Impaired mitochondrial glutamate transport in autosomal recessive neonatal myoclonic epilepsy.
Severe neonatal epilepsies with suppression-burst pattern are epileptic syndromes with either neonatal onset or onset during the first months of life. These disorders are characterized by a typical electroencephalogram pattern--namely, suppression burst, in which higher-voltage bursts of slow waves mixed with multifocal spikes alternate with isoelectric suppression phases. Here, we report the genetic mapping of an autosomal recessive form of this condition to chromosome 11p15.5 and the identification of a missense mutation (p.Pro206Leu) in the gene encoding one of the two mitochondrial glutamate/H(+) symporters (SLC25A22, also known as "GC1"). The mutation cosegregated with the disease and altered a highly conserved amino acid. Functional analyses showed that glutamate oxidation in cultured skin fibroblasts from patients was strongly defective. Further studies in reconstituted proteoliposomes showed defective [(14)C]glutamate uniport and [(14)C]glutamate/glutamate exchange by mutant protein. Moreover, expression studies showed that, during human development, SLC25A22 is specifically expressed in the brain, within territories proposed to contribute to the genesis and control of myoclonic seizures. These findings provide the first direct molecular link between glutamate mitochondrial metabolism and myoclonic epilepsy and suggest potential insights into the pathophysiological bases of severe neonatal epilepsies with suppression-burst pattern.
Molinari
Florence
F
INSERM U393, Hopital Necker-Enfants Malades, Paris, France.
Raas-Rothschild
Annick
A
Rio
Marlene
M
Fiermonte
Giuseppe
G
Encha-Razavi
Ferechte
F
Palmieri
Luigi
L
Palmieri
Ferdinando
F
Ben-Neriah
Ziva
Z
Kadhom
Noman
N
Vekemans
Michel
M
Attie-Bitach
Tania
T
Munnich
Arnold
A
Rustin
Pierre
P
Colleaux
Laurence
L
D027322:Amino Acid Transport System X-AG / Q000235:genetics*; D002675:Child, Preschool; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic / Q000235:genetics*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D007621:Karyotyping; D008297:Male; D008928:Mitochondria / Q000235:genetics*
D027322:Amino Acid Transport System X-AG; D018698:Glutamic Acid