levetiracetam and Microcephaly

Asparagine synthetase deficiency (ASNSD) refers to a congenital metabolic abnormality caused by mutation in the asparagine synthetase (ASNS) gene encoded by chromosome 7q21. Herein, we report the first case of ASNSD in China, in which novel ASNS mutations were identified.. A 6-month-old boy presented with a 4-month history of microcephaly and psychomotor developmental retardation and a 2-month history of epilepsy. Four months after birth, magnetic resonance imaging demonstrated a giant cyst in the right lateral ventricle, and a ventriculoperitoneal shunt was placed. Video electroencephalography showed a hypsarrhythmia pattern with a string of tonic-clonic and myoclonic seizures. On admission, physical examination showed microcephaly. Neurologic examination showed a decreased tension in the trunk muscles and an increased tension in the extremity muscles; tendon hyperreflexia was noted, and bilateral pathologic reflexes were positive.. A diagnosed of congenital microcephaly was made. Whole-exome sequencing revealed a heterozygous deletion mutation c.666_667delCT (p.L2221Lfs*5) in exon 6 of the ASNS gene and a heterozygous missense mutation c.1424C>T (p.T457I) in exon 13 of the ASNS gene.. After admission, intravenous adrenocorticotropic hormone and oral topiramate was administrated for 4 weeks, while the seizures persisted. Then, levetiracetam and clonazepam were added.. After the follow-up period of 18 months, video electroencephalography showed that complex episodes disappeared with changes in multiple focal spike and sharp waves; 1 focal attack arising from the left occipital region and 2 focal attacks arising from the right middle temporal and the right occipital region were recorded.. This is the first case of ASNSD in China. We identified 2 novel mutations (c.666_667delCT and c.1424C>T) in the ASNS gene, which expands the ASNS gene mutation profile and will be beneficial for genetic diagnosis.

Topics: Anticonvulsants; Aspartate-Ammonia Ligase; China; Clonazepam; Electroencephalography; Epilepsy; Humans; Infant; Levetiracetam; Male; Microcephaly; Mutation, Missense

Synaptic vesicle protein 2A (SV2a) is the binding site of the antiepileptic drug levetiracetam and the only known synaptic vesicle target of an epilepsy medication. To date, no pathogenic mutation in SV2A, which is the gene encoding synaptic vesicle glycoprotein 2A, has been identified in humans. We report a homozygous mutation in the SV2A gene in a patient with intractable epilepsy.. We investigated a patient with intractable epilepsy, involuntary movements, microcephaly, and developmental and growth retardation. Both parents were multiply consanguineous and an earlier-born brother of the proband had a similar course and died at 7 months of age. Detailed clinical history, imaging, electroencephalograph and metabolic testing were obtained. Full exome sequencing was performed using genomic DNA isolated from the patient and both parents.. Exome sequencing identified a homozygous arginine to glutamine mutation in amino acid position 383 (R383Q) in exon 5 of the SV2A gene. Both parents were carriers for the R383Q variant, suggesting that R383Q is a recessive mutation. There were no other candidate alterations in the exome that could explain the phenotype in the proband. The amino acid arginine at position 383 of SV2a gene is evolutionally conserved throughout vertebrates. R383Q change is not observed in known healthy cohorts, exome databases, or the Database of Single Nucleotide Polymorphisms. The R383Q mutation is located in the second adenine binding domain in SV2a protein and may alter adenine nucleotides binding to SV2a.. Our report provides the elusive evidence that an SV2A mutation can be a cause of epilepsy in humans. Levetiracetam, which binds to SV2A, was not effective as an antiepileptic medication. The location of the mutation in our patient supports an important role of adenine nucleotides binding in SV2A function.

Topics: Anticonvulsants; Child, Preschool; Developmental Disabilities; Dyskinesias; Epilepsy; Female; Growth Disorders; Humans; Levetiracetam; Membrane Glycoproteins; Microcephaly; Mutation; Nerve Tissue Proteins; Piracetam