau, F., Dobrzeniecka, S., Spiegelman, D., Noreau, A., Pellerin, S., Cote, M., Henrion, E., Fombonne, E., Mottron, L., Marineau, C., Drapeau, P., Lafreniere, R. G., Lacaille, J. C., Rouleau, G. A., Michaud, J. L. De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy. Ann. Neurol. 65: 748-753, 2009. [PubMed: 19557857, related citations] [Full Text]
Lammertse, H. C. A., van Berkel, A. A., Iacomino, M., Toonen, R. F., Striano, P., Gambardella, A., Verhage, M., Zara, F. Homozygous STXBP1 variant causes encephalopathy and gain-of-function in synaptic transmission. Brain 143: 441-451, 2020. [PubMed: 31855252, images, related citations] [Full Text]
Saitsu, H., Hoshino, H., Kato, M., Nishiyama, K., Okada, I., Yoneda, Y., Tsurusaki, Y., Doi, H., Miyake, N., Kubota, M., Hayasaka, K., Matsumoto, N. Paternal mosaicism of an STXBP1 mutation in OS. Clin. Genet. 80: 484-488, 2011. [PubMed: 21062273, related citations] [Full Text]
Saitsu, H., Kato, M., Mizuguchi, T., Hamada, K., Osaka, H., Tohyama, J., Uruno, K., Kumada, S., Nishiyama, K., Nishimura, A., Okada, I., Yoshimura, Y., Hirai, S., Kumada, T., Hayasaka, K., Fukuda, A., Ogata, K., Matsumoto, N. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nature Genet. 40: 782-788, 2008. [PubMed: 18469812, related citations] [Full Text]
Saitsu, H., Kato, M., Shimono, M., Senju, A., Tanabe, S., Kimura, T., Nishiyama, K., Yoneda, Y., Kondo, Y., Tsurusaki, Y., Doi, H., Miyake, N., Hayasaka, K., Matsumoto, N. Association of genomic deletions in the STXBP1 gene with Ohtahara syndrome. (Letter) Clin. Genet. 81: 399-402, 2012. [PubMed: 22211739, related citations] [Full Text]
Saitsu, H., Tohyama, J., Kumada, T., Egawa, K., Hamada, K., Okada, I., Mizuguchi, T., Osaka, H., Miyata, R., Furukawa, T., Haginoya, K., Hoshino, H., and 15 others. Dominant-negative mutations in alpha-II spectrin cause West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay. Am. J. Hum. Genet. 86: 881-891, 2010. [PubMed: 20493457, images, related citations] [Full Text]
Tohyama, J., Akasaka, N., Osaka, H., Maegaki, Y., Kato, M., Saito, N., Yamashita, S., Ohno, K. Early onset West syndrome with cerebral hypomyelination and reduced cerebral white matter. Brain Dev. 30: 349-355, 2008. [PubMed: 18065176, related citations] [Full Text]
Xian, J., Parthasarathy, S., Ruggiero, S. M., Balagura, G., Fitch, E., Helbig, K., Gan, J., Ganesan, S., Kaufman, M. C., Ellis, C. A., Lewis-Smith, D., Galer, P., and 42 others. Assessing the landscape of STXBP1-related disorders in 534 individuals. Brain 145: 1668-1683, 2022. [PubMed: 35190816, images, related citations] [Full Text]
Alternative titles; symbols
SNOMEDCT: 768666006; ORPHA: 1934, 33069, 599373; DO: 0080436;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9q34.11 | Developmental and epileptic encephalopathy 4 | 612164 | Autosomal dominant; Autosomal recessive | 3 | STXBP1 | 602926 |
A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-4 (DEE4) is caused by heterozygous mutation in the STXBP1 gene (602926) on chromosome 9q34. One family has been reported with a homozygous mutation in the STXBP1 gene.
Developmental and epileptic encephalopathy-4 (DEE4) is a neurologic disorder characterized by the onset of tonic seizures in early infancy (usually in first months of life). In most cases, seizures increase in frequency and become refractory. Affected individuals have profoundly impaired psychomotor development with poor head control, limited or no ability to walk, spastic quadriplegia, and poor or absent speech. Brain imaging may show cortical atrophy and hypomyelination. EEG studies in the more severe cases show a burst-suppression pattern, consistent with a clinical diagnosis of Ohtahara syndrome, and/or hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. Less severely affected individuals have later onset of seizures (summary by Saitsu et al., 2008; Hamdan et al., 2009).
For a general phenotypic description and a discussion of genetic heterogeneity of developmental and epileptic encephalopathy, see 308350.
