Alternative titles; symbolsEPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 81; EIEE81▼ DescriptionDevelopmental and epileptic encephalopathy-81 (DEE81) is an autosoma...
Alternative titles; symbols
Developmental and epileptic encephalopathy-81 (DEE81) is an autosomal recessive neurodevelopmental disorder typically characterized by onset of severe refractory seizures soon after birth or in the first months of life. Affected individuals show little developmental progress with no eye contact and no motor or cognitive development. Other features may include facial dysmorphism, such as hypotonic facies and epicanthal folds, as well as sensorineural hearing loss and peripheral neuropathy. Brain imaging shows cerebral atrophy, impaired myelination, thin corpus callosum, and progressive leukoencephalopathy (summary by Esposito et al., 2019; Maddirevula et al., 2019).
For a discussion of genetic heterogeneity of DEE, see 308350.
▼ Clinical Features
Maddirevula et al. (2019) reported a 3-year-old boy (patient 17-4220), born of consanguineous parents, who developed focal seizures at 3 months of age. He then showed global developmental delay, no eye contact, and macrocephaly. Dysmorphic features included long face, high forehead, short philtrum, and low-set ears. Brain imaging showed cerebral atrophy and atrophy of the brainstem.
Esposito et al. (2019) reported 6 children from 3 unrelated families with DEE81, who were clinically diagnosed with Ohtahara syndrome. Each family contained 2 affected sibs; 2 families were consanguineous and of Israeli Arab (family 2) and Turkish descent (family 3). The patients presented soon after birth with either respiratory distress or refractory focal, myoclonic, or tonic seizures. EEG showed disorganized background activity, multifocal spike discharges, and a burst-suppression pattern. The patients showed almost no developmental progress, with poor visual fixation, quadriplegia with inability to walk, hypotonia, absent spontaneous movements, and almost no cognitive, motor, communicative, or language development. Five patients died within the first 9 years of life. Brain imaging showed thin corpus callosum, hypomyelination, and progressive leukoencephalopathy. The 2 sibs from family 3 also had a simplified gyral pattern. Other features included sensorineural hearing loss, mild peripheral polyneuropathy, and dysmorphic features, such as myopathic facies, downslanting palpebral fissures, epicanthal folds, short forehead, saddle nose, and high-arched palate. The 2 sibs from family 1 had microcephaly (-3.6 SD), whereas the other patients had a large head size. Some patients had nonpitting limb edema.
The transmission pattern of DEE81 in the families reported by Esposito et al. (2019) was consistent with autosomal recessive inheritance.
▼ Molecular Genetics
In a 3-year-old boy (patient 17-4220), born of consanguineous parents, with DEE81, Maddirevula et al. (2019) identified a homozygous frameshift mutation in the DMXL2 gene (612186.0003). The variant, which was found by exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In 6 patients from 3 unrelated families with DEE81, Esposito et al. (2019) identified homozygous or compound heterozygous mutations in the DMXL2 gene (612186.0004-612186.0007). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. None of the variants were present in the gnomAD database. Fibroblasts from all 3 probands showed almost no DMXL2 protein, suggesting degradation or instability and a loss-of-function effect. Patient fibroblasts also showed lysosomal abnormalities, particularly decreased LAMP1 (153330), decreased pH within acidic organelles, impaired lysosomal degradative capacity, and defective autophagy with abnormal accumulation of autophagy receptors and substrates compared to controls. Ultrastructural analysis showed vacuolization and accumulation of atypical fusion-like structures. The abnormalities could be rescued by expression of wildtype DMXL2. Knockdown of Dmxl2 using shRNA in cultured mouse hippocampal neurons resulted in similar lysosomal abnormalities and defective autophagy, as well as a significant decrease in neurite complexity, consistent with impaired synaptic connections.