Epileptic Encephalopathy, Early Infantile, 60
A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-60 (EIEE60) is caused by homozygous or compound heterozygous mutation in the CNPY3 gene (610774) on chromosome 6p.
For a discussion of genetic heterogeneity of EIEE, see 308350.
Clinical FeaturesMutoh et al. (2018) reported 3 patients from 2 unrelated Japanese families with EIEE60. The patients presented in the first months of life with myoclonic epilepsy and other seizure types associated with hypsarrhythmia on EEG. Two sibs later showed diffuse sharp- and slow-wave complexes on EEG, and the third patient had suppression-burst patterns. The seizures were initially partially controllable in the 2 sibs, but later became intractable. At ages 12 and 13 years, the sibs were bedridden with spastic quadriplegia and inability to roll over, and had profound intellectual disability with absent speech and no communication. The third patient had refractory seizures and was severely disabled; he died at age 13 months. Brain imaging in all patients showed diffuse progressive brain atrophy and hippocampal malrotation.
InheritanceThe transmission pattern of EIEE60 in the families reported by Mutoh et al. (2018) was consistent with autosomal recessive inheritance.
Molecular GeneticsIn 3 patients from 2 unrelated Japanese families with EIEE60, Mutoh et al. (2018) identified homozygous or compound heterozygous mutations in the CNPY3 gene (610774.0001-610774.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in 1 family from whom parental DNA was available. Patient lymphoblastoid cell lines showed decreased CNPY3 protein levels compared to controls, suggesting that the variants result in a loss of function. The patients were ascertained from a cohort of 700 individuals with epileptic encephalopathy who underwent whole-exome sequencing.
Animal ModelMutoh et al. (2018) found that Cnpy3-knockout mice had decreased body weight and exhibited tremor and spastic or dystonic features under resting conditions compared to controls. Studies of locomotor activity in the open field test showed hyperactivity and anxiolytic behavior in the mutant animals. They also showed impaired motor control in the tail suspension test. The resting EEG of mutant mice showed enhanced activity, consistent with abnormally activated neuronal circuits, although the mice did not have spontaneous seizures. Histologic examination of the mutant mouse brain showed no apparent structural abnormalities. These data suggested that Cnpy3 performs essential roles in brain function in addition to known Toll-like receptor-dependent immune responses.