Saitsu et al. (2008) reported 4 unrelated Japanese patients who presented with tonic seizures between 10 days and 3 months of age. All patients had a burst-suppression pattern on EEG, consistent with a clinical diagnosis of Ohtahara syndrome; several patients showed hypsarrhythmia on EEG, consistent with West syndrome. Three patients continued to have refractory seizures, whereas the patient with onset at 10 days had remission of seizures at 3 months. All 4 patients had severe to profoundly impaired psychomotor development with intellectual disability, poor motor and language skills, and spastic di- or quadriplegia. Brain imaging showed cerebral atrophy and delayed myelination.
Deprez et al. (2010) identified heterozygous truncating mutations in the STXBP1 gene in 6 (5.7%) of 106 patients with various types of early-onset epileptic encephalopathies. Variable seizures first occurred between 3 days and 4.5 months of life, and all patients subsequently had severe to profound mental retardation. Three patients developed hypsarrhythmia by 5 months of age, consistent with a clinical diagnosis of West syndrome. Four patients showed an initial favorable response to vigabatrin and became seizure-free later in childhood even without medication, but 2 had continued seizures despite treatment with antiepileptic medications. None of the patients had a burst-suppression pattern on EEG, as had been observed in the patients reported by Saitsu et al. (2008). Three patients were wheelchair-bound due to hypotonia or dyskinesias. Five patients had proven de novo mutations; parental DNA from the sixth patient was not available. Deprez et al. (2010) emphasized the phenotypic variability in the severity of the epilepsy, but noted that all patients had mental retardation, which suggested that neurodegeneration is an intrinsic property of the disorder.
Clinical Variability
Hamdan et al. (2009) reported 2 unrelated French Canadian patients with developmental delay associated with early-onset seizures. Patient 1 was a 27-year-old woman who developed partial complex seizures at age 6 weeks. Patient 2 was a 15-year-old girl who developed partial complex seizures at 2 years, 9 months of age. Both patients had severely impaired intellectual development, hypotonia, and tremor. Brain imaging in both patients was normal; burst-suppression and hypsarrhythmia were not observed. Hamdan et al. (2009) noted that the phenotypes of these patients were slightly different from that reported by Saitsu et al. (2008), with later onset of seizures and some response to antiepileptic medication.
Carvill et al. (2014) reported 3 unrelated patients with DEE4, who were clinically diagnosed with Dravet syndrome. The patients had onset of seizures between 6 and 12 months of age, which the authors noted was later than other patients with this disorder. Seizure types included tonic-clonic, absence, atonic, myoclonic, focal dyscognitive, and status epilepticus. The seizures were fever-sensitive. Two patients showed developmental regression and had severely impaired intellectual development, whereas the third patient had learning difficulties. EEG in the patients with more severe outcomes showed multifocal discharges, whereas EEG in the patient with mild features was normal. One severely affected patient showed cerebral atrophy on brain MRI, and the other severely affected patient died at age 11 years.
Lammertse et al. (2020) reported 2 female sibs, aged 23 and 26 years, with DEE4. The 23-year-old patient presented from birth with refractory epilepsy, developmental delay, impaired intellectual development, and behavioral abnormalities. The 26-year-old patient was similarly affected but had more moderately impaired intellectual development. The seizure phenotype for both patients was clinically Lennox-Gastaut syndrome.
The heterozygous mutations in the STXBP1 gene that were identified in patients with DEE4 by Saitsu et al. (2008) occurred de novo.
Saitsu et al. (2011) reported a girl with DEE4 who inherited a heterozygous truncating mutation in the STXBP1 gene from her unaffected father, who was somatic mosaic for the mutation. Cloning of PCR products amplified with the paternal DNA samples extracted from his blood, saliva, buccal cells, and nails suggested that 5.3%, 8.7%, 11.9%, and 16.9% of alleles harbored the mutation, respectively. Although sperm was not tested, the father likely carried the mutation in the mosaic state in his germ cells. Saitsu et al. (2011) emphasized the importance of the finding for genetic counseling, as recurrence of the disorder in this family is possible.
Lammertse et al. (2020) reported a family with DEE4 with a homozygous mutation in the STXBP1 gene.
