Epileptic Encephalopathy, Infantile Or Early Childhood, 1

A number sign (#) is used with this entry because of evidence that infantile or early childhood epileptic encephalopathy-1 (IECEE1) is caused by heterozygous mutation in the PPP3CA gene (114105) on chromosome 4q24.

Heterozygous mutations in the PPP3CA gene can also cause arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development (ACCIID; 618265).

Description

IECEE1 is a neurodevelopmental disorder characterized by delayed psychomotor development apparent in infancy and resulting in severe to profound intellectual disability with poor or absent speech. Most patients never achieve independent walking. Patients typically have onset of refractory multifocal seizures between the first weeks and years of life, and some may show developmental regression. Additional features, such as hypotonia and cortical visual impairment, are more variable (summary by Myers et al., 2017).

Genetic Heterogeneity of Infantile or Early Childhood Epileptic Encephalopathy

See also IECEE2 (617829), caused by mutation in the GABRB2 gene (600232) on chromosome 5q34, and IECEE3 (618012), caused by mutation in the ATP6V1A gene (607027) on chromosome 3q13.

Clinical Features

Myers et al. (2017) reported 6 unrelated patients with an epileptic encephalopathy and severe to profound intellectual disability with poor or absent speech. The patients ranged in age from 5 to 22 years and were of various ethnicities (e.g., European, Ashkenazi, Pakistani). All presented with delayed psychomotor development apparent between birth and 2 years of age. Five patients had onset of seizures between 6 weeks and 4 years of age; the sixth patient had an abnormal EEG with multifocal epileptiform discharges in the absence of overt seizures. Seizure types varied, and included focal, spasms, tonic, myoclonic, tonic-clonic, absence, and atonic. Seizures were refractory to medication in 4 children, and 1 patient with a comparatively mild form of epilepsy had resolution of the seizures at age 16 years. EEG showed multifocal discharges, and 3 patients had hypsarrhythmia. Three patients showed developmental regression; 2 had autistic features and several had behavioral abnormalities. Four patients were nonambulatory and 1 walked with an unsteady gait. Other variable features included hypotonia, abnormal movements, spasticity, dysmorphic facial features, such as hypertelorism, talipes, and cortical visual impairment. Two patients had a feeding tube. Brain imaging was normal in 3 patients, but showed mild nonspecific abnormalities, including cerebral atrophy, delayed myelination, and white matter changes, in the other patients.

Molecular Genetics

In 6 unrelated patients with IECEE1, Myers et al. (2017) identified 5 different de novo heterozygous mutations in the PPP3CA gene (114105.0001-114105.0005). The patients were ascertained from several large independent cohorts of patients with neurodevelopmental or seizure disorders (see, e.g., the EuroEPINOMICS-RES Consortium et al., 2014 and Zhu et al., 2015); the mutations were found by exome sequencing and confirmed by Sanger sequencing. There was 1 nonsense mutation and 4 missense mutations, 3 of which occurred in the catalytic domain. Functional studies of the variants and studies of patient cells were not performed. However, Myers et al. (2017) noted that calcineurin is a key regulator of synaptic vesicle recycling at nerve terminals and interacts with DNM1, suggesting that disruption of this process could lead to early-onset epilepsy and neurodevelopmental abnormalities. Five of the individuals were found among 4,760 probands with neurodevelopmental disorders who were studied.

By whole-exome sequencing in patients with IECEE1, who had initially been diagnosed with West syndrome, Mizuguchi et al. (2018) identified heterozygosity for 3 missense mutations in the catalytic domain and a frameshift mutation (114105.0006) in the PPP3CA gene. The mutations were confirmed by Sanger sequencing; both parents were available for study in all but 1 patient and mutations were found to be de novo. Using a yeast model, the mutations were shown to be functionally null (loss-of-function mutations).