Epileptic Encephalopathy, Early Infantile, 53
A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-53 (EIEE53) is caused by homozygous or compound heterozygous mutation in the SYNJ1 gene (604297) on chromosome 21q22.Description
Early infantile epileptic encephalopathy-53 is a severe neurodegenerative disorder characterized by onset of intractable seizures in infancy. Affected individuals show hypotonia and very poor or absent global development, resulting in severe intellectual disability and spastic quadriplegia. Some patients may die in childhood (summary by Hardies et al., 2016).
For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).Clinical Features
Hardies et al. (2016) reported 3 unrelated families in which 2 sibs each had EIEE53. Two of the families were consanguineous and of Moroccan origin, whereas the third family was Caucasian and nonconsanguineous. In 2 families, the affected infants presented in the first days of life with refractory seizures, whereas in the third family, the patients developed seizures at 2.5 and 6 months of age after presenting with hypotonia and poor feeding in early infancy. Seizure types included tonic, tonic-clonic, myoclonic, and eye-blinking, and EEG showed hypsarrhythmia and multifocal epileptic activity on a slowed background. At least 1 patient had several episodes of status epilepticus. The patients showed little or no psychomotor development, progressive spastic quadriplegia, severe or profound intellectual disability, central visual impairment or absent eye contact, and inability to feed, necessitating gastrostomy. In 1 family, laboratory studies showed increased serum creatine kinase, increased lactate, and combined deficiency of mitochondrial respiratory complexes III and IV in liver and fibroblasts, all suggestive of a mitochondrial disorder. Brain imaging was normal in 5 patients, but showed thin corpus callosum, limited gliosis, and atrophy of the periventricular white matter in one. In 1 family, the 2 affected sibs died at 2.5 and 8 years of age.Inheritance
The transmission pattern of EIEE53 in the families reported by Hardies et al. (2016) was consistent with autosomal recessive inheritance.Molecular Genetics
In 6 children from 3 unrelated families with EIEE53, Hardies et al. (2016) identified homozygous or compound heterozygous mutations in the SYNJ1 gene (604297.0003-604297.0006). The mutations, which were found by whole-genome or whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. One of the mutations was a missense mutation (Y888C; 604297.0003) that was demonstrated to significantly reduce the enzymatic activity of both the 5-PP and Sac1 domains compared to controls, whereas the other mutations were truncating or frameshift mutations resulting in nonsense-mediated mRNA decay and an almost complete loss of function. The findings indicated that dysregulation of endocytic recycling of synaptic vesicles in neurons can adversely affect neurodevelopment. Screening of the SYNJ1 gene in 543 patients with epilepsy and/or developmental delay did not reveal any additional pathogenic variants.