In a 29-month-old Japanese girl with early-onset epileptic encephalopathy and cerebral hypomyelination (Tohyama et al., 2008), Saitsu et al. (2008) identified a de novo heterozygous 2.0-Mb microdeletion at chromosome 9q33.3-q34.11 including the STXBP1 gene. Forty other genes mapped within the deletion. Saitsu et al. (2010) later reported that the microdeletion in this patient was 2.25 Mb long and encompassed both the STXBP1 and SPTAN1 (182810) genes. Saitsu et al. (2010) hypothesized that this patient's phenotype was due more to haploinsufficiency of STXBP1, but that haploinsufficiency of SPTAN1 may have had some effect on myelination, because dominant-negative SPTAN1 mutations cause a similar phenotype with hypomyelination and widespread brain atrophy (DEE5; 613477). The patient was originally reported by Tohyama et al. (2008) as presenting with tonic seizures, tremulous arm movements, and oral automatisms at 45 days of age. The pregnancy resulted from in vivo fertilization; her dizygotic twin was unaffected. She continued to have seizures with increased frequency; EEG showed a suppression-burst pattern and hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. She had severely delayed psychomotor development with no language acquisition, inability to sit, spastic quadriplegia, poor visual attention, and poor overall growth with microcephaly (-3.9 SD). Brain MRI showed diffuse hypomyelination, cortical atrophy, and a thin corpus callosum.
Using array CGH, Saitsu et al. (2012) identified 2 different de novo heterozygous deletions involving the STXBP1 gene in 2 (7.1%) of 28 patients with cryptogenic early-onset epileptic encephalopathy. One was a 4.6-kb deletion involving only exon 4 of the STXBP1 gene, and the other was a 2.85-Mb deletion involving 70 genes, including both STXBP1 and SPTAN1. The patient with the smaller deletion developed tonic and myoclonic seizures on day 32 of life. EEG showed a suppression-burst pattern, and brain MRI was normal. Seizure frequency was reduced with high-dose phenobarbital. The patient with the larger deletion had multiple anomalies, including low birth weight, cleft lip and palate, ventricular septal defect, small penis, thin corpus callosum, and small cerebellum. Seizures with suppression-burst pattern on EEG developed around age 1 month. At 19 months, the child showed spastic quadriplegia and profound intellectual disability. Analysis of the breakpoints in both patients suggested that nonhomologous recombination led to the rearrangements.
In 4 unrelated Japanese patients with DEE4, Saitsu et al. (2008) identified heterozygous missense mutations in the STXBP1 gene (602926.0001-602926.0004). The mutations were proven to occur de novo in 3 patients. All mutations occurred in the hydrophobic core of the protein and were predicted to result in destabilization and disruption of protein structure. In vitro studies of the mutant proteins suggested a tendency for aggregation. Saitsu et al. (2008) postulated that the mutations resulted in STXBP1 haploinsufficiency, causing impaired synaptic vesicle release and the DEE phenotype.
In 2 unrelated French Canadian patients with severe mental retardation and epilepsy, Hamdan et al. (2009) identified respective de novo heterozygous truncating mutations in the STXBP1 gene (602926.0005 and 602926.0006). The patients were ascertained from a larger group of 95 patients with idiopathic mental retardation.
In an 11-year-old boy with DEE4, who had a clinical diagnosis of Dravet syndrome but was negative for mutations in the SCN1A gene (182389), Carvill et al. (2014) identified a de novo heterozygous missense mutation in the STXBP1 gene (E283K; 602926.0008). The mutation was found by whole-exome sequencing. Targeted resequencing of 67 patients with a similar disorder identified 2 additional probands with de novo heterozygous missense mutations in the STXBP1 gene. Functional studies of the variants were not performed.
In 2 sibs with DEE4, Lammertse et al. (2020) identified a homozygous missense mutation in the STXBP1 gene (L446F; 602926.0009). The mother and an asymptomatic sib were heterozygous for the mutation; the father was not available for study. Expression of STXBP1 with the L446F mutation in STXBP1-null mouse neurons resulted in shorter dendrites and fewer synapses per dendrite compared to cells expressing wildtype STXBP1. Patch-clamp studies in the mutant cells demonstrated an increased evoked synaptic transmission and impaired recovery after high-frequency stimulation. This appeared to be due to an increased synaptic vesicle response after stimulation with a single action potential. Lammertse et al. (2020) concluded that the L446F mutation leads to a gain-of-function pathogenic mechanism.
In a review of clinical and molecular data from 271 patients with DEE4, Xian et al. (2022) identified 54 recurrent mutations in the STXBP1 gene. Sixteen of the mutations were identified in 5 or more patients, with the most common mutations being R406H (in 20 patients), R406C (in 20 patients), and R292H (in 18 patients). Compared to the entire cohort of patients, those with recurrent mutations did not show an overall phenotypic similarity. However, patients with R406H and R406C mutations were more likely to have a burst suppression pattern on EEG and spastic tetraplegia, and less likely to have ataxia, compared to the rest of the cohort. Additionally, patients with premature termination mutations or deletions in the STXBP1 gene were more likely to have infantile spasms, hypsarrhythmia on EEG, ataxia, hypotonia, and neonatal seizure onset compared to patients with missense mutations.
