A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-111 (DEE111) is caused by homozygous mutation in the DEPDC5 gene (614191) on chromosome 22q12.

Developmental and epileptic encephalopathy-111 (DEE111) is an autosomal recessive severe neurologic disorder characterized by early-onset refractory seizures, global developmental delay, hypotonia, impaired gross motor development, impaired intellectual development, and absent speech. Most patients have macrocephaly. Brain imaging shows frontal, parietal, and perisylvian polymicrogyria, dysmorphic basal ganglia and corpus callosum, and hypoplastic pons. Additional features may include feeding difficulties, poor vision with ocular anomalies, congenital cardiac abnormalities, and recurrent infections associated with neutropenia. Death in early childhood may occur (Ververi et al., 2023).

For a discussion of genetic heterogeneity of DEE, see 308350.

Ververi et al. (2023) reported 9 children from 5 unrelated families with an early-onset severe neurologic disorder. Families 1-3 were of Irish Traveller origin (family 1 was consanguineous), family 4 was a consanguineous Tunisian family, and family 5 was a consanguineous Lebanese family. Five of the 6 affected Irish Traveller patients died in early childhood: P2 died of congenital heart disease on the first day of life, whereas P1, P4, and P5 died between 15 and 37 months of age from respiratory-related illnesses; clinical information from deceased patient 9 was not available, although he reportedly had a similar phenotype. The living children were between 10 months and 6 years of age. All patients except 1 were born prematurely between 28 and 36 weeks' gestation due to intrauterine growth retardation or maternal preeclampsia, and several had neonatal hypotonia, respiratory insufficiency, and/or feeding difficulties. Almost all were noted to have macrocephaly with frontal bossing, and a few had dysmorphic features, such as hypertelorism, midface hypoplasia, bushy eyebrows, low-set ears, and capillary malformations. The patients had severe global developmental delay with hypotonia, inability to sit or walk, poor head control, absent speech, and variably impaired visual fixation and tracking; tube-feeding was sometimes required. All patients had onset of seizures in the first weeks, months, or years of life, including infantile spasms, febrile seizures, multifocal seizures, generalized tonic-clonic seizures, and status epilepticus; the seizures were often refractory to medication. Some patients showed developmental regression after seizure onset. About half had ocular abnormalities, including rod-cone dystrophy, hypopigmented retina, amblyopia, and nystagmus. Brain imaging showed extensive frontal, perisylvian, or diffuse polymicrogyria, dysmorphic corpus callosum and basal ganglia, large frontal lobes, and hypoplastic pons. Enlarged ventricles and cerebellar abnormalities were found in some. Four patients had cardiac findings, including hypoplastic left heart syndrome, pulmonary artery stenosis, arrhythmia, hypertension, and ventricular hypertrophy, 2 had umbilical or inguinal hernia, and 3 had recurrent infections or sepsis associated with neutropenia.

The transmission pattern of DEE111 in the families reported by Ververi et al. (2023) was consistent with autosomal recessive inheritance.

In 9 patients from 5 unrelated families with DEE111, Ververi et al. (2023) identified homozygous missense mutations in the DEPDC5 gene: T337R (614191.0016) and R806C (614191.0017). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families and were not present in the gnomAD database. Molecular modeling predicted that the mutations would result in a loss of protein stability and adversely affect protein function. Functional studies of the variants were not performed, but immunohistochemical studies of a skin sample from 1 of the patients with the T337R mutation was consistent with an overall increase in mTOR (601231) activity. Since heterozygous carriers in the families were unaffected, Ververi et al. (2023) postulated that these missense mutations resulted in a partial loss of function.