NeONATAL epilepsies / EESB

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known causes

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Patients suffering from early epileptic encephalopathy with a suppression burst EEG pattern display early onset epileptic seizures and developmental retardation. They are all investigated with brain MRI to eliminate brain malformations or brain anoxo-ischemic lesions. If brain MRI shows no abnormality, extensive metabolic investigations are performed to ensure the absence of any neurometabolic disease. Indeed, some known conditions are associated with the occurrence of a suppression-burst pattern and must been checked systematically :

- Pyridoxine-dependent seizure, due to a mutation of the antiquitin gene. This well-known entity is characterized by early onset epileptic encephalopathy with incessant myoclonic jerks. The electro-encephalogramm often displays a SB pattern. The epilepsy dramatically improves after treatment with pyridoxine. Pipecolic acid is usually present in blood, CSF and urine samples, alpha-amino-adipic semi aldehyde is increased in urine.

- Pyridoxal phosphate-dependent seizures, due to a mutation of the PNPO gene. This condition is associated with the presence of vanilactic acid in urine, and displays same characteristics that pyridoxin-dependent seizures.

- Non ketotic hyperglycinemia, that is caused by a deficiency of the glycine cleavage system (GCS), leading to the accumulation of glycine in the central nervous system.

- D-glyceric acidemia, methylmalonic acidemia, propionic acidemia and oligosacharidosis have been occasionally reported in patients suffering from EESB.

Mutations in three genes have been implicated in these conditions :

- Hemizygous, de novo, 33-bp duplications in exon 2 of the ARX gene have been described in 3 unrelated male patients with early onset epileptic encephalopathy (Ohtahara syndrome) that evolved to West syndrome in two of them. This mutation is thought to cause the expansion of the original 16 alanine residues to 27 alanine residues in the first polyalanine tract of the ARX protein (Kato et al. 2007). ARX is a crucial gene for the development of interneurons in the fetal brain, and a polyalanine expansion in that gene causes mental retardation and seizures, including those of early epileptic encephalopathy in males (Kato et al. 2007). Clinical observations demonstrated the correlation between the length of the repeat and the severity of the clinical phenotype.

- A mutation of the GC1 gene has been described in a consanguineous Arab muslim family in Jerusalem with 4 affected sibs with early infantile epileptic encephalopathy. The Pro206Leu missense mutation was identified in three of them in the SLC25A22 (GC1) gene (Molinari et al. 2005). Proline-206 is highly conserved across species in the glutamate and aspartate/glutamate carriers of the SLC25A22 type, suggesting that this amino acid change may impair glutamate transport.

- In a Japanese girl with early infantile epileptic encephalopathy, Saitsu et al. identified a de novo heterozygous microdeletion in chromosome 9q33.3-q34.11 that included the MUNC18-1 gene. Screening of this gene in 13 additional unrelated patients with a similar phenotype identified 4 different heterozygous mutations in the MUNC18-1 gene in 4 patients. All mutations occurred in the hydrophobic core of the protein and were predicted to result in destabilization and disruption of protein structure. In vitro studies of the mutant proteins suggested a tendency for aggregation. The phenotype included infantile onset of tonic-clonic or tonic seizures, suppression-burst pattern on EEG, profound mental retardation, and MRI evidence of hypomyelination, without any brain malformation (Saitsu et al. 2008). In our cohort, we identified more than 20 STXBP1 mutations in EEP patients (Milh et al. 2011; Di Meglio et al. 2015).

  1. -In collaboration with a group in Germany, we were able to find mutations in the GRIN2A gene in a patient with a typical form of  EESB (Endele et al. 2010). GRIN2B encodes a subunit of the NMDA glutamate receptor. In addition to EESB, mutations in this gene cause milder forms of epilepsy. Other collaborations allowed us to contribute to the identification of mutations in the SLC13A5 (Thevenon et al. 2014) or more recently AP3B2 genes (Assoum et al. 2016).

  2. -Recently, de novo KCNQ2 mutations have been found in several patients with an EOEE (Weckhuysen et al. 2012; Kato et al. 2013). Screening KCNQ2 in our cohort led to the identification of >30 patients in whom the gene was mutated de novo and 6 additional patients in which a mutation was found but in whom parental origin could not be determined. This is the largest series of patients to date (Milh et al. 2013; Milh et al. 2015).

=> In 2017, mutations in >100 genes can cause early onset epileptic encephalopathy. This is the reason why we develop a strategy using « gene panels », currently being used by our group in collaboration with the department of medical genetics in La Timone Children’s Hospital.