Neonatal epilepsy with suppression burst pattern
Context
It is estimated that worldwide 10.5 million children under 15 years have active epilepsy (Guerrini, 2006) and clearly its incidence is higher during the first year of life. Thus, it is widely accepted that the maturing brain, for not yet well-understood reasons, is highly excitable as compared to the adult. Neonatal epilepsy constitutes a major problem of public health because it has important impact on cognitive development and social integration of children. Knowledge of the cause and pathophysiology of neonatal epilepsy has considerably improved with modern neuroimaging and molecular genetic studies. However, our understanding of early onset epilepsy is still very limited.
Our project is focused on a particular form of neonatal epilepsy called early onset epileptic encephalopathy with a suppression burst pattern (EESB). This is a very rare form of epilepsy that is characterized by :
- Early onset, before the third month of age,
- Seizure activity characterized by myoclonies, epileptic spasms and focal or multifocal seizures,
- Specific EEG features consisting in discontinuous traces with bursts of generalized spikes and polyspikes lasting 2 to 10 seconds, alternating with periods of silence lasting 1 to 20 seconds (see figure below),
- Encephalopathy with a severe developmental delay, poor neurological outcome and high mortality rate in the first years of life.
This nosological entity has been defined as Ohtahara syndrome, or early onset myoclonic epilepsy, according to the main type of epileptic seizures (epileptic spasms in Ohtahara syndrome, myoclonic jerks in early myoclonic epilepsy), but the distinction between the two entities is often difficult.
This electro-clinical entity can be observed in several frequent pathological conditions including :
- Severe and diffuse anoxo-ischemic lesions during the perinatal period,
- Cortical malformations such as hemimegalencephaly, lissencephaly, diffuse polymicrogyria, that are easily recognizable with brain MRI.
Our project focuses on the patients without any obvious cause. Indeed, they represent more than half of the patients with EESB.
Known causes
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.
Recently, 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).
All these patients displayed early onset epileptic encephalopathy with a suppression-burst EEG pattern. Brain MRI was normal or displayed hypomyelinisation, without any brain structural malformation.