A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-110 (DEE110) is caused by homozygous or compound heterozygous mutation in the CACNA2D1 gene (114204) on chromosome 7q21.

Developmental and epileptic encephalopathy-110 (DEE110) is an autosomal recessive disorder characterized by profound global developmental delay and hypotonia apparent in infancy followed by onset of seizures in the first months or years of life. Affected individuals achieve almost no developmental milestones and show impaired intellectual development, poor or absent speech, inability to walk or grasp objects, peripheral spasticity, and poor eye contact. Brain imaging shows hypoplastic corpus callosum and cortical atrophy (Dahimene et al., 2022).

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

Dahimene et al. (2022) reported 2 unrelated 4-year-old boys who presented in infancy with hypotonia, severe global developmental delay, small head circumference, poor head control, and cortical visual impairment with limited eye contact. Patient 1 had suspected absence seizures at 9 months of age that later developed into generalized seizures, whereas patient 2 had onset of epilepsy at 11.5 months of age. Brain imaging showed hypoplastic corpus callosum and progressive cortical atrophy in both patients. They also had feeding problems requiring a gastrostomy tube, failure to thrive, inability to sit or roll over, absent language, sleep disturbances, peripheral spasticity, hyperkinetic choreiform movements, dystonic movements, orofacial dyskinesia, and insensitivity to pain. One patient had nystagmus and the other had disconjugate gaze. Dysmorphic features included bitemporal narrowing, low-set and large ears, and facial hypotonia with open mouth and tented upper lip; 1 had a high-arched palate.

The transmission pattern of DEE110 in the families reported by Dahimene et al. (2022) was consistent with autosomal recessive inheritance.

In 2 unrelated boys with DEE110, Dahimene et al. (2022) identified homozygous or compound heterozygous mutations in the CACNA2D1 gene (114204.0001-114204.0003). The mutations, which were found by trio-based exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Patient 1 was homozygous for a frameshift allele, and patient 2 was compound heterozygous for a frameshift and a missense allele. Studies of patient fibroblasts and in vitro functional studies of cells transfected with the missense variant (G209D; 114204.0003) indicated that the variants resulted in a loss-of-function effect on calcium channel function.