Epileptic Encephalopathy, Early Infantile, 66

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-66 (EIEE66) is caused by heterozygous mutation in the PACS2 gene (610423) on chromosome 14q32.

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

Clinical Features

Olson et al. (2018) reported 14 unrelated children, ranging in age from 9 months to 16 years, with EIEE66. Most patients had onset of seizures in the first days or weeks of life, although 1 had onset at 2 months of age. The predominant seizure types were focal motor, and some had accompanying autonomic, tonic, and generalized tonic-clonic seizures. One individual had myoclonic seizures. EEG showed focal onset or diffuse attenuation with later focal features, with episodes of status epilepticus. Hypsarrhythmia was not observed. The seizures tended to attenuate with time, especially after the first year of life, and a few patients even became seizure free with treatment. The patients had variable developmental delay with walking around age 2 or 3 years, intellectual disability, and delayed speech. About half of patients had behavioral disturbances, such as autism spectrum disorder or obsessive compulsive disorder. Common neurologic features included hypotonia, hand stereotypies, wide-based gait, hyperreflexia, nystagmus, myopia, and hypermetropia, astigmatism, and cortical visual impairment. Dysmorphic facial features were somewhat variable, but included coarse features, synophrys, hypertelorism, downslanting palpebral fissures, broad nasal root, thin upper lip, and wide mouth with downturned corners. Extraneurologic features observed in some patients included distal limb anomalies, cardiac septal defects, cryptorchidism, and hematologic disturbances, such as anemia or neutropenia. Brain MRI in over half of patients showed dysgenesis of the cerebellar folia, inferior vermian hypoplasia, and mega cisterna magna. Three patients had hypothalamic fusion.

Molecular Genetics

In 14 unrelated patients with EIEE66, Olson et al. (2018) identified a de novo heterozygous missense mutation in the PACS2 gene (E209K; 610423.0001). The mutation in the first 2 patients was found by whole-exome sequencing and confirmed by Sanger sequencing. Subsequent patients were identified through international data-sharing. In vitro functional expression studies showed that the PACS2 E209K variant interacted to a greater extent with the client proteins SIRT1 (604479), HDAC1 (601241), and TRPV1 (602076) compared to wildtype. These findings suggested that the mutation reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 and client proteins, which may disturb cellular function. The findings may be consistent with a dominant-negative effect.