Carvill, G. L., Weckhuysen, S., McMahon, J. M., Hartmann, C., Moller, R. S., Hjalgrim, H., Cook, J., Geraghty, E., O'Roak, B. J., Petrou, S., Clarke, A., Gill, D., and 14 others. GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology 82: 1245-1253, 2014. [PubMed: 24623842] [Full Text: https://doi.org/10.1212/WNL.0000000000000291]
Deprez, L., Weckhuysen, S., Holmgren, P., Suls, A., Van Dyck, T., Goossens, D., Del-Favero, J., Jansen, A., Verhaert, K., Lagae, L., Jordanova, A., Van Coster, R., Yendle, S., Berkovic, S. F., Scheffer, I., Ceulemans, B., De Jonghe, P. Clinical spectrum of early-onset epileptic encephalopathies associated with STXBP1 mutations. Neurology 75: 1159-1165, 2010. [PubMed: 20876469] [Full Text: https://doi.org/10.1212/WNL.0b013e3181f4d7bf]
Hamdan, F. F., Piton, A., Gauthier, J., Lortie, A., Dubeau, F., Dobrzeniecka, S., Spiegelman, D., Noreau, A., Pellerin, S., Cote, M., Henrion, E., Fombonne, E., Mottron, L., Marineau, C., Drapeau, P., Lafreniere, R. G., Lacaille, J. C., Rouleau, G. A., Michaud, J. L. De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy. Ann. Neurol. 65: 748-753, 2009. [PubMed: 19557857] [Full Text: https://doi.org/10.1002/ana.21625]
Lammertse, H. C. A., van Berkel, A. A., Iacomino, M., Toonen, R. F., Striano, P., Gambardella, A., Verhage, M., Zara, F. Homozygous STXBP1 variant causes encephalopathy and gain-of-function in synaptic transmission. Brain 143: 441-451, 2020. [PubMed: 31855252] [Full Text: https://doi.org/10.1093/brain/awz391]
Saitsu, H., Hoshino, H., Kato, M., Nishiyama, K., Okada, I., Yoneda, Y., Tsurusaki, Y., Doi, H., Miyake, N., Kubota, M., Hayasaka, K., Matsumoto, N. Paternal mosaicism of an STXBP1 mutation in OS. Clin. Genet. 80: 484-488, 2011. [PubMed: 21062273] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01575.x]
Saitsu, H., Kato, M., Mizuguchi, T., Hamada, K., Osaka, H., Tohyama, J., Uruno, K., Kumada, S., Nishiyama, K., Nishimura, A., Okada, I., Yoshimura, Y., Hirai, S., Kumada, T., Hayasaka, K., Fukuda, A., Ogata, K., Matsumoto, N. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nature Genet. 40: 782-788, 2008. [PubMed: 18469812] [Full Text: https://doi.org/10.1038/ng.150]
Saitsu, H., Kato, M., Shimono, M., Senju, A., Tanabe, S., Kimura, T., Nishiyama, K., Yoneda, Y., Kondo, Y., Tsurusaki, Y., Doi, H., Miyake, N., Hayasaka, K., Matsumoto, N. Association of genomic deletions in the STXBP1 gene with Ohtahara syndrome. (Letter) Clin. Genet. 81: 399-402, 2012. [PubMed: 22211739] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01733.x]
Saitsu, H., Tohyama, J., Kumada, T., Egawa, K., Hamada, K., Okada, I., Mizuguchi, T., Osaka, H., Miyata, R., Furukawa, T., Haginoya, K., Hoshino, H., and 15 others. Dominant-negative mutations in alpha-II spectrin cause West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay. Am. J. Hum. Genet. 86: 881-891, 2010. [PubMed: 20493457] [Full Text: https://doi.org/10.1016/j.ajhg.2010.04.013]
Tohyama, J., Akasaka, N., Osaka, H., Maegaki, Y., Kato, M., Saito, N., Yamashita, S., Ohno, K. Early onset West syndrome with cerebral hypomyelination and reduced cerebral white matter. Brain Dev. 30: 349-355, 2008. [PubMed: 18065176] [Full Text: https://doi.org/10.1016/j.braindev.2007.10.006]
Xian, J., Parthasarathy, S., Ruggiero, S. M., Balagura, G., Fitch, E., Helbig, K., Gan, J., Ganesan, S., Kaufman, M. C., Ellis, C. A., Lewis-Smith, D., Galer, P., and 42 others. Assessing the landscape of STXBP1-related disorders in 534 individuals. Brain 145: 1668-1683, 2022. [PubMed: 35190816] [Full Text: https://doi.org/10.1093/brain/awab327]
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Ada Hamosh, MD, MPH
Scientific Director, OMIM