Epileptic Encephalopathy, Early Infantile, 48

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-48 (EIEE48) is caused by homozygous or compound heterozygous mutation in the AP3B2 gene (602166) on chromosome 15q25.


Early infantile epileptic encephalopathy-48 is a severe autosomal recessive neurologic disorder characterized by global developmental delay with intellectual disability and absent speech, poor, if any, motor development, and onset of seizures in the first year of life. Affected individuals have poor eye contact and may develop microcephaly and abnormal movements (summary by Assoum et al., 2016).

For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).

Clinical Features

Assoum et al. (2016) reported 12 patients from 8 unrelated families with EIEE48. The families were of various ethnic origins and 6 were consanguineous. Most of the patients were children, but one patient was 24 years of age. All patients presented in early infancy with hypotonia, feeding difficulties, delayed development, or seizures, and later showed severe to profound global developmental delay with intellectual disability and absent speech. Most patients were unable to sit or walk, although the 24-year-old began walking at age 12 years. All patients developed seizures before 9 months of age, except 1 patient who had no history of seizures at age 4 years. Most patients had intractable seizures, and several patients had hypsarrhythmia on EEG and/or status epilepticus. Nine patients had microcephaly, but there were no common dysmorphic features. All patients had poor eye contact, but only 4 patients from 2 families had optic nerve pallor on examination; 2 sibs in 1 of these families also had retinitis pigmentosa. Other common, but variable, features included hyporeflexia, median stereotypical movements, hypermobility, dyskinesia, and/or sleep disturbances. Four patients had abnormal brain imaging, including enlarged ventricles, cerebral atrophy, cerebellar atrophy, and thin corpus callosum.

Anazi et al. (2017) reported 3 children from 2 unrelated consanguineous families with EIEE48. The patients had global developmental delay, early-onset seizures (noted in 2 patients), severe hypotonia, microcephaly, and absent speech with only a few words.


The transmission pattern of EIEE48 in the families reported by Assoum et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 12 patients from 8 unrelated families with EIEE48, Assoum et al. (2016) identified homozygous or compound heterozygous splice site, nonsense, or frameshift mutations in the AP3B2 gene (see, e.g., 602166.0001-602166.0005). Mutations in the first 2 families were found by whole-exome sequencing of 57 individuals; mutations in subsequent families were found by direct sequencing of this candidate gene in 86 individuals or through the Matchmaker Exchange Initiative. Analysis of patient cells from 2 families suggested a loss of-function effect of the mutations; additional functional studies were not performed.

In 2 unrelated patients, each born of consanguineous parents, with EIEE48, Anazi et al. (2017) identified a homozygous truncating mutation in the AP3B2 gene (602166.0006). The mutation, which was found by exome sequencing of 337 individuals with intellectual disability, segregated with the disorder in the families. Functional studies of the variant and studies of patient cells were not performed. Haplotype analysis suggested a common origin.