Epileptic Encephalopathy, Early Infantile, 16

A number sign (#) is used with this entry because early infantile epileptic encephalopathy-16 (EIEE16) is caused by homozygous or compound heterozygous mutation in the TBC1D24 gene (613577) on chromosome 16p13.

Mutation in the TBC1D24 gene can also cause familial infantile myoclonic epilepsy (FIME; 605021), a less severe disorder.

Description

Early infantile epileptic encephalopathy-16 is a severe autosomal recessive neurologic disorder characterized by onset of seizures in the first weeks or months of life. Seizures can be of various types, are unresponsive to medication, last for long periods of time, and occur frequently. Affected infants show psychomotor regression or lack of psychomotor development, as well as other neurologic features such as extrapyramidal signs and hypotonia. Most die in childhood (summary by Duru et al., 2010 and Milh et al., 2013).

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

Clinical Features

Duru et al. (2010) reported a large consanguineous Turkish family in which 5 children had a severe early infantile epileptic encephalopathy characterized by myoclonic seizures, alternating and migrating jerks of the extremities, focal seizures, and neurologic deterioration with permanent neurologic sequelae. Features included long-lasting myoclonic seizures that were not responsive to medication, hemiparesis with pyramidal signs, severe hypotonia, dystonia, and status epilepticus. EEG in initial stages were characterized by multiple spikes, but later showed a steady and progressive slowing of background activity. Brain imaging showed progressive atrophic changes in the brain and cerebellum and/or delayed myelination. The seizures occurred spontaneously or were triggered by common infections. The patients became inattentive to visual and acoustic stimuli as the disease progressed; 1 patient examined late in the disease course showed optic atrophy and macular degeneration. None of the patients had photosensitivity. All patients died by age 7 years. Duru et al. (2010) referred to the disorder as 'progressive myoclonic epilepsy with dystonia (PMED).'

Milh et al. (2013) reported 2 sisters, born of unrelated parents, with a severe early infantile epileptic encephalopathy presenting clinically as malignant migrating partial seizures of infancy (MMPSI). Both had onset of clonic seizures early in the second month of life that progressed to a 'stormy' phase, with almost continuous clonic migrating seizures and psychomotor regression. Both patients had severe neurologic impairment with axial hypotonia, no voluntary movement, no eye contact, and acquired microcephaly. Brain MRI at birth was normal in both patients, but later showed brain atrophy. One sib died of seizures at age 18 months.

Inheritance

The transmission pattern of EIEE16 in the families reported by Duru et al. (2010) and Milh et al. (2013) was consistent with autosomal recessive inheritance.

Mapping

By linkage analysis of a large consanguineous Turkish family with early infantile epileptic encephalopathy, Duru et al. (2010) identified a locus on chromosome 16pter-p13.3 (maximum multipoint lod score of 7.83 between markers TTTA028 and D16S3-26; maximum 2-point lod score of 4.25 at D16S2618). Haplotype analysis delineated a 6.73-Mb candidate interval. Sequencing of the ATP6V0C gene (108745) did not reveal any pathogenic mutations. The locus overlapped that reported by Zara et al. (2000) for FIME, but Duru et al. (2010) noted that the phenotypes differed significantly in severity.

Molecular Genetics

In affected members of the family reported by Duru et al. (2010), Guven and Tolun (2013) identified a homozygous truncating mutation in the TBC1D24 gene (613577.0004). The severity of the mutation paralleled the severity of the phenotype.

In 2 sisters with EIEE16, Milh et al. (2013) identified compound heterozygous mutations in the TBC1D24 gene (F229S, 613577.0005 and C156X, 613577.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not present in several large exome databases and segregated with the disorder in the family.