title: Epileptic Phenotype of Two Siblings with Asparagine Synthesis Deficiency Mimics Neonatal Pyridoxine-Dependent Epilepsy.
abstract: We report the cases of a brother and a sister of nonconsanguineous parents who developed progressive microcephaly and had tremor, irritability, spasticity, startle reflexes, and permanent erratic myoclonus since birth. Focal clonic seizures, status epilepticus, and infantile spasms appeared later, during the first months of life, while erratic myoclonic jerks persisted. Electroencephalogram initially showed multifocal spikes that evolved into modified hypsarrhythmia and then discontinuous activity, evoking the progressive nature of the condition. Magnetic resonance imaging showed brain atrophy and poor myelination. Plasma and cerebrospinal fluid asparagine levels were normal or moderately reduced on repeat testing. Both infants died at the age of 8 months in status epilepticus. Neuropathology of the brother revealed diffuse neuronal loss and astrocytic gliosis predominating in superficial layers of temporal and frontal lobes and in thalamus with almost absent myelin, as a consequence of the neuronal death. Whole exome sequencing of the siblings and parents revealed compound heterozygous c.1439C > T (p.Ser480Phe) and c.1648C > T (p.Arg550Cys) mutations in theASNSgene, indicating asparagine synthetase (ASNS) deficiency. Electroclinical epileptic phenotype and neuropathological findings of ASNS deficiency are reminiscent of neonatal pyridoxine-dependent epilepsy, thus suggesting common pathophysiological mechanism possibly related to cytotoxic glutamate accumulation.
authors: Inserm U1129, Hôpital Necker-Enfants Malades, Paris, France.
authors: Svetlana
authors: S
authors: Gataullina
authors: Pôle de Biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors: Julia
authors: J
authors: Lauer-Zillhardt
authors: Inserm U1129, Hôpital Necker-Enfants Malades, Paris, France.
authors: Anna
authors: A
authors: Kaminska
authors: Département d'Anatomie et Cytologie Pathologiques, Hôpital Necker-Enfants Malades, APHP, Paris, France.
authors: Louise
authors: L
authors: Galmiche-Rolland
authors: Inserm U1016, Institut Cochin, Paris, France.
authors: Nadia
authors: N
authors: Bahi-Buisson
authors: Service de Biochimie Métabolomique et Protéomique, Université Paris Descartes, Hôpital Necker-Enfants Malades, APHP, Paris, France.
authors: Clément
authors: C
authors: Pontoizeau
authors: Service de Biochimie Métabolomique et Protéomique, Université Paris Descartes, Hôpital Necker-Enfants Malades, APHP, Paris, France.
authors: Chris
authors: C
authors: Ottolenghi
authors: Inserm U1129, Hôpital Necker-Enfants Malades, Paris, France.
authors: Olivier
authors: O
authors: Dulac
authors: Département de Pathologie, CHU Sainte-Justine-Université de Montréal, Quebec, Canada.
authors: Catherine
authors: C
authors: Fallet-Bianco
mesh_terms: D001217:Aspartate-Ammonia Ligase / Q000172:deficiency*; D001927:Brain Diseases / Q000235:genetics*; D002675:Child, Preschool; D003933:Diagnosis; D004827:Epilepsy / Q000503:physiopathology*; D005260:Female; D018698:Glutamic Acid / Q000097:blood; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008661:Metabolism, Inborn Errors / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology*; D035781:Siblings
chemical_list: D018698:Glutamic Acid; D001217:Aspartate-Ammonia Ligase