A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-43 (DEE43) is caused by heterozygous mutation in the GABRB3 gene (137192) on chromosome 15q11.

Developmental and epileptic encephalopathy-43 (DEE43) is a neurologic disorder characterized by the onset of various types of seizures usually in the first year of life. The age at onset is highly variable, ranging from the neonatal period to about 12 months of age. Later onset may rarely occur. Seizure types include febrile, infantile spasms, focal, tonic-clonic, and myoclonic; they tend to be refractory to treatment. Affected individuals show global developmental delay with mild to moderate intellectual disability, although some may have normal early development before the onset of seizures. EEG shows focal, multifocal, or generalized sharp waves associated with seizures, sometimes with hypsarrhythmia. Additional more variable features include tube feeding, hypotonia, peripheral hypertonia, ataxia, dyskinesia, and behavioral difficulties, including aggression, ADHD, stereotypic, and impulsive behavior (summary by the Epi4K Consortium, 2016).

For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

The Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) reported 4 unrelated patients with infantile epileptic encephalopathy. The patients had onset of multiple seizure types within the first year of life, including absence, myoclonic, and generalized tonic-clonic seizures. Three patients with available clinical information showed global developmental delay; 2 of these had behavioral abnormalities. The Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) concluded that their results implicated the GABRB3 gene in epileptic encephalopathy. The Epi4K Consortium (2016) reported follow-up of the patients reported by the Epi4K Consortium and Epilepsy Phenome/Genome Project (2013), who ranged from 11 to 20 years of age. One had mildly delayed development and the 3 others had mild to severe intellectual disability.

The Epi4K Consortium (2016) reported 7 additional patients with DEE43. Six had onset of multiple seizures types within the first year of life. Only 2 of these patients had normal development prior to onset of seizures. All had mild to profound intellectual disability. The seventh patient, a 19-year-old girl with severe intellectual disability, had delayed development apparent at age 6 months, but did not develop seizures until age 12 years. One case had a family history of genetic epilepsy and febrile seizures plus (GEFS+). Combined with the 4 previously reported patients (11 patients total) 5 had severe to profound intellectual disability, 3 had mild to moderate disability, and the degree of cognitive impairment was unclear in the remaining 3. Predominant seizure types were myoclonic, tonic, absence, and generalized tonic-clonic seizures. EEG showed multiple variable abnormalities, including generalized spike-wave discharges, background slowing, and hypsarrhythmia.

Papandreou et al. (2016) reported a patient who presented early in infancy with neonatal hypotonia, feeding difficulties, and failure to thrive. He developed seizures at 3 months of age. Initially, he had cessation of seizures with treatment with the GABA transaminase inhibitor vigabatrin; however, he developed severe hypotonia, sedation, and respiratory difficulties. After vigabatrin was weaned, the seizures recurred, which were resistant to other therapies. At 3 years and 2 months of age, he had severe global developmental delay, hypotonia, and absence of speech.

Absalom et al. (2020) reported a mother and her 29-month-old child (cases 1 and 2). The child presented at 7 months of age with infantile spasms and an EEG showed hypsarrhythmia. She was treated with vigabatrin and prednisolone, with a good clinical result. Later she was weaned to just vigabatrin and then transitioned to valproic acid. At 21 months of age she had global developmental delay and right-sided hemiplegia. Her mother had a history of atonic and tonic clonic seizures at 2 years of age. She was treated with valproic acid and had been without seizures since 18 years of age.

In 4 unrelated patients with DEE43, the Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) identified different de novo heterozygous mutations in the GABRB3 gene. The patients were part of a larger cohort of 264 probands with epileptic encephalopathy who underwent exome sequencing. A statistical likelihood analysis indicated that the probability of this finding occurring by chance was p = 4.1 x 10(-10). Functional studies of the mutations were not performed. The Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) concluded that their results implicated the GABRB3 gene in epileptic encephalopathy.

In 7 previously unreported patients with DEE43, the Epi4K Consortium (2016) identified heterozygous mutations in the GABRB3 gene (see, e.g., 137192.0005-137192.0008). The mutations were found by targeted sequencing of 27 candidate genes in 531 patients with a similar disorder. Functional studies of the variants and studies of patient cells were not performed. Five of the mutations were confirmed de novo, 1 could not be confirmed de novo, and 1 segregated with a GEFS+ phenotype in a family (proband EG0258). GABRB3 mutations accounted for 1.3% of the cohort.

In a male patient with DEE43, Papandreou et al. (2016) identified a de novo heterozygous missense mutation in the GABRB3 gene (T287I; 137192.0009). The mutation was identified by sequencing of a panel of 48 genes associated with early infantile epileptic encephalopathy.

In a mother and child (cases 1 and 2) with DEE43, Absalom et al. (2020) identified a heterozygous nonsense mutation in the GABRB3 gene (R194X; 137192.0010). The mutation was identified by sequencing of a panel of genes associated with epilepsy and confirmed by Sanger sequencing.