Early Infantile Epileptic Encephalopathy or Kohlschütter-Tönz Syndrome via the SLC13A5 Gene

Early infantile epileptic encephalopathy 25 is characterized by neonatal seizures as early as the first hours and first week of life. Symptoms include focal chronic seizures, hemiconvulsions and generalized tonic-clonic seizures. Almost all patients have severe developmental delay and absence of speech. Other clinical manifestations include mild to severe intellectual disability, tooth dysplasia, plus variable combinations of ataxia, axial hypotonia, peripheral hypertonia, choreoathetosis, spasticity, and microcephaly. The frequency and severity of seizures tend to improve with age. A few patients can be even seizure-free between 3 and 7 years of age. EEG studies show mostly focal abnormalities. Experiments with a ketogenic diet have produced conflicting results (Thevenon et al. 2014; Hardies et al. 2015; Klotz et al. 2016). Some antiepileptic drugs targeting the γ-aminobutyric acid system may reduce seizure frequency (Klotz et al. 2016).

SLC13A5-related Kohlschütter-Tönz syndrome is characterized by neonatal epileptic encephalopathy and hypoplastic amelogenesis imperfecta (Schossig et al. 2016).

Early infantile epileptic encephalopathy 25 is inherited in an autosomal recessive manner and is caused by pathogenic variants in SLC13A5 encoding solute carrier family 13, member 5, which is a sodium/citrate cotransporter. Pathogenic variants in SLC13A5 include missense, nonsense, small deletion/insertion and splice pathogenic variants. No large deletions/duplications in the SLC13A5 locus have been reported (Thevenon et a.l 2014; Hardies et al. 2015; Klotz et al. 2016; Human Gene Mutation Database). Pathogenic variants produce inactive sodium/citrate transporter due to affected helix packing and substrate binding (Klotz et al. 2016). However, the mechanisms by which pathogenic variants in SLC13A5 cause epilepsy are not understood (Klotz et al. 2016).

Kohlschütter-Tönz syndrome is also inherited in an autosomal-recessive manner and is frequently caused by biallelic pathogenic variants in ROGDI. Recently, SLC13A5 was discovered as the second major gene associated with Kohlschütter-Tönz syndrome (Schossig et al. 2016).

Clinical sensitivity of SLC13A5 testing in a large cohort of patients with early infantile epileptic encephalopathy is unavailable in the literature, because only a limited number of cases have been reported. For Kohlschütter-Tönz syndrome, SLC13A5 pathogenic variants were identified in all 10 patients with ROGDI-negative Kohlschütter-Tönz syndrome (Schossig et al. 2016). All reported SLC13A5 pathogenic variants are detectable by sequencing.

This test provides full coverage of all coding exons of the SLC13A5 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.