Epileptic Encephalopathy, Early Infantile, 25, With Amelogenesis Imperfecta

A number sign (#) is used with this entry because of evidence that early-onset epileptic encephalopathy-25 (EIEE25) is caused by homozygous or compound heterozygous mutation in the SLC13A5 gene (608305) on chromosome 17p13.

The disorder shows phenotypic similarities to Kohlschutter-Tonz syndrome (KTZS; 226750), which is caused by mutation in the mutation in the ROGDI gene (614574) on chromosome 16p13.

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

Clinical Features

Thevenon et al. (2014) reported 8 patients from 3 unrelated families with early infantile epileptic encephalopathy. One of the families was consanguineous and of Algerian origin. The patients had onset of seizures between the first hours and first 7 days of life. Seizures were manifest as chewing, cyanosis, clonic movements, abnormal ocular movements, and status epilepticus. EEG studies performed in several patients showed multiple abnormalities, such as rhythmic theta/delta focal discharges from both hemispheres that often involved the temporal or occipital lobes, or multifocal status epilepticus. All patients had profound or severe delayed development with lack of speech, and most patients did not acquire the ability to sit. Eye contact and head control were achieved in most, but not all, patients. Additional variable features included axial hypotonia, peripheral hypertonia, and abnormal involuntary movements such as dystonia and choreoathetosis. The frequency and severity of seizures tended to improve with age, although neurologic outcome remained severe.

Hardies et al. (2015) reported 8 patients from 4 unrelated families of European descent with EIEE25. All patients developed focal clonic seizures on the first day of life, followed by ongoing multiple seizure types, including hemiconvulsions and generalized tonic-clonic seizures. Seven patients had status epilepticus, including 1 who died from it, and 6 showed fever sensitivity. Two patients became seizure-free between 3 and 7 years of age. Interictal EEG showed focal abnormalities in all but 1 patient. Three patients responded well to a ketogenic diet. Neurologic outcome varied from mild to severe intellectual disability, plus variable combinations of ataxia, choreoathetosis, spasticity, and microcephaly. All also had tooth hypoplasia or hypodontia, which was also noted in 3 of the patients reported by Thevenon et al. (2014).

Schossig et al. (2017) reported 10 patients from 5 unrelated families with EIEE25 with amelogenesis imperfecta. Nine patients presented with a clinical diagnosis of KTZS, but did not carry pathogenic mutations in the ROGDI gene. The patients developed refractory seizures in the first days or months of life and thereafter showed global developmental delay with moderate to severe intellectual disability and delayed walking or difficulty walking. They had EEG abnormalities, such as focal slowing, multiepileptiform potentials, generalized spike-wave activity, and sometimes hypsarrhythmia. Additional features included axial hypotonia, limb spasticity causing gait impairment, cerebellar ataxia, coordination defects, dystonia, and pyramidal signs. Communication skills were very poor. Brain imaging was normal. Two sibs (family C) had previously been reported by De Souza et al. (2014) and 3 other German sibs (family D) had previously been reported by Hardies et al. (2015). All patients had dental abnormalities, including delayed eruption, hypodontia, tooth hypoplasia, yellow discoloration, thin enamel, and enamel chipping. Permanent teeth were small and cylindrical with discoloration and secondary molars and premolars were extremely worn.

Weeke et al. (2017) reported 8 patients from 5 families with EIEE25 confirmed by genetic analysis. All patients presented with refractory neonatal seizures on the first day of life after an uncomplicated pregnancy. Six of 7 infants with a neonatal MRI had a characteristic MRI pattern with punctate white matter lesions (PWML), which were no longer visible at the age of 6 months but resulted in gliotic scarring visible on MRI at the age of 18 months. The same pattern of gliotic scarring was seen on the MRIs of the infant without a neonatal scan. The findings indicated that some patients with EIEE25 may have subtle or transient brain imaging abnormalities.

Inheritance

The transmission pattern of EIEE25 in the families reported by Thevenon et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 7 patients from 3 unrelated families with early infantile epileptic encephalopathy, Thevenon et al. (2014) identified homozygous or compound heterozygous missense mutations in the SLC13A5 gene (608305.0001-608305.0003). The mutations in the first 2 families were found by whole-exome sequencing. The mutations occurred at highly conserved residues in the sodium-binding domains, which are important for citrate transport, but functional studies were not performed.

In 8 patients from 4 unrelated families with EIEE25, Hardies et al. (2015) identified 7 different biallelic mutations in the SLC13A5 gene (608305.0001-608305.0002; 608305.0004-608305.0008). Mutations in the first 3 families were found by whole-exome or whole-genome sequencing and segregated with the disorder in the families. Five mutations were missense mutations and 2 were truncating mutations; 2 mutations had previously been reported by Thevenon et al. (2014). In vitro functional expression studies in HEK293T cells showed that all mutant proteins lost citrate transport activity, even though some missense mutations were correctly expressed at the plasma membrane. Hardies et al. (2015) noted that neurons are considered incapable of de novo synthesis of tricarboxylic acid cycle intermediates and thus rely on the uptake of intermediates, such as citrate, to maintain energy status and neurotransmitter production.