MPSI. Migrating partial seizures of infancy (MPSI) are a catastrophic form of infantile epilepsy that was entirely unexplained until de novo mutations in KCNT1 were identified in a subset of sporadic cases in 2012. For familial MPSI, however, the genetic basis remained unknown. In a recent publication in Annals of Neurology, Poduri and collaborators identify mutations in SCL25A22 in a family with recessive MPSI. Their study sheds light on the genetic basis of catastrophic epilepsies and the phenotypic range of mitochondrial glutamate starvation.
Three things to know about SLC25A22
(1) SCL25A22 transports glutamate into mitochondria
(2) Recessive mutations result in catastrophic epilepsy
(3) Respiratory chain or ammonia synthesis impaired
Migrating seizures. Even though we frequently refer to the epileptic encephalopathies (EE) as a group of severe epilepsies with shared clinical features, there are distinct subtypes of these rare and severe seizure disorders. Malignant migrating partial seizures of infancy are one of these distinct subtypes. Seizures in patients usually start in the first weeks of life, and the epilepsy is characterized by more or less continuous seizure activity. On EEG recording, seizures tend to migrate between various brain regions and both hemispheres. Even though prominent electrographic activity is seen in many epileptic encephalopathies, migrating seizures are very rare.
Lumping and splitting. It remains a topic of ongoing discussion whether particular clinical presentations of epileptic encephalopathies should be regarded as distinct entities or should be grouped under a more general phenotypic description. Sometimes, this discussion is influenced by particular genetic findings that are either specific for a given syndrome or span various phenotypes. Research on MPSI received new attention when KCNT1 mutations were identified in a significant subset of cases. Previously, cases with mutations in SCN1A and PLCB1 had been reported, but these genes were only found in single cases. Recently, a family with MPSI was found to have a compound heterozygous mutation in QARS. In their recent publication, Poduri and collaborators add SLC25A22 to the list of genes causing familial MPSI.
What does SLC25A22 do? Mitochondria are the cellular energy plant of the cell, and molecular transport is tightly regulated at both the outer and inner mitochondrial membrane. SCL25A22, also known as GC1, is the main glutamate transporter across the inner mitochondrial membrane. Why do the mitochondria need glutamate? Glutamate plays an important role in fuelling both the Krebs cycle and urea cycle, and impairment of glutamate import may have a devastating effect on the energy homeostasis of the cell. As demonstrated by the catastrophic epilepsy arising from SLC25A22 deficiency, the effect is particularly damaging in the developing nervous system where SLC25A22 is highly expressed. However, it remains to be shown whether the effect of recessive SLC25A22 mutations actually result in mitochondrial glutamate starvation.
The SLC25A22 phenotype. Recessive mutations in SCL25A22 were previously described in a family with neonatal epileptic encephalopathy with suppression bursts (NEESB), cerebellar hypoplasia, and microcephaly. Even though this epilepsy phenotype also represents a catastrophic epilepsy of infancy, it is clinically distinct from MPSI. Other genes implicated in the pathogenesis of infantile epilepsies with suppression-burst patterns include STXBP1, GNAO1, and PIGA. Also, various metabolic epilepsies with neonatal onset may present with this EEG pattern. Ohtahara Syndrome or Early Myoclonic Encephalopathy are the epilepsy syndromes associated with this EEG pattern. By identifying SCL25A22 mutations in two electrographically distinct catastrophic epilepsies, Poduri and collaborators show that both entities can be due to a shared genetic cause.
Lessons learned. We have recently published various posts about the genetics of the catastrophic epilepsies of infancy, a group of epileptic encephalopathies with an earlier onset than the classical epileptic encephalopathies that comprise Infantile Spasms and Lennox-Gastaut Syndrome. With massive parallel sequencing technologies increasingly applied to familial epilepsies, novel causes for these devastating disorders have been identified. Interestingly, we stumble upon molecular mechanisms that are counter-intuitive at first glance – tRNA metabolism, glycosylation, glutamate metabolism, and others. It will be exciting to see how these single puzzle pieces will finally be integrated into a comprehensive picture of the underlying pathophysiology.